Aerosolizable formulation

Abstract

(a) At least one active agent, (b) an aerosol-forming agent material, (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and (d) one or more binders, an aerosolizable formulation is provided.

Description

Technical Field

[0001] The present disclosure relates to aerosolizable formulations, methods of forming them, devices for forming them, and their methods of use.

Background Art

[0002] Electronic aerosol supply systems such as electronic cigarettes generally include a reservoir of a liquid to be vaporized, typically containing a flavoring or an active agent such as nicotine. When the user inhales on the device, a heater is activated to vaporize a small amount of the liquid, which is then inhaled by the user.

[0003] The use of electronic cigarettes in the UK has been increasing rapidly, and it is currently estimated that over one million people in the UK are using electronic cigarettes.

[0004] One challenge in providing such a system is to provide an aerosol that is inhaled from an aerosol supply device to provide an acceptable experience to the consumer. Some consumers may prefer an electronic cigarette that produces an aerosol that closely "imitates" the smoke inhaled from tobacco products such as cigarettes. The aerosol from an electronic cigarette and the smoke from tobacco products such as cigarettes provide the user with a complex series of flavors in the mouth, and, when nicotine is present, nicotine absorption in the mouth and throat, followed by nicotine absorption in the lungs. These various aspects are described by the user in terms of flavor, strength / quality, impact, harshness / mouthfeel, and reward. Flavorants contribute to some of these factors and are strongly associated with providing flavor in the mouth and desirable taste and smell, whether mimicking the taste and smell of a tobacco product or providing alternative flavorants. Ensuring the provision of specific tastes and smells is made more difficult by the volatile and heat-sensitive nature of some flavorants. Heating of flavorant components in an electronic cigarette can result in some flavorants degrading. This has several drawbacks. The flavorants present in the liquid may be lost, resulting in a reduced flavor experience for the user or the need to include excess flavorant in the liquid at additional cost. Further, if the e-liquid contains multiple flavorants and only some of these multiple flavorants are decomposed, this can negatively affect the taste and smell balance. Additionally, degraded flavorants can have an undesirable or "off-taste". Each of these factors and their balance can strongly contribute to the consumer acceptance of an electronic cigarette. Therefore, it is desirable for electronic cigarette manufacturers to provide means for optimizing the overall vaping experience.

[0005] A further challenge that such a system faces is the ongoing demand for harm reduction. The harm from cigarettes and electronic cigarette devices mainly originates from poisons. Therefore, it is desirable to reduce the potential for the formation of poisons. SUMMARY OF THE INVENTION

[0006] In one aspect, (a) At least one active agent, (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, An aerosolizable formulation or an aerosol formulation comprising the same is provided.

[0007] In one aspect, (a) At least one active agent, (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A method of forming an aerosol comprising the same, (A) (a) At least one active agent, (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, The step of aerosolizing an aerosolizable formulation comprising the same Or (B) (a) At least one active agent, (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, The step of aerosolizing an aerosolizable formulation comprising the same, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof A step of aerosolizing an aerosolizable formulation comprising or (C) (a) At least one active agent, (b) An aerosol-forming agent material, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, (d) One or more binders, A step of aerosolizing an aerosolizable formulation comprising or (D) (a) A plant-based material, (b) An aerosol-forming agent, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A step of aerosolizing an aerosol-generating composition comprising A method comprising one of the above is provided.

[0008] In one aspect, (i) A container, (ii) (a) At least one active agent, (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof An aerosolizable formulation comprising An aerosolizable formulation contained therein is provided.

[0009] In one aspect, (i) a first container, and (ii) (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof an aerosolizable formulation comprising, and (iii) a second container, and (iv) a modulator formulation comprising a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof A kit comprising is provided.

[0010] In one aspect, (1) (i) a first container, and (ii) (a) at least one active agent, and (b) an aerosol-forming agent material an aerosolizable formulation comprising a first component comprising, and (2) (i) a second container, and (ii) a modulator formulation comprising a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof a second component comprising, and A kit comprising is provided.

[0011] In one aspect, (i) an aerosoliser or aerosol generator for aerosolizing a formulation for inhalation by a user of an electronic aerosol delivery system, and (ii) a power source comprising a cell or battery for powering the aerosoliser or aerosol generator (iii) at least (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof an aerosolizable formulation comprising the same, and (iv) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof an electronic aerosol supply system comprising the same is provided.

[0012] In one aspect, (i) an atomizer or aerosol generator for aerosolizing the formulation for inhalation by a user of the electronic aerosol supply system, and (ii) a power source comprising a cell or battery for powering the atomizer or aerosol generator, and (iii) at least (a) at least one active agent, and (b) an aerosol-forming agent material an aerosolizable formulation comprising the same, and (iv) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof an electronic aerosol supply system comprising the same is provided.

[0013] In one aspect, use of a modulator to reduce the unpleasantness upon inhalation of the aerosolized formulation, wherein the modulator is selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and the aerosolized formulation (a) at least one active agent, and (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof is provided for use.

[0014] In one aspect, the use of a modulator for reducing the discomfort upon inhalation of an aerosolized formulation, wherein the modulator is selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and the aerosolized formulation (a) at least one active agent, and (b) an aerosol-forming agent material is provided for use.

[0015] In one aspect, (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, wherein an aerosolizable formulation or an aerosol formulation comprising the same, or (a) at least one active agent, and (b) an aerosol-forming agent material, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, wherein an aerosolizable formulation or an aerosol formulation comprising the same is provided.

[0016] In one aspect, (a) at least one active agent, and (b) an aerosol-forming agent material, and (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, (d) One or more binders, An aerosolizable formulation comprising the same is provided.

[0017] In one aspect, (a) A plant-based material, (b) An aerosol former, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, An aerosol generating composition comprising the same is provided.

[0018] In one aspect, a consumable for use in a non-combustible aerosol supply device comprising an aerosolizable formulation or an aerosol generating composition as defined herein is provided.

[0019] In one aspect, a non-combustible aerosol supply system comprising a consumable of the present invention and a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device comprises an aerosol generating device arranged to generate an aerosol from the consumable when the consumable is used with the non-combustible aerosol supply device is provided.

[0020] In one aspect, use of an aerosolizable formulation or an aerosol generating composition as defined herein in a consumable for use with a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device comprises an aerosol generating device arranged to generate an aerosol from the consumable when the consumable is used with the non-combustible aerosol supply device is provided.

[0021] Here, with reference to the accompanying drawings, the present invention will be described in more detail by way of example only.

Brief Description of the Drawings

[0022]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0023] As discussed in this specification, in one aspect, (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) a modulator selected from TRPA1 agonists, TRPM8 agonists, TRPV1 agonists, TRPV3 agonists, TRPA1 antagonists, TRPA1 inhibitors, and combinations thereof, an aerosolizable formulation comprising is provided.

[0024] As will be understood by those skilled in the art, an "aerosolizable formulation" is a formulation that can generate an aerosol when energized, for example, by heating, irradiation, or any other method. An "aerosolizable formulation", i.e., an aerosol-generating formulation, may be in the form of a solid, liquid, or semi-solid (such as a gel), which may or may not contain an active substance and / or a flavorant.

[0025] The inventors have found that an advantageous system can be provided in which the aerosolized formulation contains a modulator that acts on specific receptors in the body. In particular, the inventors have found that the provision of a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof in an aerosol can improve the sensory properties of the aerosol upon inhalation. More specifically, the presence of this one or more modulators can reduce the unpleasantness of the aerosol upon inhalation.

[0026] For ease of reference, these and further aspects of the invention are discussed herein under the headings of the appropriate sections. However, the teachings under each section are not necessarily limited to each particular section.

[0027] Modulator As discussed herein, the present invention utilizes a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof. In one aspect, the modulator comprises at least one or more of a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist. In one aspect, the modulator comprises at least a TRPA1 antagonist or a TRPA1 inhibitor.

[0028] In one aspect, the modulator comprises at least (i) one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor is included.

[0029] In one aspect, the modulator comprises at least (i) a TRPM8 agonist or a TRPV1 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In one aspect, the modulator comprises at least (i) a TRPM1 agonist or a TRPV3 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In one aspect, the modulator comprises at least (i) a TRPM3 agonist or a TRPV8 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor.

[0030] It will be understood by those skilled in the art that each modulator can bind to the appropriate receptor and act as the required agonist, antagonist, or inhibitor. When a potential modulator interacts with a receptor, the interaction has a given binding energy. The binding energy can be determined based on the following equation:

Equation

[0031] More specifically, the modulator and the receptor are accompanied by several molecular interactions (e.g., van der Waals, electrostatic binding, hydrogen bonding, hydrophobicity, etc.) and physicochemical complementarity between the receptor and the modulator. The protein structure file (receptor) can be retrieved from the Protein Data Bank and is described using an electron microscopy model. The details are as follows: TRPV1: PDB: 7LR0, https: / / www.rcsb.org / structure / 7LR0, DOI: 10.2210 / pdb7lr0 / pdb; TRPV3: PDB: 6DVZ, https: / / www.rcsb.org / structure / 6DVZ, DOI: 10.2210 / pdb6dvz / pdb TRPM8: PDB: 6NR2, https: / / www.rcsb.org / structure / 6NR2, DOI: 10.2210 / pdb6nr2 / pdb TRPA1 inhibitor: 6WJ5, https: / / www.rcsb.org / structure / 6WJ5, DOI: 10.2210 / pdb6wj5 / pdb TRPA1 antagonist: 7JUP, https: / / www.rcsb.org / structure / 7JUP, DOI: 10.2210 / pdb7jup / pdb TRPA1 agonist: 6X2J, https: / / www.rcsb.org / structure / 6X2J, DOI: 10.2210 / pdb6X2J / pdb.

[0032] Receptor hydrogen atoms can be added to those atoms based on the incorporation module according to the appropriate hybridization geometry, adding partial charges and protonation states, followed by assigning bond orders and setting rotatable bonds of the receptor.

[0033] The active site pocket of a protein molecule is the site where potential modulators bind to the protein. To perform these experiments, one simulation box can be used to determine the search region of the modulator. This theoretical procedure can be carried out using a TRPA1 agonist grid box size with dimensions of X = 20 Å, Y = 20 Å, Z = 20 Å and center coordinates of X = 179.3 Å, Y = 146.94 Å, Z = 191.79 Å to evaluate modulator interactions. The TRPA1 inhibitor analysis can be carried out using a grid box size with dimensions of X = 20 Å, Y = 20 Å, Z = 20 Å and center coordinates of X = 156.75 Å, Y = 139.94 Å, Z = 185.30 Å. The TRPA1 antagonist can be carried out using a grid box size with dimensions of X = 20 Å, Y = 20 Å, Z = 20 Å and center coordinates of X = 62.58 Å, Y = 63.50 Å, Z = 86.13 Å. In the case of TRPV3, this can be carried out using a grid box size with dimensions of X = 20 Å, Y = 20 Å, Z = 20 Å and center coordinates of X = 88.45 Å, Y = 107.91 Å, Z = 122.14 Å. In the case of TPV1, this can be carried out using a grid box size with dimensions of x = 20 Å, y = 20 Å, z = 20 Å and center coordinates of X = 106.82 Å, Y = 82.40 Å, Z = 90.48 Å. In the case of TRPM8, this can be carried out using a grid box size with dimensions of X = 20 Å, Y = 20 Å, Z = 20 Å and center coordinates of X = 136.90 Å, Y = 106.92 Å, Z = 169.89 Å.

[0034] The Gibbs free energy of binding (FEB (Kcal / mol)) for the receptor-modulator complex structure can be calculated using a scoring function that approximates the chemical potential (ΔG 結合 ).

[0035] The docking free energy of binding (FEB dock ) is the ΔG for all docking poses of the formed complex (protein-modulator) 結合It includes the internal steric energy of a given protein and modulator that is defined by a value and can be expressed as the sum of the individual molecular mechanics terms of the standard chemical potential.

Number

[0036] A more negative value (kcal / mol) of FEB means a higher affinity between the receptor and a different type of modulator substrate. The docking simulation results show that if the Gibbs free energy of the formed complex is ΔG 結合 ≧0 kcal / mol, it can be classified as energetically unfavorable, indicating that the binding affinity is extremely low or completely absent. Otherwise, it is classified as having medium to high docking affinity.

[0037] The docking simulation results show that if the Gibbs free energy of the formed complex is ΔG 結合 ≧0 kcal / mol, it can be classified as energetically unfavorable, indicating that the binding affinity is extremely low or completely absent. In summary, the FEB threshold is 0 kcal / mol. A FEB value greater than 0 means there is no affinity for the receptor. When FEB is less than 0 kcal / mol, it begins to have an affinity for the receptor. The lowest FEB value means a better affinity for the receptor.

[0038]

Table 1

[0039]

Table 2

[0040] Ab initio modeling shows that the above compound binds to the agonist sites of both TRPA1 and TRPV1 (FEB within ±2.0 kcal / mol compared to the reference ligand)dock variation).

[0041] The sampled cannabinoids show improved affinity for both TRPA1 and TRPV1 compared to nicotine and favorable interactions with key amino acid residues, indicating that the binding site may be the same as that of nicotine.

[0042] In one aspect, a TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity for each of one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist for their respective receptors. In one aspect, a TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of a TRPM8 agonist for the TRPM8 receptor. In one aspect, a TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of a TRPV1 agonist for the TRPV1 receptor. In one aspect, a TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of a TRPV3 agonist for the TRPV3 receptor. In one aspect, a TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinities of a TRPM8 agonist for the TRPM8 receptor, a TRPV1 agonist for the TRPV1 receptor, and a TRPV3 agonist for the TRPV3 receptor.

[0043] In one aspect, the modulator comprises at least (i) a TRPM8 agonist and a TRPV1 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In one aspect, the modulator comprises at least (i) a TRPM8 agonist and a TRPV3 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In one aspect, the modulator comprises at least (i) a TRPM1 agonist and a TRPV3 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In one aspect, the modulator comprises (i) a TRPM1 agonist, a TRPV3 agonist, and a TRPV8 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor.

[0044] One of ordinary skill in the art will understand that a given compound can be a modulator of one or more of TRPM1, TRPV3, TRPV8, and TRPA1. In one aspect, the modulator utilized in the present invention is a single compound. In one aspect, each modulator of one or more of TRPM1, TRPV3, TRPV8, and TRPA1 is a distinct compound.

[0045] To modulate the activity of each of TRPM1, TRPV3, TRPV8, and TRPA1, the modulator can bind to any suitable binding site necessary to modulate the activity.

[0046] In one aspect, the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof. In one aspect, the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, and combinations thereof. In one aspect, in one aspect, the TRPA1 agonist binds to one or more sites selected from Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof.

[0047] In one aspect, the TRPM8 agonist binds to one or more sites selected from Arg1007, Arg841, Asn741, Asp781, Ile845, Leu1000, Phe738, Tyr1004, Tyr745, Val848, and combinations thereof.

[0048] In one aspect, the TRPV1 agonist binds to one or more sites selected from Ala548, Ala568, Ala667, Asn553, Glu572, Ile571, Ile663, Leu517, Leu555, Leu664, Leu671, Met549, Phe518, Phe545, Phe593, Ser514, Thr552, Tyr513, Tyr556, and combinations thereof.

[0049] In one aspect, the TRPV3 agonist binds to one or more sites selected from Arg693, His430, His426, His417, Leu420, Leu694, Leu429, Trp433, Thr421, and combinations thereof.

[0050] In one aspect, the TRPA1 inhibitor binds to one or more sites selected from Leu867, Leu870, Leu871, Ile946, Ser873, Thr873, Thr874, Phe944, Val948, Phe877, Ile878, Leu880, Leu881, Met912, Phe909, Thr908, Ile906, Ile905, Ile950, Leu956, Val942, Met953, Leu952, Phe884, and combinations thereof.

[0051] The modulator can be selected from any suitable compound that provides the necessary regulatory activity. In one aspect, the modulator is 3-phenylpropionic acid; acetic acid; benzaldehyde; benzoic acid; benzyl alcohol; 1-butanol; butyric acid; 4-isopropylbenzaldehyde; 2-methoxy-4-vinylphenol; octanoic acid; octanal; guaiacol; lactic acid; 3,4-dihydrocoumarin; ethanol; glycerol; 1-octanol; phenylacetaldehyde; phenylacetic acid; propylene glycol; propionic acid; pyruvic acid; dimethyl sulfide; 4-methyl-5-thiazoleethanol; vanillin; menthol; camphor; eucalyptol; decanoic acid; eugenol; hexylresorcinol; lauric acid; triacetin; 2-phenylethanol; hexanal; 1-pentanol; bornyl acetate; ethyl methylphenylglycidate; triethyl citrate; linalool; isobutanol; isobutyraldehyde; isobutyric acid; 4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; alpha-pinene; cyclotene; 3-methylindole; methyl 2-(methylamino)benzoate; (1R,9S)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene; p-menthan-3-one; piperitone; thymol; 2-ethylphenol; 2,6-dimethoxyphenol; 6-methylquinoline; methylisoeugenol; 2-methoxy-4-methylphenol; methyl benzoate; ethyl benzoate; 2-methylbutyraldehyde; gamma-butyrolactone; 2-methylvaleric acid; ethyl isobutyrate; ethyl lactate; furfuryl mercaptan; acetophenone; carveol; carvon; gamma-terpinene; 4'-methoxyacetophenone; methyl phenylacetate; diphenyl ether; ethyl phenylacetate; isoamyl phenylacetate; phenethyl phenylacetate; 3-phenyl-2-propenoic acid, phenylmethyl ester; phenethyl acetate; phenethyl isobutyrate; 4-methoxybenzyl acetate; gamma-octalactone; benzyl formate; gamma-nonalactone; gamma-undecalactone; 4-methylbenzaldehyde; 1-methoxy-4-methylbenzene; 4-methoxybenzyl alcohol; gamma-heptalactone;Ethyl propionate; 3-methylvaleric acid; diethyl malonate; ethyl butyrate; acetal; propyl butyrate; isoamyl propionate; (-)-citronellol; citronellal; isoamyl butyrate; ethyl heptanoate; ethyl octanoate; ethyl dodecanoate; methyl hexanoate; hydroxycitronellal; 2-pentanone; gamma-valerolactone; 2,6-dimethylpyridine; 2,6-dimethylpyrazine; ethyl isovalerate; 4-methylpyridine; 3-methylpyridine; 2-methylpyrazine; butyl isovalerate; butyl butyrate; valeric acid; propyl acetate; ethyl formate; isobutyl acetate; isopropyl myristate; ethyl decanoate; diethyl sebacate; 2-heptanone; pentanal; heptanoic acid; 1-hexanol; 1-heptanol; nonenoic acid, methyl ester; nonanoic acid; 2-undecanone; octyl acetate; decanal; 1-dodecanol; dodecanal; linalyl acetate; 2-methylbutyric acid; maltol; veratraldehyde; piperonal; ethyl vanillin; methyl 4-methoxybenzoate; 4'-methylacetophenone; methyl anthranilate; 2-methyl-1-butanol; benzyl acetate; phenethyl isovalerate; p-tolyl acetate; citronellol; ethyl acetate; ethyl acetoacetate; hexanoic acid; hexyl acetate; 1,4-dimethoxybenzene; citronellyl acetate; (7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol; 1,3-dimethoxybenzene; 6-methyl-5-hepten-2-one; camphor, (1S,4S)-(-)-; 1,4-cineole; 2-cyclopenten-1-one, 3-methyl-2-(2Z)-2-pentenyl-; 2,4,5-trimethylphenol; carvacrol; isovaleric acid; gluconic acid; 2,4,6-trimethylphenol; 4-ethylpyridine; 3-ethylpyridine; ethyl valerate; ethyl levulinate; isobutyl butyrate; pentyl hexanoate; pentyl butyrate; terpinene-4-ol; terpinolene; isobutyl isovalerate; 3-methylbutanal; alpha-angelica lactone; methyl 2-furoate; 5-methylfurfural; 3-ethylphenol; methyl butyrate; ethyl 2-butenoate; 4-propylphenol; isoamyl isovalerate; gamma-caprolactone; 2,3,5-trimethylphenol;Delta - octalactone; Delta - decalactone; Gamma - decalactone; Delta - dodecalactone; 2 - nonanone; Delta - hexalactone; Methyl 2 - methylbutyrate; 2 - acetylpyrrole; Hexyl octanoate; 4 - acetylpyridine; 2 - acetylpyridine; 2,3,5,6 - tetramethylpyrazine; 2 - acetyl - 5 - methylfuran; Beta - pinene; 1 - hexen - 3 - one; Fenchol; Hex - 3 - enyl acetate; 3 - methylbutyl octanoate; 3 - methylbutyl hexanoate; l - menthol; d - carvone; Gamma - dodecalactone; Alpha - terpineol; Hexyl butyrate; 2 - methoxy - 4 - propylphenol; 2 - methoxy - 3 - methylpyrazine; 2 - pentenoic acid, 2 - methyl -; 2 - methyltetrahydrofuran - 3 - one; 3 - (methylthio) propionaldehyde; Delta - nonalactone; Beta - ocimene; Sabinene; 1 - octen - 3 - ol; Neomenthol; Flaneol; Dimethyl trisulfide; 2,3 - hexanedione; Hex - 3 - enoic acid; Benzeneacetaldehyde, alpha - ethylidene -; Ethyl maltol; 4 - (4 - hydroxyphenyl) - 2 - butanone; 2,3 - dimethylpyrazine; Linalyl oxide; Hexyl hexanoate; Alpha - caryophyllene; Ethyl 2 - methylbutyrate; Butyl butyryllactate; Hexyl 2 - methylbutanoate; Butanoic acid, 1,1 - dimethyl - 2 - phenylethyl ester; 3 - ethyl - 2,5 - dimethylpyrazine; Bicyclo[7.2.0]undeca - 4 - ene, 4,11,11 - trimethyl - 8 - methylene -, (1S,4E,9R) -; 2 - ethyl - 3,5 - dimethylpyrazine; Menthone; 2,3,5 - trimethylpyrazine; 2 - ethyl - 3 - methylpyrazine; 2,3 - diethylpyrazine; Menthyl acetate; Propylidenephthalide; Acetylpyrazine; Alpha - amylcinnamaldehyde; 2 - propenoic acid, 3 - phenyl -, 3 - phenyl - 2 - propenyl ester; 3 - phenyl - 1 - propanol; 4 - ethylphenol; 4 - methoxybenzaldehyde; 4 - heptanone; Ethyl nonanoate; 2,5 - dimethylpyrazine; Isoamyl alcohol; Ethyl hexanoate; Allyl hexanoate; Butyl acetate; Isoamyl acetate; Ethyl tetradecanoate; Nonanal; Linalyl benzoate;Beta-damascone; 5-Methyl-6,7-dihydro-5H-cyclopenta[b]pyrazine; 2-Isobutyl-3-methoxypyrazine; 2-Ethyl-4-hydroxy-5-methyl-3(2H)-furanone; 2,6-Nonadien-1-ol; Hex-3-enyl formate; 5,6,7,8-Tetrahydroquinoxaline; Cis-3-hexenyl 3-methylbutanoate; Massoia lactone; (+)-Isomenthol; Isobutyl phenylacetate; Benzyl phenylacetate; 4-(4-Methoxyphenyl)-2-butanone; 2,6-Dimethyl-5-heptenal; 1-Penten-3-one, 1-[(1R)-2,6,6-trimethyl-2-cyclohexen-1-yl]-, (1E)-; Furfuryl propionate; Hexyl formate; 5-Ethyl-3-hydroxy-4-methylfuran-2(5H)-one; 2-Hydroxy-4-methylbenzaldehyde; 6-Hexyltetrahydro-2H-pyran-2-one; 3-Methylcyclopentane-1,2-dione; d-Piperitone; 3-Hexenyl 2-methylbutyrate; Ethyl 3-(methylthio)propionate; 3,4-Dimethyl-1,2-cyclopentanedione; 3,5-Dimethyl-1,2-cyclopentanedione; Methyl 3-(methylthio)propionate; 5-Methyl-2-thiophenecarboxaldehyde; 5-Methylquinoxaline; 2-Isopropyl-4-methylthiazole; Butyl 2-methylbutyrate; 2,4-Dimethylbenzaldehyde; Theaspirane; p-Mentha-8-thiol-3-one; p-Cresyl isovalerate; Orange oil; Linalyl butyrate; 1-Phenylethyl acetate; 2,6,6-Trimethyl-2-cyclohexene-1,4-dione; S-Methyl butanethioate; 4-Ethyl-2-methoxyphenol; (-)-Beta-bulbonene; Ethyl 3-hydroxybutyrate; 3-Ethyl-2-hydroxy-2-cyclopenten-1-one; 3-Hydroxy-4,5-dimethylfuran-2(5H)-one; Whiskey lactone; N-Ethyl-p-menthane-3-carboxamide; Borneol; 3-(Methylthio)-1-hexanol; (+)-Linalool; 2-Methoxybenzyl alcohol; 3-Propylphenol; (+)-Isomentone; 3-Methylbutyl pentanoate; 2-Methoxy-6-methylphenol; Ethyl (methylthio)acetate;Linalool; (+)-alpha-Pinene; Isoamyl lactate; Nicotine; 2-Mercaptopinane; 1,6-Cyclodecadiene, 1-methyl-5-methylene-8-(1-methylethyl)-; (+)-Camphene; Spathulenol; (-)-Bornyl acetate; 5-Ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 3,5,5-Trimethylcyclohexane-1,2-dione; 1-Oxacycloheptadec-10-en-2-one; (3R)-3,7-Dimethylocta-6-en-1-ol; 6-Methyl-2-(oxiran-2-yl)hepta-5-en-2-ol; Isobutyl 2-methylbutyrate; Methyl dihydrojasmonate; Ambrox; 2-Cyclohexen-1-one, 4-(2-butenylidene)-3,5,5-trimethyl-; L-Lactic acid; Alpha-terpinyl acetate; 3-Ethylcyclopentane-1,2-dione; 5-Nonen-2-one; Isobutyl decanoate; 2-Ethoxy-3-methylpyrazine; Tiglic acid; 3,7,11,15-Tetramethylhexadec-2-en-1-ol; 3-Methyl-2-buten-1-thiol; (+)-Nicotine; D-Camphor; (+)-Menthol; 2-Ethyl-6-methoxyphenol; L-Menthyl acetate; Guaiol; Oxacyclohexadecan-2-one; Beta-bulbonene; Ethyl crotonate; (+)-Neomenthol; (1R,2S,4R)-Borneol; Bicyclo[2.2.1]heptan-2-ol, 1,7,7-trimethyl-, exo-; (-)-Carvone; D-Limonene; (-)-Camphene; (-)-Beta-pinene; (-)-Alpha-pinene; (1S,2R,4S)-(-)-Bornyl acetate; (-)-Linalool; (+)-Menthone; (-)-Alpha-terpineol; (-)-Camphor; L(+)-Tartaric acid; Cinnamic acid; Liquiritin; Exo-1,7,7-trimethylbicyclo(2.2.1)heptan-2-ol; Hexyl lactate; 2-sec-Butyl-3-methoxypyrazine; 2-Acetylthiazole; Beta-spathulenol; Isobutyl acetoacetate; 1-Methyl-2-oxopropyl butyrate; 3-Methylnonane-2,4-dione; 2,6,8-Decatrieneamide, N-(2-methylpropyl)-, (2E,6Z,8E)-; 3-Mercaptohexyl hexanoate;3,7-Dimethylocta-7-en-1-ol; 2-methyl-1-[1-(2-methylbutoxy)ethoxy]butane; Menthy lisovalerate; 4-methyl-2-phenyl-1,3-dioxolane; Cinnamaldehyde; Methyl cinnamate; Isoborneol, acetate; Anethole; Geraniol; Ethyl cinnamate; Methyl isoeugenol; Citral; Beta-ionone; Sorbic acid; Trans-2, cis-6-nonadienal; Neral; Nerol; Sumatra camphor; Isoeugenol; (-)-Borneol; Notketone; Jasmon; (E)-Jasmon; Nerol acetate; Geranyl acetate; Geranyl acetone; Cinnamic acid, cinnamyl ester; Cinnamyl cinnamate; (Z)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one; Amyl cinnamaldehyde; 2-Benzylidene heptanal; (-)-Neo-isomenthol; Caryophyllene oxide; Trans-2-hexenyl acetate; 5-Ethyl-2-methoxyphenol; 3-Methylcyclohexane-1,2-dione; (7E)-1-oxacycloheptadec-7-en-2-one; 4-Hydroxy-5-methylfuran-3(2H)-one; Vanillyl butyl ether; Isopentyl cinnamate; Benzyl cinnamate; Phytol; Cis-3-hexen-1-ol; 2-Hexenal; Beta-caryophyllene; Humulene; 3-Buten-2-one, 4-(2,5,6,6-tetramethyl-2-cyclohexen-1-yl)-; Isocaryophyllene; (E)-Beta-ocimene; Alpha-ionone; Geranyl formate; Cinnamyl acetate; Trans-2-hexenoic acid; 3-Hexenoic acid; Trans-3-hexen-1-ol; Nerolidol; Cinnamyl alcohol; 2-Hexen-1-ol; (1Z,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (2E,6E)-Nona-2,6-dien-1-ol; (Z)-3,7,11,15-tetramethylhexadec-2-en-1-ol; (4Z)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.Undeca-4-ene; cis-3-hexenyl butyrate; cis-3-hexenyl hexanoate; trans-3-hexenyl acetate; spirantol; ethyl (2Z)-but-2-enoate; vanitrope; trans-caryophyllene; cis-3-hexenoic acid; oxacycloheptadeca-10-en-2-one; geranyl butyrate; 2-nonenoic acid, methyl ester; 5-methyl-2-hepten-4-one; cis-4-decenal; ethyl 3-hexanoate; cis-6-nonenal; (Z)-nona-6-en-1-ol; cis-4-heptenal; (2E,6Z)-nona-2,6-dien-1-ol; cis-3-hexenyl acetate; ethyl 2-octenoate; cis-3-hexenyl 2-methylbutanoate; cis-3-hexenyl formate; 2-octen-4-one; 2-methyl-2-pentenoic acid; damascenone; 3,7,11,15-tetramethyl-2-hexadecen-1-ol; methyl 2-nonenoate; 6-methyl-3,5-heptadien-2-one; (2Z)-2-phenyl-2-butenal; alpha-ionone; 3-propylidenephthalide; 1-methyl-5-methylene-8-(1-methylethyl)-1,6-cyclodecadiene; trans-4-decen-1-al; ethyl 2-chloro-2-(phenylhydrazono)acetate; 3-hexenyl 2-methylbutanoate; propylidenephthalide; 3-hexen-1-ol, formate; (E)-2-epi-beta-caryophyllene; 2-phenyl-2-butenal; isomenthone; 2-pentenoic acid, 2-methyl-, (2Z)-; megastigmatrienone A; (1E,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; oxacycloheptadeca-7-en-2-one, (7Z)-; (+)-borneol; (-)-neomenthol; exo-1,7,7-trimethylbicyclo[2.2.1] Hepta-2-yl acetate; (+)-Isoborneol; (+)-Camphor; (2E,6Z,8E,10E)-N-(2-Hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; Hydroxy-beta-sanshool; (+)-Beta-pinene; Ambroxan; Cubebol; (2e,6e,8e)-N-(2-Methylpropyl)-2,6,8-decatrienamide; Oxacycloheptadeca-10-en-2-one, (E)-; Pichtosin; (1S)-6,6-Dimethyl-2-methylenebicyclo[3.1.1]heptane; (1R)-(-)-Menthyl acetate; (2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl acetate; Spathulenol; Benzyl alcohol, cinnamate; (2E,6E,8Z)-N-(2-Methylpropyl)deca-2,6,8-trieneamide; (S)-Alpha-methylionone; Methyl-alpha-ionone; (1S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ol; 4-(But-2-en-1-ylidene)-3,5,5-trimethylcyclohex-2-enone; Ethyl 3-(methylthio)butyrate; Bicyclo[3.1.1]heptane, 6,6-dimethyl-2-methylene-, (1S,5S)-; (2Z,6E)-2,6-Dimethyl-10-methylidenedodeca-2,6,11-trienaal; (2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ol; Hydroxy-alpha-sanshool; N-(2-Hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; Ascorbic acid; (S,1Z,6Z)-8-Isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; Jasmine oil; Alpha-caryophyllene; 3-Phenylpropyl homovanillate; 1,4,8-Cycloundecatriene, 2,6,6,9-tetramethyl-, (1E,4E,8E)-; (1E,8E)-2,6,6,9-Tetramethylcycloundeca-1,4,8-triene; (1R,2S,6S,7R,8S)-1-Methyl-5-methylidene-8-propan-2-yltricyclo[5.3.0.Selected from decane; (8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; and mixtures thereof.

[0052] In one embodiment, the TRPA1 antagonist is selected from cinnamic acid, cinnamyl esters; hexylresorcinol; l-menthol; 2-ethyl-6-methoxyphenol; linalyl oxide; 2-methoxy-6-methylphenol; methyl 2-(methylamino)benzoate; eucalyptol; and mixtures thereof.

[0053] In one embodiment, the TRPM8 agonist is selected from (1Z,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; beta-caryophyllene; liquiritin; ambrettolide; (E)-2-epi-beta-caryophyllene; bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8-methylene-, (1R,4E,9S)-; (4Z)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene; bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8-methylene-, (1S,4E,9R)-; isocaryophyllene; ambroxan; spathulenol; caryophyllene oxide; (-)-beta-bulbonene; oxacycloheptadeca-10-en-2-one, (E)-; cubebol; trans-caryophyllene; gamma-dodecalactone; hydroxy-alpha-sanshool; citronellyl acetate; (2E,6Z,8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; (8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; hydroxy-beta-sanshool; 2-hexenal; and mixtures thereof.

[0054] In one aspect, the TRPV1 agonist is selected from phenethyl phenylacetate; 2-propenoic acid, 3-phenyl-, 3-phenyl-2-propenyl ester; theaspirane; (7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol; 4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; cinnamyl cinnamate; alpha-ionone; beta-spathulenol; spathulenol; phytol; 1-penten-3-one, 1-[(1R)-2,6,6-trimethyl-2-cyclohexen-1-yl]-, (1E)-; (S)-alpha-methylionone; guaiol; 3,7,11,15-tetramethylhexadec-2-en-1-ol; 3,7,11,15-tetramethyl-2-hexadecen-1-ol; (Z)-3,7,11,15-tetramethylhexadec-2-en-1-ol; vanillyl butyl ether; 4-ethyl-2-methoxyphenol; 6-methyl-2-(oxiran-2-yl)hepta-5-en-2-ol; 2-methoxy-4-methylphenol; 2-methoxy-4-vinylphenol; benzyl cinnamate; 2-propenoic acid; 3-phenyl-, phenylmethyl ester; and mixtures thereof.

[0055] In one aspect, the TRPV3 agonist is selected from ethyl vanillin; 2,6-dimethoxyphenol; vanillin; and mixtures thereof.

[0056] In one aspect, the TRPA1 inhibitor is selected from 3-phenylpropyl homovanillate; benzyl alcohol, cinnamate; benzyl phenylacetate; alpha-amyl cinnamaldehyde; linalyl benzoate; phenethyl isovalerate; carvacrol; thymol; 5-ethyl-2-methoxyphenol; vanitrope; and mixtures thereof.

[0057] In one aspect, the TRPA1 antagonist is selected from cinnamyl cinnamate, glycyrrhizin, 3-phenylpropyl homovanillate, benzyl cinnamate, caryophyllene (beta-), phenethyl phenylacetate, hydroxy-alpha-sanshool, phytol, bulvone (beta), and mixtures thereof.

[0058] In one aspect, the TRPA1 inhibitor is selected from cinnamyl cinnamate, citronellyl acetate, eucalyptol, 2-hexenal, dodecalactone (gamma-), menthol (l-), spathulenol, bulvone (beta), benzyl cinnamate, caryophyllene oxide, caryophyllene (beta-), alpha-ionone, phenethyl phenylacetate, methyl-alpha-ionone, phytol, and mixtures thereof.

[0059] In one aspect, the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof.

[0060] In one aspect, the modulator is at least a mixture of caryophyllene oxide and benzyl cinnamate.

[0061] In one aspect, the total amount of the modulator present is 20% by weight or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.01 to 20% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 20% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.05 to 20% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.08 to 20% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.1 to 20% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 15% by weight or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.01 to 15% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 15% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.05 to 15% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.08 to 15% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation.In one aspect, the total amount of the modulator present is 10 wt% or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.01 to 10 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 10 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.05 to 10 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.08 to 10 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 8 wt% or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.01 to 8 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 8 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.05 to 8 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.08 to 8 wt% based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 6 wt% or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation.In one aspect, the total amount of the modulator present is from 0.01 to 6% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 6% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.05 to 6% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.08 to 6% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.01 to 5% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 5% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.05 to 5% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.08 to 5% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 4% by weight or less, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.01 to 4% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 4% by weight, based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation.In one aspect, the total amount of the modulator present is 0.05 to 4% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.08 to 4% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 3% by weight or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.01 to 3% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.02 to 3% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.05 to 3% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.08 to 3% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 2% by weight or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.01 to 2% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.02 to 2% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 0.05 to 2% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation.In one aspect, the total amount of the modulator present is from 0.08 to 2% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is 1% by weight or less based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.01 to 1% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.02 to 1% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.05 to 1% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.08 to 1% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the total amount of the modulator present is from 0.1 to 1% by weight based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation.

[0062] In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 20% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 to 20% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 to 20% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 to 20% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 to 20% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.1 to 20% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 15% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 to 15% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 to 15% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 to 15% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 to 15% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 10% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 to 10% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 to 10% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 to 10% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 to 10% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 8% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 to 8% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 to 8% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 to 8% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 to 8% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 6% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 to 6% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 to 6% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 to 6% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 to 6% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 to 5% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 to 5% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 to 5% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 to 5% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 4% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 - 4% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 - 4% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 - 4% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 - 4% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 3% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 - 3% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 - 3% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 - 3% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 - 3% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 2% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 - 2% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 - 2% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 - 2% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 - 2% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 1% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.01 - 1% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.02 - 1% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.05 - 1% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.08 - 1% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, caryophyllene oxide and benzyl cinnamate are present in a total amount of 0.1 to 1% by weight, based on an aerosolizable formulation, or based on an aerosol formulation, or based on an aerosolized formulation.

[0063] Binder As discussed herein, in one aspect, (a) at least one active agent, and (b) an aerosol-forming agent material, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and (d) one or more binders, and an aerosolizable formulation comprising the same is provided.

[0064] Suitably, the aerosolizable formulation comprises from about 10% to about 80% by weight of a binder, such as from about 10%, 15%, 20%, or 25% to about 70%, 60%, 50%, 45%, 40%, 35%, or 30% by weight of one or more binders (all calculated on a dry weight basis). For example, the aerosolizable formulation may comprise from about 10 to 50%, 15 to 45%, 20 to 45%, 15 to 40%, or 20 to 40% by weight of a binder.

[0065] In some embodiments, the aerosolizable formulation may comprise from about 20 to 40% by weight of a binder.

[0066] In some embodiments, one or more binders comprise one or more gelling agents. In some embodiments, one or more binders consist of one or more gelling agents. In some embodiments, the gelling agent comprises a hydrophilic colloid.

[0067] In some embodiments, the one or more binders include (or are) one or more compounds selected from polysaccharide gelling agents such as alginate, pectin, starch or its derivatives, cellulose or its derivatives, pullulan, carrageenan, agar, and agarose; gelatin; gums such as xanthan gum, guar gum, and gum acacia; silica or silicone compounds such as PDMS and sodium silicate; clays such as kaolin; and polyvinyl alcohol.

[0068] In some embodiments, the one or more binders include (or are) one or more polysaccharide gelling agents.

[0069] In some embodiments, the polysaccharide gelling agent is selected from alginate, pectin, starch or its derivatives, or cellulose or its derivatives. In some embodiments, the polysaccharide gelling agent is selected from alginate and cellulose derivatives.

[0070] In some embodiments, the one or more binders are polysaccharide gelling agents, and optionally, the polysaccharide gelling agent is selected from alginate and cellulose derivatives.

[0071] In some embodiments, the alginate is sodium alginate.

[0072] In some embodiments, the polysaccharide gelling agent is a cellulose derivative. Without wishing to be bound by theory, such gelling agents are thought not to react with calcium ions to form crosslinks.

[0073] In some embodiments, the polysaccharide gelling agent is alginate.

[0074] In some embodiments, the binder is uncrosslinked. The absence of crosslinking in the gelling agent can facilitate more rapid delivery of cannabinoids (and any additional active substances and / or fragrances) from the aerosolizable formulation.

[0075] Examples of cellulose binders (also referred to herein as cellulose gelling agents or cellulose derivatives) include, but are not limited to, microcrystalline cellulose (MCC), hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate (CA), cellulose acetate butyrate (CAB), and cellulose acetate propionate (CAP). In some embodiments, the cellulose or its derivative is selected from microcrystalline cellulose (MCC), hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate (CA), cellulose acetate butyrate (CAB), and cellulose acetate propionate (CAP). In some embodiments, the cellulose derivative is MCC and / or CMC.

[0076] For example, in some embodiments, the binder comprises (or is) one or more of alginate, pectin, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, pullulan, xanthan gum, guar gum, carrageenan, agarose, acacia gum, fumed silica, PDMS, sodium silicate, kaolin, and polyvinyl alcohol.

[0077] In some embodiments, the binder comprises (or is) one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, guar gum, acacia gum, alginate, and / or pectin.

[0078] In some embodiments, the binder comprises (or is) microcrystalline cellulose, carboxymethyl cellulose, guar gum, alginate, and / or pectin.

[0079] In some embodiments, the binder comprises (or is) microcrystalline cellulose, carboxymethyl cellulose, and guar gum.

[0080] In some embodiments, the binder comprises (or is) carboxymethyl cellulose and guar gum.

[0081] In some embodiments, the binder comprises (or is) carboxymethyl cellulose, guar gum, and alginate.

[0082] Optionally, the binder comprises (or is) alginate and / or pectin and can be combined with a curing agent (such as a calcium source) during the formation of the aerosolizable formulation. Optionally, the aerosolizable formulation can comprise calcium crosslinked alginate and / or calcium crosslinked pectin.

[0083] In some embodiments, the binder comprises (or is) alginate, and optionally, the alginate is present in the aerosolizable formulation in an amount of about 1 to 40 wt%, such as about 5 to 25 wt% (calculated on a dry weight basis) of the aerosolizable formulation.

[0084] In some embodiments, the alginate is the only binder present in the aerosolizable formulation.

[0085] In other embodiments, the binder comprises alginate and at least one additional binder such as pectin.

[0086] In certain embodiments, the binder is carboxymethyl cellulose, and optionally, the carboxymethyl cellulose (CMC) is present in an amount of about 1 to 50 wt%, such as about 5 to 40 wt% or about 30 wt%. In some embodiments, the CMC is the only binder present in the aerosolizable formulation.

[0087] Filler The aerosolizable formulation may further include a filler. The use of a filler can help reduce the tackiness of the aerosolizable formulation, for example, when a high level of aerosol-forming agent material is present.

[0088] Suitably, the aerosolizable formulation comprises from about 10% to about 60% by weight of a binder and any optional filler.

[0089] In some embodiments, the aerosolizable formulation may comprise less than about 60% by weight, such as less than about 50% by weight, such as from about 1% to 60% by weight, or from 1% to 50% by weight, or from 5% to 40% by weight, or from 5% to 30% by weight, or from 10% to 20% by weight of a filler.

[0090] In other embodiments, the aerosolizable formulation comprises more than 20% by weight, suitably more than 30% by weight, or more than 40% by weight of a filler. In some cases, the aerosolizable formulation comprises from about 20% to 60% by weight, or from 30% to 60% by weight, or from 40% to 60% by weight of a filler.

[0091] In other embodiments, the aerosolizable formulation comprises less than 20% by weight, suitably less than 10% by weight, or less than 5% by weight of a filler. In some cases, the aerosolizable formulation comprises less than 1% by weight of a filler and in some cases does not comprise a filler.

[0092] The filler, if present, may include one or more inorganic filler materials such as calcium carbonate, perlite, vermiculite, diatomaceous earth, colloidal silica, magnesium oxide, magnesium sulfate, magnesium carbonate, and a suitable inorganic adsorbent such as molecular sieve. The filler may include one or more organic filler materials such as wood pulp; tobacco pulp; hemp fiber; starch and starch derivatives such as maltodextrin; chitosan; and cellulose and cellulose derivatives such as ground cellulose, microcrystalline cellulose, and nanocrystalline cellulose. In certain cases, the aerosolizable formulation does not contain calcium carbonate such as chalk.

[0093] In certain embodiments that include a filler, the filler is fibrous. For example, the filler may be a fibrous organic filler material such as wood pulp, tobacco pulp, hemp fiber, cellulose or cellulose derivative. In some embodiments, the fibrous organic filler material may be wood pulp, hemp fiber, cellulose or cellulose derivative. In some embodiments, the fibrous filler is wood pulp. Without wishing to be bound by theory, it is believed that including a fibrous filler in the aerosolizable formulation can increase the tensile strength of the material. This can be particularly effective in examples where the aerosolizable formulation is provided as a sheet, such as when the aerosolizable formulation sheet circumscribes a rod of the aerosolizable material.

[0094] In some embodiments, the binder is CMC and is used with wood pulp as a filler.

[0095] In some embodiments, the binder is CMC and is used with wood pulp and cellulose or cellulose derivative as fillers.

[0096] In some embodiments, the binders are CMC and guar gum and are used with wood pulp and cellulose or cellulose derivative as fillers.

[0097] In some embodiments, the binder is CMC, MCC, and guar gum and is used with wood pulp as a filler.

[0098] In some embodiments, the binder is alginate and pectin and is used with wood pulp as a filler.

[0099] In some embodiments, the aerosol-generating composition may further comprise one or more other functional materials.

[0100] In some embodiments, the aerosolizable formulation may further comprise one or more additional active substances and / or fragrances, and optionally one or more other functional materials.

[0101] Aerosol-generating composition In one aspect, (a) a plant-based material, (b) an aerosol former, (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, is provided an aerosol-generating composition comprising.

[0102] As used herein, the term "vegetable material" includes any material derived from a plant, including but not limited to extracts, leaves, bark, fibers, stems, roots, seeds, flowers, fruits, pollen, husks, shells, etc. Alternatively, the material may contain synthetically obtained active compounds that are naturally present in the vegetable material. The material may be in the form of a liquid, gas, solid, powder, dust, crushed particles, granules, pellets, chips, strips, or sheets. Exemplary vegetable materials are tobacco, eucalyptus, star anise, hemp, cocoa, cannabis, fennel, lemongrass, peppermint, spearmint, rooibos, chamomile, flax, ginger, ginkgo, hops, hibiscus, laurel, licorice, matcha, mate, orange peel, papaya, rose, sage, tea such as green tea or black tea, thyme, clove, cinnamon, coffee, aniseed, basil, bay leaf, cardamom, coriander, cumin, nutmeg, oregano, paprika, rosemary, saffron, lavender, lemon peel, mint, bilberry, chrysanthemum flower, vanilla, wintergreen, perilla, turmeric, gardenia, sandalwood, silantro, bergamot, orange flower, ginger lily, blackcurrant, valerian, pimento, mace, damiana, marjoram, olive, lemon balm, lemon basil, chive, caraway, vervain, tarragon, geranium, mulberry, Chinese carrot, theanine, theacrine, maca, ashwagandha, damiana, guarana, chlorophyll, baobab, or any combination thereof. Mint may be selected from the following mint varieties: Japanese mint, mint c.v., Egyptian mint, European mint, odoratum mint, candy mint, curly mint, Kentucky kernel mint, horsemint, pineapple mint, pennyroyal mint, green mint, and apple mint.

[0103] In some embodiments, the plant material includes tobacco. In some embodiments, the plant material is tobacco. In some embodiments, the plant material is selected from eucalyptus, star anise, cocoa, and hemp. In some embodiments, the plant material includes rooibos and / or fennel. In some embodiments, the plant material is selected from rooibos and fennel. In some embodiments, the plant material includes rooibos.

[0104] In one aspect, there is provided a consumable for use in a non-combustible aerosol supply device comprising an aerosolizable formulation or aerosol generating composition as defined herein.

[0105] In one aspect, there is provided a non-combustible aerosol supply system comprising a consumable of the present invention and a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device comprises an aerosol generating device arranged to generate an aerosol from the consumable when the consumable is used with the non-combustible aerosol supply device.

[0106] In one aspect, there is provided the use of an aerosolizable formulation or aerosol generating composition as defined herein in a consumable for use with a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device comprises an aerosol generating device arranged to generate an aerosol from the consumable when the consumable is used with the non-combustible aerosol supply device.

[0107] Aerosol former material The aerosol former material may include one or more components capable of forming an aerosol.

[0108] Suitably, the aerosolizable formulation can contain from about 5 wt% to about 30 wt%, such as about 7 wt%, 10 wt%, or 12 wt% to about 15 wt%, 17 wt%, 20 wt%, or 25 wt% of an aerosol-forming agent material (all calculated on a dry weight basis). In some embodiments, the aerosolizable formulation can contain from about 5 to 25 wt% of an aerosol-forming agent material. In some embodiments, the aerosolizable formulation can contain from about 5 to 20 wt%, such as from about 5 to 15 wt% of an aerosol-forming agent material. In some embodiments, the aerosolizable formulation can contain from about 10 to 20 wt% of an aerosol-forming agent material, such as from about 10 to 15 wt% of an aerosol-forming agent material.

[0109] In some embodiments, the aerosol-forming agent material can include one or more of glycerol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 1,3-butylene glycol, erythritol, meso-erythritol, ethyl vanillate, ethyl laurate, diethyl suberate, triethyl citrate, triacetin, a diacetin mixture, benzyl benzoate, benzyl phenylacetate, tributyrin, lauryl acetate, lauric acid, myristic acid, and propylene carbonate.

[0110] In some embodiments, the aerosol-forming agent material can include one or more of erythritol, propylene glycol, glycerol, and triacetin. Optionally, the aerosol-forming agent material can include, consist essentially of, or consist of one or more of propylene glycol, glycerol, triethyl citrate, and benzyl alcohol. Optionally, the aerosol-forming agent material can include, consist essentially of, or consist of glycerol, or a mixture of glycerol and propylene glycol.

[0111] In some embodiments, the aerosol-forming agent material comprises a mixture of glycerol and propylene glycol at a weight ratio of glycerol to propylene glycol of about 3:1 to 1:3, about 2:1 to 1:2, about 1.5:1 to 1:1.5, about 55:45 to 45:55, or about 45:55.

[0112] The aerosol-forming agent material can act as a plasticizer. If the content of the plasticizer is too high, the aerosolizable formulation may absorb water, resulting in a material that does not provide a proper consumer experience during use. If the plasticizer content is too low, the aerosolizable formulation may be brittle and can be easily broken. The plasticizer content specified herein provides the flexibility of the aerosolizable formulation that enables winding a sheet of the aerosolizable formulation or aerosol-generating composition around a bobbin, which is useful for the manufacture of aerosol-generating articles (consumables).

[0113] Activator Aerosolizable formulations, aerosol formulations, and aerosolized formulations contain an active agent. "Active agent" means a drug that has a biological effect, such as a sensory and / or physiological effect, on a subject when the aerosol is inhaled. In one aspect, "active agent" means a drug that has a physiological effect on a subject when the aerosol is inhaled. In some cases, the active agent can be a fragrance. The active agent can be selected, for example, from nutraceuticals, nootropics, psychotropics, and sensates. The active substance may be naturally occurring or obtained synthetically. The active agent can include, for example, nicotine, caffeine, taurine, theine, vitamins such as B6 or B12 or C, melatonin, cannabinoids, or their constituents, derivatives, or combinations. The active agent can include one or more constituents, derivatives, or extracts of tobacco, cannabis, or another plant substance. In some embodiments, the active agent includes caffeine, melatonin, or vitamin B12. The one or more active agents can be selected from nicotine, plant substances, and mixtures thereof. The one or more active agents can be synthetic or of natural origin. The active agent can be an extract derived from a plant substance such as a plant of the Solanaceae family. In one aspect, the active agent is at least nicotine. In one aspect, the active agent consists of nicotine and / or its salts.

[0114] As described herein, the active agent can include one or more components, derivatives or extracts of cannabis, such as one or more cannabinoids or terpenes. Cannabinoids are a class of natural or synthetic chemical compounds that act on intracellular cannabinoid receptors (i.e., CB1 and CB2) in the brain to suppress the release of neurotransmitters. Cannabinoids are cyclic molecules that exhibit certain properties, such as the ability to easily cross the blood-brain barrier. Cannabinoids can be naturally occurring ones from plants such as cannabis (phytocannabinoids), ones from animals (endocannabinoids), or ones artificially manufactured (synthetic cannabinoids). Cannabis species express at least 85 different phytocannabinoids, which include cannabigerol, cannabinchromene, cannabidiol, tetrahydrocannabinol, cannabinol and cannabidivarin, and other cannabinoids, such as cannabigerol (CBG), cannabinchromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC) (isomers of tetrahydrocannabinol (THC) Δ 6a,10a -tetrahydrocannabinol (Δ 6a,10a -THC), Δ 6a(7) -tetrahydrocannabinol (Δ 6a(7) -THC), Δ 8 -tetrahydrocannabinol (Δ 8 -THC), Δ 9 -tetrahydrocannabinol (Δ 9 -THC), Δ 10 -tetrahydrocannabinol (Δ 10 -THC), Δ 9,11 -tetrahydrocannabinol (Δ 9,11It can be divided into subclasses including cannabinol (CBN), cannabidiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidi varin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarinic acid (THCV A), which contain (-THC).

[0115] The legal status of specific cannabinoids varies by jurisdiction, but certain active ingredients, such as cannabidiol (CBD), tetrahydrocannabinol (THC), and cannabinol (CBN), are being considered for use in a variety of applications, such as formulations for use in aerosol delivery systems. However, it has been found that the stability of cannabinoids such as cannabidiol (CBD), tetrahydrocannabinol (THC), and cannabinol (CBN) changes depending on specific environmental conditions, such as exposure to air or light, or fluctuations in temperature and pH. This can lead to unintended harmful consequences.

[0116] For example, CBD can oxidize and decompose when exposed to light and / or air to form cannabidiol hydroxyquinone (CBDHQ or HU-331) and isomeric or functional derivatives of cannabidiol hydroxyquinone (CBDHQ or HU-331). Furthermore, CBD responds to fluctuations in temperature and / or pH to form Δ 9 -tetrahydrocannabinol (Δ 9-THC). As a result, the accuracy of the specific cannabinoid content and / or concentration can vary widely in the formulation, but regulated and restricted cannabinoids are produced unintentionally, which may render the product illegal or ineligible in certain jurisdictions. Thus, it is desirable to provide a formulation that maintains a high degree of purity during manufacture and storage and then prevents the loss or degradation of one or more cannabinoids such as cannabidiol (CBD), tetrahydrocannabinol (THC), or cannabinol (CBN) in the formulation.

[0117] In addition to these stability requirements for cannabinoid formulations, consumer feedback on CBD formulations used in aerosol delivery systems (otherwise referred to as CBD aerosolizable materials) has, in some cases, been negative with respect to the sensory experience. The natural taste of CBD is often described as "earthy" or "skunky," and the addition of one or more flavoring agents has been used previously to mask this taste, but this has not always been successful. In particular, consumers have indicated that flavored CBD aerosolizable materials can still have a bitter or off-note taste and that the inhalation of CBD aerosols can be unpleasant and unsatisfactory. Users may even develop an aversion to the taste, aroma, and / or other sensations experienced during use and decide to avoid all CBD aerosolizable materials. It is known that the negative sensory experiences associated with CBD can be due to TRPA1 agonist activation. Thus, antagonists and / or inhibitors of TRPA1 may be suitable for reducing the negative physiological experiences associated with aerosolizable materials containing CBD. This knowledge can be extended to other cannabinoids. The modulators of the present invention may improve these negative sensory experiences.

[0118] In one embodiment, the cannabinoid is a synthetic cannabinoid. In one embodiment, the cannabinoid is added to the material in the form of an isolate. The isolate is an extract from a plant such as a cannabis plant. The cannabinoid of interest is typically present in high purity, for example, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or about 99% purity. Synthetic cannabinoids are derived from chemical synthesis, as opposed to being isolated from plants or biological sources.

[0119] In one embodiment, the cannabinoid of interest is cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC) (isomers of tetrahydrocannabinol (THC) Δ 6a,10a -tetrahydrocannabinol (Δ 6a,10a -THC), Δ 6a(7) -tetrahydrocannabinol (Δ 6a(7) -THC), Δ 8 -tetrahydrocannabinol (Δ 8 -THC), Δ 9 -tetrahydrocannabinol (Δ 9 -THC), Δ 10 -tetrahydrocannabinol (Δ 10 -THC), Δ 9,11 -tetrahydrocannabinol (Δ 9,11 -THC) (including), cannabinol (CBN) and cannabidiolic acid (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarinic acid (THCV A). In one embodiment, the cannabinoid of interest is cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), Δ 8 -tetrahydrocannabinol (Δ8 -THC), Δ 9 -tetrahydrocannabinol (Δ 9 -THC), and cannabinol (CBN).

[0120] In one embodiment, the target cannabinoid is cannabidiol (CBD), Δ 8 -tetrahydrocannabinol (Δ 8 -THC), Δ 9 -tetrahydrocannabinol (Δ 9 -THC). In one embodiment, the target cannabinoid is cannabidiol (CBD). In one embodiment, the target cannabinoid is Δ 8 -tetrahydrocannabinol (Δ 8 -THC). In one embodiment, the target cannabinoid is Δ 9 -tetrahydrocannabinol (Δ 9 -THC). In one embodiment, the target cannabinoid is cannabinol (CBN).

[0121] In one embodiment, the target cannabinoid is cannabidiol (CBD), Δ 8 -tetrahydrocannabinol (Δ 8 -THC), Δ 9 -tetrahydrocannabinol (Δ 9 -THC), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), and mixtures thereof. In one embodiment, the target cannabinoid is at least cannabidiol (CBD). In one embodiment, the target cannabinoid is at least Δ 8 -tetrahydrocannabinol (Δ 8 -THC). In one embodiment, the target cannabinoid is at least Δ 9 -tetrahydrocannabinol (Δ 9-THC). In one embodiment, the target cannabinoid is at least cannabidiol (CBN). In one embodiment, the target cannabinoid is at least cannabigerol (CBG). In one embodiment, the target cannabinoid is at least cannabichromene (CBC) and mixtures thereof.

[0122] The cannabinoid may be present in the formulation based on the mg / ml standard of the formulation.

[0123] In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 300 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 250 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 200 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 150 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 100 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 90 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 80 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 70 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 60 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 50 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 40 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 30 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 20 mg / ml. In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml to a maximum of about 10 mg / ml.

[0124] In one embodiment, the cannabinoid is present in an amount of about 5 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 10 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 15 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 20 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 25 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 30 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 35 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 40 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 45 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 50 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 55 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 60 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 65 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 70 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 80 mg / ml or more. In one embodiment, the cannabinoid is present in an amount of about 90 mg / ml or more.

[0125] As described herein, the active agent can include or be derived from one or more phytochemicals, or components, derivatives, or extracts thereof.

[0126] In some embodiments, the active agent includes or is derived from one or more phytochemicals, or components, derivatives, or extracts thereof, and the phytochemical is tobacco.

[0127] In some embodiments, the active agent includes or is derived from one or more phytochemicals, or components, derivatives, or extracts thereof, and the phytochemical is selected from eucalyptus, star anise, cocoa, and hemp.

[0128] In some embodiments, the active agent comprises, or is derived from, one or more botanical substances, or components, derivatives, or extracts thereof, and the botanical substances are selected from rooibos and fennel.

[0129] The aerosolizable material comprises one or more specified concentrations of a sensory agent. As used interchangeably herein, the terms “sensory compound” or “sensory agent” mean a compound that elicits a sensation mediated by the user's trigeminal nerve. The use of sensory compounds is well documented in the food and pharmaceutical industries, and the sensations elicited include a cooling sensation, a warming sensation, and a tingling sensation. When used in an aerosolizable material, such sensations should be experienced in the oral cavity, nasal cavity, and / or by the user's skin. The present disclosure is not limited in this regard.

[0130] In one embodiment, the one or more sensory agents are selected from cooling agents, warming agents, or tingling agents. The terms “cooling,” “warming,” and “tingling” are well understood in the art.

[0131] Cooling agents, warming agents, and tingling agents are each typically organic small molecules that deliver a cooling, warming, or tingling sensation to the user upon contact with the oral cavity, nasal cavity, and / or skin. This sensation is included in the category of chemesthesis and occurs because the organic small molecule activates specific receptors in the skin and / or mucosa. Thus, the experience of a cooling, warming, and / or tingling sensation depends on the user's chemesthesis. Chemesthesis is typically mediated by the trigeminal nerve and is an element of the somatosensory system, and is distinguished from olfaction (sense of smell) and taste, and is therefore also referred to in the art as “general chemesthesis” or trigeminal chemesthesis.

[0132] In one embodiment, the one or more sensation-inducing agents include a cooling agent. The cooling agent is typically not menthol. In one embodiment, the one or more sensation-inducing agents include a cooling agent selected from the group consisting of N-ethyl-5-methyl-2-(propan-2-yl) cyclohexanecarboxamide, ethyl 2-(5-methyl-2-propan-2-ylcyclohexanecarbonylamino) acetate, N-(4-methoxyphenyl)-p-menthanecarboxamide, N-2,3-trimethyl-2-propan-2-ylbutanamide, N-(2-pyridin-2-yl) ethyl) menthylcarboxamide, menthone-1,2-glycerol ketal, menthyl lactate, isopulegol, 3-menthoxypropane-1,2-diol, and menthyl succinate.

[0133] In one embodiment, the one or more sensation-inducing agents include a warming agent or a stinging agent. In one embodiment, the warming agent or stinging agent is selected from the group consisting of vanilloids, sanshool, piperine, allyl isothiocyanate, cinnamyl phenylpropyl compounds, ethyl esters, and combinations thereof, or the warming agent or stinging agent is an extract from at least one of Japanese horseradish oil, ginger oil, black pepper, long pepper, Chinese prickly ash, cayenne pepper, Uzazi or mustard oil.

[0134] In one embodiment, the one or more sensation-inducing agents consist of a cooling agent. In one embodiment, the one or more sensation-inducing agents consist of a warming agent. In one embodiment, the one or more sensation-inducing agents consist of a stinging agent. In one embodiment, the one or more sensation-inducing agents consist of a cooling agent and a warming agent. In one embodiment, the one or more sensation-inducing agents consist of a cooling agent and a stinging agent. In one embodiment, the one or more sensation-inducing agents consist of a warming agent and a stinging agent.

[0135] In one aspect, one or more active agents are present in a total amount of 50% by weight or less (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 - 50% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 40% by weight or less (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 - 40% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 30% by weight or less (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 - 30% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 20% by weight or less (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 - 20% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 10% by weight or less (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, one or more active agents are present in a total amount of 0.01 to 10% by weight (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 8% by weight or less (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 to 8% by weight (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 6% by weight or less (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 to 6% by weight (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.02 to 6% by weight (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.05 to 6% by weight (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.08 to 6% by weight (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 to 5% by weight (for example, in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, one or more active agents are present in a total amount of 0.02 to 5% by weight (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.05 to 5% by weight (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.08 to 5% by weight (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 4% by weight or less (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 to 4% by weight (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.02 to 4% by weight (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.05 to 4% by weight (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.08 to 4% by weight (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 3% by weight or less (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, the one or more active agents are present in a total amount of 0.01 to 3% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.02 to 3% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.05 to 3% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.08 to 3% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 2% by weight or less (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.01 to 2% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.02 to 2% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.05 to 2% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.08 to 2% by weight (e.g., in an amount where there is nicotine), based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, one or more active agents are present in a total amount of 1 wt% or less (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 - 1 wt% (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.02 - 1 wt% (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.05 - 1 wt% (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.08 - 1 wt% (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.1 - 1 wt% (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.6 wt% or less (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 - 0.6 wt% (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.02 - 0.6 wt% (e.g., in the amount of nicotine present) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.In one aspect, the one or more active agents are present in a total amount of 0.05 to 0.6% by weight (e.g., in an amount where there is nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.08 to 0.6% by weight (e.g., in an amount where there is nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.1 to 0.6% by weight (e.g., in an amount where there is nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, the one or more active agents are based on the aerosolizable formulation, or based on the aerosol formulation, or based on... Subsequently, or based on the aerosolized formulation, it is present in a total amount of 0.5% by weight or less (for example, present in an amount of nicotine). In one aspect, one or more active agents are present in a total amount of 0.01 to 0.5% by weight (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.02 to 0.5% by weight (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.05 to 0.5% by weight (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.08 to 0.5% by weight (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.2% by weight or less (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.01 to 0.2% by weight (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.02 to 0.2% by weight (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation. In one aspect, one or more active agents are present in a total amount of 0.05 to 0.2% by weight (for example, present in an amount of nicotine) based on the aerosolizable formulation, or based on the aerosol formulation, or based on the aerosolized formulation.In one aspect, the one or more active agents are present in a total amount of 0.08 to 0.2% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.1% by weight or less (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.01 to 0.1% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.02 to 0.1% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.05 to 0.1% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the one or more active agents are present in a total amount of 0.08 to 0.1% by weight (e.g., in an amount where there is nicotine) based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.

[0136] In one aspect, the cannabinoid is present in an amount of 50% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 10 - 50% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 40% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 10 - 40% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 30% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 10 - 30% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 20% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 10 - 20% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 15% by weight or less, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation. In one aspect, the cannabinoid is present in an amount of 10 - 15% by weight, based on an aerosolizable formulation, or an aerosol formulation, or an aerosolized formulation.

[0137] carrier The carrier comprises one or more components that are capable of forming an aerosol, particularly when evaporated and condensed. Typically, the carrier is selected from water, propylene glycol, glycerol, and mixtures thereof. However, other suitable carriers may also be used. Thus, in one aspect, (a) at least one active agent, and (b) a liquid carrier, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, An aerosolizable formulation or an aerosol formulation comprising the same is provided.

[0138] In one aspect, the carrier comprises at least water. In one aspect, the carrier comprises at least propylene glycol. In one aspect, the carrier comprises at least glycerol. In one aspect, the carrier comprises at least water and glycerol. In one aspect, the carrier comprises at least propylene glycol and glycerol. In one aspect, the carrier comprises at least propylene glycol and water. In one aspect, the carrier comprises at least propylene glycol, glycerol, and water.

[0139] The carrier may be present in any suitable amount based on the total weight of the aerosolizable material. In one aspect, the carrier component constitutes at least 50% by weight based on the total weight of the aerosolizable material. In one aspect, the carrier component constitutes at least 60% by weight based on the total weight of the aerosolizable material.

[0140] In one aspect, the carrier component constitutes at least 70% by weight based on the total weight of the aerosolizable material. In one aspect, the carrier component constitutes at least 80% by weight based on the total weight of the aerosolizable material. In one aspect, the carrier component constitutes at least 90% by weight based on the total weight of the aerosolizable material.

[0141] In some embodiments, the carrier may further comprise one or more of glycerol, triethylene glycol, tetraethylene glycol, 1,3-butylene glycol, erythritol, meso-erythritol, ethyl laurate, diethyl suberate, triethyl citrate, triethylene glycol diacetate, triacetin, diacetin mixture, benzyl benzoate, benzyl phenylacetate, tributyrin, lauryl acetate, lauric acid, myristic acid, and propylene carbonate.

[0142] In one aspect, the carrier is selected from propylene glycol, glycerol, triethyl citrate, benzyl alcohol, and mixtures thereof.

[0143] In one embodiment, the aerosolizable material is liquid at about 25°C.

[0144] acid As described above, the aerosolizable formulations, aerosol formulations, and aerosolized formulations of the present invention may contain one or more additional components. These components may be selected according to the nature of the formulation. In one aspect, the aerosolizable formulations, aerosol formulations, and aerosolized formulations further comprise an acid.

[0145] In one aspect, the acid is an organic acid. In one aspect, the acid is a carboxylic acid. In one aspect, the acid is an organic carboxylic acid.

[0146] In one aspect, the acid is selected from the group consisting of acetic acid, lactic acid, formic acid, citric acid, benzoic acid, pyruvic acid, levulinic acid, succinic acid, tartaric acid, sorbic acid, propionic acid, phenylacetic acid, and mixtures thereof. In one aspect, the acid is selected from the group consisting of citric acid, benzoic acid, levulinic acid, lactic acid, sorbic acid, and mixtures thereof. In one aspect, the acid is selected from the group consisting of citric acid, benzoic acid, levulinic acid, and mixtures thereof.

[0147] In one aspect, the acid is selected from the group consisting of acetic acid, lactic acid, formic acid, citric acid, benzoic acid, pyruvic acid, levulinic acid, succinic acid, tartaric acid, sorbic acid, propionic acid, phenylacetic acid, salicylic acid, malic acid, caffeic acid, fumaric acid, nicotinic acid, o-toluic acid, m-toluic acid, p-toluic acid, capric acid, glucono delta-lactone, gluconic acid, malonic acid, phosphoric acid, 4-hydroxyphenylacetic acid, and mixtures thereof.

[0148] In one aspect, the acid is selected from the group consisting of salicylic acid, malic acid, citric acid, succinic acid, caffeic acid, fumaric acid, nicotinic acid, o-toluic acid, m-toluic acid, p-toluic acid, capric acid, glucono delta-lactone, pyruvic acid, sorbic acid, levulinic acid, tartaric acid, gluconic acid, malonic acid, phosphoric acid, 4-hydroxyphenylacetic acid, and mixtures thereof.

[0149] In one aspect, the acid is selected from acids having a pKa of 2 to 5. In one aspect, the acid is a weak acid. In one aspect, the acid is a weak organic acid.

[0150] In one aspect, the acid has a solubility in water of at least 5 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 10 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 20 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 50 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 100 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 200 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 300 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 400 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 500 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 600 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 700 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 800 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 900 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 1000 g / L at 20°C. In one aspect, the acid has a solubility in water of at least 1100 g / L at 20°C.

[0151] The molar ratio of the acid to the activator (such as nicotine) can be selected as desired. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 5:1 to 1:5. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 4:1 to 1:4. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 3:1 to 1:3. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 2:1 to 1:2. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 1.5:1 to 1:1.5. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 1.2:1 to 1:1.2. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 5:1 to 1:1. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 4:1 to 1:1. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 3:1 to 1:1. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 2:1 to 1:1. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 1.5:1 to 1:1. In one embodiment, the molar ratio of the acid to the activator (such as nicotine) is from 1.2:1 to 1:1.

[0152] In one embodiment, the total content of the acid present in the formulation is 5 molar equivalents or less based on the activator (such as nicotine). In one embodiment, the total content of the acid present in the formulation is 4 molar equivalents or less based on the activator (such as nicotine). In one embodiment, the total content of the acid present in the formulation is 3 molar equivalents or less based on the activator (such as nicotine). In one embodiment, the total content of the acid present in the formulation is 2 molar equivalents or less based on the activator (such as nicotine). In one embodiment, the total content of the acid present in the formulation is 1 molar equivalent or less based on the activator (such as nicotine).

[0153] In one aspect, the total acid content present in the formulation is 0.01 molar equivalents or more based on the active agent (such as nicotine). In one aspect, the total acid content present in the formulation is 0.05 molar equivalents or more based on the active agent (such as nicotine). In one aspect, the total acid content present in the formulation is 0.1 molar equivalents or more based on the active agent (such as nicotine). In one aspect, the total acid content present in the formulation is 0.2 molar equivalents or more based on the active agent (such as nicotine). In one aspect, the total acid content present in the formulation is 0.3 molar equivalents or more based on the active agent (such as nicotine). In one aspect, the total acid content present in the formulation is 0.4 molar equivalents or more based on the active agent (such as nicotine). In one aspect, the total acid content present in the formulation is 0.5 molar equivalents or more based on the active agent (such as nicotine). In one aspect, the total acid content present in the formulation is 0.7 molar equivalents or more based on the active agent (such as nicotine).

[0154] In one aspect, the acid is present in an amount of 6 wt% or less, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 - 6 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.02 - 6 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 - 6 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 - 6 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 - 5 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.02 - 5 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 - 5 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 - 5 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 4 wt% or less, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 - 4 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.02 - 4 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 - 4 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 - 4 wt%, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 3 wt% or less, based on the aerosolizable formulation or the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 - 3 wt%, based on the aerosolizable formulation or the aerosol formulation.In one aspect, the acid is present in an amount of 0.02 to 3% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 to 3% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 to 3% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 2% by weight or less, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 to 2% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.02 to 2% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 to 2% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 to 2% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 1% by weight or less, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 to 1% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.02 to 1% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 to 1% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 to 1% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.1 to 1% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.6% by weight or less, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 to 0.6% by weight, based on the aerosolizable formulation or based on the aerosol formulation.In one aspect, the acid is present in an amount of 0.02 to 0.6% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 to 0.6% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 to 0.6% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.1 to 0.6% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.5% by weight or less based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 to 0.5% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.02 to 0.5% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 to 0.5% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 to 0.5% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.2% by weight or less based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 to 0.2% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.02 to 0.2% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 to 0.2% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 to 0.2% by weight based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.1% by weight or less based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.01 to 0.1% by weight based on the aerosolizable formulation or based on the aerosol formulation.In one aspect, the acid is present in an amount of 0.02 to 0.1% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.05 to 0.1% by weight, based on the aerosolizable formulation or based on the aerosol formulation. In one aspect, the acid is present in an amount of 0.08 to 0.1% by weight, based on the aerosolizable formulation or based on the aerosol formulation.

[0155] The amount of acid and the solubility of the acid can be selected such that a given amount of acid dissolves in water. In one aspect, at 20 °C, at least 20% of the acid dissolves in water. In one aspect, at 25 °C, at least 20% of the acid dissolves in water. In one aspect, at 30 °C, at least 20% of the acid dissolves in water. In one aspect, at 20 °C, at least 35% of the acid dissolves in water. In one aspect, at 20 °C, at least 40% of the acid dissolves in water. In one aspect, at 20 °C, at least 45% of the acid dissolves in water. In one aspect, at 20 °C, at least 50% of the acid dissolves in water. In one aspect, at 20 °C, at least 55% of the acid dissolves in water.

[0156] As will be understood by those skilled in the art, nicotine can exist in the non-protonated form, the monoprotonated form, or the diprotonated form. The structures of each of these forms are shown below.

[0157]

Table 3

[0158] References herein to the protonated form mean both monoprotonated nicotine and diprotonated nicotine. References herein to the amount of the protonated form mean the total amount of monoprotonated nicotine and diprotonated nicotine. Further, when referring to a fully protonated formulation, it will be understood that at any given time, a very small amount of non-protonated nicotine may be present, for example, less than 1% non-protonated nicotine may be present.

[0159] The complex may contain protonated nicotin. The complex may contain unprotonated nicotin. In one aspect, the complex contains unprotonated nicotin and monoprotonated nicotin. In one aspect, the complex contains unprotonated nicotin and diprotonated nicotin. In one aspect, the complex contains unprotonated nicotin, monoprotonated nicotin, and diprotonated nicotin.

[0160] In one aspect, at least 5% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 10% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 15% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 20% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 25% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 30% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 35% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 40% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 45% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 50% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 55% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 60% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 65% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 70% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 75% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 80% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 85% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 90% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 99% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, at least 99.9% by weight of the nicotine present in the formulation is in the protonated form.

[0161] In one aspect, 50 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 55 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 60 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 65 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 70 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 75 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 80 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 85 to 95% by weight of the nicotine present in the formulation is in the protonated form. In one aspect, 90 to 95% by weight of the nicotine present in the formulation is in the protonated form.

[0162] The relevant amounts of nicotine present in the formulation in the protonated form are specified herein. These amounts can be readily calculated by one skilled in the art. Nicotine, 3-(1-methylpyrrolidin-2-yl)pyridine, is a dibasic base with a pKa of 3.12 for the pyridine ring and 8.02 for the pyrrolidine ring and can exist in pH-dependent protonated (mono- and di-) forms and non-protonated (free base) forms with different bioavailabilities.

[0163]

Chemical formula

[0164] The distribution of protonated and non-protonated nicotine changes with various pH increases.

[0165]

Chemical formula

[0166] The proportion of non-protonated nicotine is dominant at high pH levels, and a decrease in pH indicates an increase in the proportion of protonated nicotine (mono- or di- depending on pH). If the relative proportion of protonated nicotine and the total amount of nicotine in the sample are known, the absolute amount of protonated nicotine can be calculated.

[0167] The relative proportion of protonated nicotine in the formulation can be calculated by using the Henderson-Hasselbalch equation that describes pH as a derivation of the acid dissociation constant formula, and is widely used in chemical and biological systems. Consider the following equilibrium:

Number

[0168] The Henderson-Hasselbalch equation for this equilibrium is as follows:

Number

[0169] Where [B] is the amount of non-protonated nicotine (i.e., free base), [BH+] is the amount of protonated nicotine (i.e., conjugate acid), and pKa is the reference pKa value for the pyrrolidine ring nitrogen of nicotine (pKa = 8.02). The relative proportion of protonated nicotine can be derived as follows from the alpha value of non-protonated nicotine calculated from the Henderson-Hasselbalch equation:

Number

[0170] The determination of the pKa values of the nicotine formulations was carried out using the basic method described in “Spectroscopic investigations into the acid-base properties of nicotine at different temperatures”, Peter M. Clayton, Carl A. Vas, Tam T. T. Bui, Alex F. Drake and Kevin McAdam, Anal. Methods, 2013, 5, 81 - 88.

[0171] Flavor The aerosolizable formulation, aerosol formulation, and aerosolized formulation of the present invention may contain one or more additional components. These components can be selected according to the properties of the formulation. The aerosolizable formulation or aerosol formulation may include one or more fragrances or flavor components. As used herein, the terms "fragrance" and "flavoring" refer to materials that can be used to create a desired taste or aroma in products for adult consumers, when permitted by regional regulations. Fragrances include extracts (e.g., licorice, hydrangea, hinoki leaves, chamomile, fenugreek, clove, menthol, peppermint, anise, cinnamon, herbs, wintergreen, strawberry, berry, peach, apple, drambuie, bourbon, scotch, whiskey, spearmint, peppermint, lavender, cardamom, celery, cascarilla, nutmeg, sandalwood, bergamot, geranium, honey essence, rose oil, vanilla, lemon oil, orange oil, cassia, caraway, cognac, jasmine, ylang-ylang, sage, fennel, pepper, ginger, anise, coriander, coffee, or peppermint oil from any species of the genus Mentha), flavor enhancers, bitter receptor site blockers, sensory receptor site activators or stimulants, sugars and / or alternative sugars (e.g., sucralose, acesulfame potassium, aspartame, saccharin, cyclamate, lactose, sucrose, glucose, fructose, sorbitol, or mannitol), and other additives such as charcoal, chlorophyll, minerals, plant substances, or breath fresheners. They may be mimetic, synthetic, or natural components, or blends thereof. They may be in any suitable form, such as an oil, liquid, or powder. One or more fragrances may be selected from the group consisting of (4-(para-)methoxyphenyl)-2-butanone, vanillin, γ-undecalactone, menthone, 5-propenylguaethol, menthol, para-mentha-8-thiol-3-one, and mixtures thereof. In one aspect, the fragrance is at least menthol.

[0172] When present, the one or more fragrances may be present in any suitable amount. In one embodiment, the one or more fragrances are present in a total amount of 10% by weight or less, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 7% by weight or less, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 5% by weight or less, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 4% by weight or less, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 3% by weight or less, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 2% by weight or less, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 1% by weight or less, based on the aerosolizable formulation.

[0173] In one embodiment, the one or more fragrances are present in a total amount of 0.01 - 5% by weight, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 - 4% by weight, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 - 3% by weight, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 - 2% by weight, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 - 1% by weight, based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 - 0.5% by weight, based on the aerosolizable formulation.

[0174] In one aspect, one or more fragrances are present in a total amount of 10% by weight or less based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 7% by weight or less based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 5% by weight or less based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 4% by weight or less based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 3% by weight or less based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 2% by weight or less based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 1% by weight or less based on the aerosolized formulation.

[0175] In one aspect, one or more fragrances are present in a total amount of 0.01 - 5% by weight based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 0.01 - 4% by weight based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 0.01 - 3% by weight based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 0.01 - 2% by weight based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 0.01 - 1% by weight based on the aerosolized formulation. In one aspect, one or more fragrances are present in a total amount of 0.01 - 0.5% by weight based on the aerosolized formulation.

[0176] Formulation One or more cyclodextrins may or may not be present in any suitable amount in the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 12 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 10 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 9 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 8 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 7 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 6 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 5 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 4 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 3 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 2 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 1 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.5 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.1 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.01 wt% or less, based on the aerosolizable formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.001 wt% or less, based on the aerosolizable formulation.

[0177] One or more cyclodextrins may or may not be present in any suitable amount in the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 12 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 10 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 9 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 8 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 7 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 6 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 5 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 4 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 3 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 2 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 1 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.5 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.1 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.01 wt% or less, based on the aerosolized formulation. In one aspect, one or more cyclodextrins are present in a total amount of 0.001 wt% or less, based on the aerosolized formulation.

[0178] One or more cyclodextrins can be selected from the group consisting of unsubstituted cyclodextrins, substituted cyclodextrins, and mixtures thereof. In one aspect, at least one cyclodextrin is an unsubstituted cyclodextrin. In one aspect, one or more cyclodextrins are selected from the group consisting of unsubstituted cyclodextrins. In one aspect, at least one cyclodextrin is a substituted cyclodextrin. In one aspect, one or more cyclodextrins are selected from the group consisting of substituted cyclodextrins.

[0179] In one aspect, one or more cyclodextrins are selected from the group consisting of unsubstituted (α)-cyclodextrin, substituted (α)-cyclodextrin, unsubstituted (β)-cyclodextrin, substituted (β)-cyclodextrin, unsubstituted (γ)-cyclodextrin, substituted (γ)-cyclodextrin, and mixtures thereof. In one aspect, one or more cyclodextrins are selected from the group consisting of unsubstituted (β)-cyclodextrin, substituted (β)-cyclodextrin, and mixtures thereof.

[0180] In one aspect, one or more cyclodextrins are selected from the group consisting of unsubstituted (α)-cyclodextrin, unsubstituted (β)-cyclodextrin, unsubstituted (γ)-cyclodextrin, and mixtures thereof. In one aspect, one or more cyclodextrins are selected from unsubstituted (β)-cyclodextrin.

[0181] In one aspect, one or more cyclodextrins are selected from the group consisting of substituted (α)-cyclodextrin, substituted (β)-cyclodextrin, substituted (γ)-cyclodextrin, and mixtures thereof. In one aspect, one or more cyclodextrins are selected from substituted (β)-cyclodextrin. Chemical substitutions at the 2-, 3-, and 6-hydroxyl sites, particularly substitution at the 2-position, are contemplated.

[0182] In one aspect, the one or more cyclodextrins are selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, and mixtures thereof. In one aspect, the one or more cyclodextrins are at least 2-hydroxypropyl-α-cyclodextrin. In one aspect, the one or more cyclodextrins are at least 2-hydroxypropyl-β-cyclodextrin. In one aspect, the one or more cyclodextrins are at least 2-hydroxypropyl-γ-cyclodextrin.

[0183] 2-hydroxypropyl derivatives of cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin have increased solubility in water compared to the base cyclodextrins such as β-cyclodextrin.

[0184] In one aspect, when the aerosolizable formulation contains one or more cyclodextrins, the aerosolizable formulation does not contain a fragrance that can be encapsulated by the one or more cyclodextrins.

[0185] Method As discussed herein, in one aspect, (a) at least one active agent and, (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A method of forming an aerosol comprising: (A) (a) at least one active agent and, (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, a step of aerosolizing an aerosolizable formulation comprising or (B) (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, a step of aerosolizing an aerosolizable formulation comprising (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof a step of aerosolizing an aerosolizable formulation comprising is provided.

[0186] As will be appreciated, this method forms an aerosol containing three components of the present formulation, namely (a) at least one active agent, (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof.

[0187] In this method, all three components may be formulated together and then formed into an aerosol, or components (a) and (b) may be formulated together, formed into an aerosol, and then contacted with component (c).

[0188] Thus, in one aspect, (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A method of forming an aerosol comprising, (a) at least one active agent, (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A method is provided that includes the step of aerosolizing an aerosolizable formulation comprising.

[0189] Accordingly, in one aspect, (a) at least one active agent, (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A method of forming an aerosol comprising, (a) at least one active agent, (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, The step of aerosolizing an aerosolizable formulation comprising, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof A method is provided that includes the step of aerosolizing an aerosolizable formulation comprising.

[0190] In one aspect of the method, the aerosol can be formed by heating the formulation. For example, the aerosolizable formulation may be provided in a container such as a bottle or may be a component for use with an aerosol supply device. For example, the article may comprise a region (store) for receiving the aerosolizable formulation as defined herein, an aerosol generating component, an aerosol generating region, and / or a mouthpiece. In some embodiments, an article for use with an aerosol supply system is provided, the article comprising a store containing the aerosolizable formulation as defined herein, an aerosol generating component (such as a heater), an aerosol generating region, a transport element, and a mouthpiece.

[0191] The aerosolizable formulation can be transferred from a store for receiving the aerosolizable formulation through a transport element such as a wick, pump, etc. to the aerosol generating component. One of ordinary skill in the art can select an appropriate transport element depending on the type of aerosolizable formulation being transported and the rate at which it must be supplied. Particular examples of transport elements include wicks formed from fibrous materials, foamed materials, sintered materials, woven and non-woven materials.

[0192] The air flow path typically extends through the article (optionally via a device) to an outlet. The path is oriented to be entrained in the air flow such that the generated aerosol can be delivered to the outlet for inhalation by the user.

[0193] In one embodiment, the aerosol generating component is a heater.

[0194] In one embodiment, the aerosol generating component is not a heater. In aspects of this method, the aerosol can be formed by a process carried out at a temperature below 60°C. In this method, the aerosol can be formed by a process carried out at a temperature below 50°C. In this method, the aerosol can be formed by a process carried out at a temperature below 40°C. In this method, the aerosol can be formed by a process carried out at a temperature below 30°C. In this method, the aerosol can be formed by a process carried out at a temperature below 25°C. In this method, the aerosol can be formed by a process without heating.

[0195] In this method, the aerosol can be formed by applying ultrasonic energy to an aerosolizable formulation. In one embodiment, the aerosol generating component is an ultrasonic aerosol generator.

[0196] The formulation can be contained or delivered by any means. In one aspect, the present invention provides a contained aerosolizable formulation comprising (a) one or more containers and (b) an aerosolizable formulation as defined herein. The container can be any suitable container for enabling storage or delivery of the formulation, for example. In one aspect, the container is configured to engage with an electronic aerosol supply system. The container can be configured to be in fluid communication with the electronic aerosol supply system such that the formulation can be delivered to the electronic aerosol supply system. As described above, the present disclosure relates to a container that can be used in an electronic aerosol supply system such as an electronic cigarette. Throughout the following description, the term "electronic cigarette" is used. However, this term can be used interchangeably with an electronic aerosol supply system.

[0197] The components may be provided together in a single formulation or separately for combination prior to inhalation. In one aspect, (1)(i) A first component comprising a first container and (ii) an aerosolizable formulation comprising (a) at least one active agent and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof. (2)(i) A second component comprising a second container and (ii) a modulator formulation comprising a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof. A kit comprising the above is provided.

[0198] As discussed herein, the containers of the present invention are typically provided for delivering an aerosolizable formulation to or into an electronic cigarette. The aerosolizable formulation may be retained within the electronic cigarette or may be sold with or as a separate container for subsequent use with or within the electronic cigarette. As will be understood by those skilled in the art, an electronic cigarette typically contains a unit known as a removable atomizer that comprises a reservoir for the aerosolizable formulation and an aerosolizer or aerosol generator such as a wicking material and a heating element for vaporizing the aerosolizable formulation. In some electronic cigarettes, the atomizer is part of a single-piece device and is not removable. In one aspect, the container is the atomizer or part of the atomizer. In one aspect, the container is not the atomizer nor part of the atomizer, but is a container such as a tank that can be used to deliver a nicotine formulation to or into an electronic cigarette.

[0199] In one aspect, the container is part of an electronic cigarette. Thus, in a further aspect, the present invention provides an electronic aerosol supply system comprising an aerosolizable formulation as defined herein, an aerosolizer or aerosol generator for aerosolizing the formulation for inhalation by a user of an electronic aerosol supply system, and a power source comprising a cell or battery for powering the aerosolizer or aerosol generator. (i) An aerosolizer or aerosol generator for aerosolizing the formulation for inhalation by a user of the electronic aerosol supply system; (ii) A power source comprising a cell or battery for powering the aerosolizer or aerosol generator; (iii) At least (a) At least one active agent, and (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof An aerosolizable formulation comprising; (iv) A modulator selected from TRPA1 agonists, TRPM8 agonists, TRPV1 agonists, TRPV3 agonists, TRPA1 antagonists, TRPA1 inhibitors, and combinations thereof. An electronic aerosol supply system is provided. An aerosol generator is a device configured to generate an aerosol from an aerosolizable formulation. In some embodiments, the aerosol generator is a heater configured to subject the aerosolizable formulation to thermal energy to release one or more volatile substances from the aerosolizable formulation to form an aerosol. In some embodiments, the aerosol generator is configured to generate an aerosol from the aerosolizable formulation without heating. For example, the aerosol generator may be configured to subject the aerosolizable formulation to one or more of vibration, pressure increase, or electrostatic energy. In one aspect, the modulator is present in the aerosolizable formulation. In one aspect, the modulator is separate from the aerosolizable formulation. In one aspect, the electronic aerosol supply system further comprises an acid. The acid may be present in the aerosolizable formulation or may be separate from the aerosolizable formulation.

[0200] In addition to aerosolizable formulations of the present invention, and systems such as containers and electronic aerosol supply systems containing the same, the present invention relates to the use of a modulator for reducing the discomfort upon inhalation of an aerosolized formulation, wherein the modulator is selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, wherein the aerosolizable formulation (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof is provided for use.

[0201] The method of the present invention may include additional steps either before, after, or during one or more of the recited steps.

[0202] Hereinafter, the present invention will be described with reference to the following non-limiting examples.

[0203] Examples Example 1 A product developer test (PDT) (sensory test) on an e-liquid using a mixture of up to three TRP receptor modulators (alpha-ionone, caryophyllene oxide, and benzyl cinnamate) was conducted using a sequential monadic scale (1-9) to evaluate the sensory performance of the TRP receptor modulators for non-protonated and protonated products. In doing so, 12 participants were asked to evaluate the irritation, impact, flavor intensity, and overall likability of the provided products. The results for each of these evaluations are shown in FIGS. 1-4.

[0204] From the data, the inventors concluded that products containing the TRP receptor modulator showed a decrease in irritation. This was particularly pronounced with the TRP receptor modulator compared to the non-protonated product, and furthermore, the flavor intensity and impact were increased compared to the current protonated product (0.6 benzoic acid, currently commercially available).

[0205] Example 2 Test design Quantitative in-home placement consumer evaluations were completed with a balanced set of 108 independent participants with respect to age and gender. The participants used the products at home and completed a questionnaire to evaluate each product. This test was administered by an independent third-party consumer research agency and conducted according to industry standards.

[0206] Formulation Prototypes were prepared to evaluate the effect of materials identified as active against the displeasure receptor. The active agents were caryophyllene oxide and benzyl cinnamate. The same device was used for both samples. The same instructions were provided. There were benchmark and test samples.

[0207] The only difference was related to the presence of the two active agents in the liquid, as shown in Table 1. The benchmark product was an e-liquid formulation containing propylene glycol, glycerin, nicotine, and flavor. The test sample contained the same four components and furthermore contained benzyl cinnamate and caryophyllene oxide.

[0208] [Table 4]

[0209] Consumer evaluation The consumers, whom the inventors asked to test each product over a one-day period, then completed an online quantitative questionnaire to evaluate the product. Two different scales were used: 1. Size Scale: A 7 - point scale used to evaluate the sensory level from low (1) to high (7). 2. Just - Right Scale: Evaluates how close the sensation is to being "just right". This is a 5 - point scale.

[0210] Size Scale and Results The size scale poses a question and then provides a 1 - to - 7 - point scale. The scale requires that rankings be provided based on the following question: "Think about the e - liquid vaped today. How would you rate each of the following characteristics as low or high?"

[0211] Then, rank the throat discomfort from 1 [low] to 7 [high].

[0212] Provide the results in Tables 2 and 3.

[0213]

Table 5

[0214]

Table 6

[0215] Just - Right Scale and Results The evaluation scale used is shown below to measure how "just right" the sample is with respect to the "level of irritation during the vaping session". The possible evaluations were as follows: - 2 Much less than desired - 1 Slightly less than desired 0 Just right + 1 Slightly more than desired + 2 Much more than desired

[0216]

Table 7

[0217]

Table 8

[0218] Overall conclusion The presence of benzyl cinnamate and caryophyllene oxide results in a less irritating and more "just right" product with respect to the irritation level of the vapor and the palatability level.

[0219] The present invention is further described in more detail in the following numbered embodiments. 1. (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and an aerosolizable formulation or an aerosol formulation comprising, or (a) at least one active agent, and (b) an aerosol forming agent material, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and an aerosolizable formulation or an aerosol formulation comprising. 2. The aerosolizable formulation or aerosol formulation according to embodiment 1, wherein the modulator comprises at least one or more of a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist. 3. The aerosolizable formulation or aerosol formulation according to embodiment 1 or 2, wherein the modulator comprises at least a TRPA1 antagonist or a TRPA1 inhibitor. 4. The modulator comprises at least (i) one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol formulation according to embodiment 1, 2, or 3. 5. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 4, wherein the TRPA1 antagonist or TRPA1 inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity for each of the receptors of one or more of the TRPM8 agonist, the TRPV1 agonist, and the TRPV3 agonist. 6. The modulator comprises at least (i) a TRPM8 agonist or a TRPV1 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 5. 7. The modulator comprises at least (i) a TRPM8 agonist and a TRPV1 agonist, and (ii) a TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 6. 8. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 7, wherein the modulator is a single compound. 9. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 8, wherein the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof. 10. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 9, wherein the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, and combinations thereof. 11. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 10, wherein the TRPA1 agonist binds to one or more sites selected from Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof. 12. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 11, wherein the TRPM8 agonist binds to one or more sites selected from Arg1007, Arg841, Asn741, Asp781, Ile845, Leu1000, Phe738, Tyr1004, Tyr745, Val848, and combinations thereof. 13. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 12, wherein the TRPV1 agonist binds to one or more sites selected from Ala548, Ala568, Ala667, Asn553, Glu572, Ile571, Ile663, Leu517, Leu555, Leu664, Leu671, Met549, Phe518, Phe545, Phe593, Ser514, Thr552, Tyr513, Tyr556, and combinations thereof. 14. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 13, wherein the TRPV3 agonist binds to one or more sites selected from Arg693, His430, His426, His417, Leu420, Leu694, Leu429, Trp433, Thr421, and combinations thereof. 15. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 14, wherein the TRPA1 inhibitor binds to one or more sites selected from Leu867, Leu870, Leu871, Ile946, Ser873, Thr873, Thr874, Phe944, Val948, Phe877, Ile878, Leu880, Leu881, Met912, Phe909, Thr908, Ile906, Ile905, Ile950, Leu956, Val942, Met953, Leu952, Phe884, and combinations thereof. 16. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 15, wherein the TRPA1 antagonist is selected from cinnamic acid, cinnamyl ester; hexylresorcinol; l-menthol; 2-ethyl-6-methoxyphenol; linalyl oxide; 2-methoxy-6-methylphenol; methyl 2-(methylamino)benzoate; eucalyptol; and mixtures thereof. 17. The TRPM8 agonist is selected from (1Z,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; beta-caryophyllene; liquiritin; ambrox; (E)-2-epi-beta-caryophyllene; bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8-methylene-, (1R,4E,9S)-; (4Z)-4,11,11-trimethyl-8-methylidene bicyclo[7.2.0]undec-4-ene; bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8-methylene-, (1S,4E,9R)-; isocaryophyllene; ambroxan; spathulenol; caryophyllene oxide; (-)-beta-bulbonene; oxacycloheptadeca-10-en-2-one, (E)-; cubebol; trans-caryophyllene; gamma-dodecalactone; hydroxy-alpha-sanshool; citronellyl acetate; (2E,6Z,8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; (8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; hydroxy-beta-sanshool; 2-hexenal; and mixtures thereof, and the aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 16. 18. The TRPV1 agonist is selected from phenethyl phenylacetate; 2-propenoic acid, 3-phenyl-, 3-phenyl-2-propenyl ester; theaspirane; (7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol; 4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; cinnamyl cinnamate; alpha-ionone; beta-spathulenol; spathulenol; phytol; 1-penten-3-one, 1-[(1R)-2,6,6-trimethyl-2-cyclohexen-1-yl]-, (1E)-; (S)-alpha-methylionone; guaiol; 3,7,11,15-tetramethylhexadec-2-en-1-ol; 3,7,11,15-tetramethyl-2-hexadecen-1-ol; (Z)-3,7,11,15-tetramethylhexadec-2-en-1-ol; vanillyl butyl ether; 4-ethyl-2-methoxyphenol; 6-methyl-2-(oxiran-2-yl)hepta-5-en-2-ol; 2-methoxy-4-methylphenol; 2-methoxy-4-vinylphenol; benzyl cinnamate; 2-propenoic acid; 3-phenyl-, phenylmethyl ester; and mixtures thereof, and is an aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 17. 19. The TRPV3 agonist is selected from ethyl vanillin; 2,6-dimethoxyphenol; vanillin; and mixtures thereof, and is an aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 18. 20. The TRPA1 inhibitor is selected from 3-phenylpropyl homovanillate; benzyl alcohol, cinnamate; benzyl phenylacetate; alpha-amyl cinnamaldehyde; linalyl benzoate; phenethyl isovalerate; carvacrol; thymol; 5-ethyl-2-methoxyphenol; vanitrope; and mixtures thereof, and is an aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 19. 21. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 20, wherein the TRPA1 antagonist is selected from cinnamyl cinnamate, liquiritin, 3-phenylpropyl homovanillate, benzyl cinnamate, caryophyllene (beta-), phenethyl phenylacetate, hydroxy-alpha-sanshool, phytol, bulbonene (beta), and mixtures thereof. 22. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 21, wherein the TRPA1 inhibitor is selected from cinnamyl cinnamate, citronellyl acetate, eucalyptol, 2-hexenal, dodecalactone (gamma-), menthol (l-), spathulenol, bulbonene (beta), benzyl cinnamate, caryophyllene oxide, caryophyllene (beta-), alpha-ionone, phenethyl phenylacetate, methyl-alpha-ionone, phytol, and mixtures thereof. 23. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 21, wherein the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof. 24. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 21, wherein the modulator is at least a mixture of caryophyllene oxide and benzyl cinnamate. 25. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 24, wherein the active agent is at least nicotine. 26. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 25, wherein the active agent is present in an amount of 6% by weight or less based on the aerosolizable formulation or aerosol formulation. 27. The aerosolizable formulation or aerosol formulation according to embodiment 26, wherein the active agent is present in an amount of 0.01 to 5% by weight based on the aerosolizable formulation or aerosol formulation. 28. The aerosolizable formulation or aerosol formulation according to any one of embodiments 1 to 27, further comprising at least one acid. 29. The aerosolizable formulation or aerosol formulation according to embodiment 28, wherein the acid is selected from the group consisting of acetic acid, lactic acid, formic acid, citric acid, benzoic acid, pyruvic acid, levulinic acid, succinic acid, tartaric acid, sorbic acid, propionic acid, phenylacetic acid, salicylic acid, malic acid, coffee acid, fumaric acid, nicotinic acid, o-toluic acid, m-toluic acid, p-toluic acid, capric acid, glucono-delta-lactone, gluconic acid, malonic acid, phosphoric acid, 4-hydroxyphenylacetic acid, and mixtures thereof. 30. The aerosolizable formulation or aerosol formulation according to embodiment 28, wherein the acid is selected from the group consisting of salicylic acid, malic acid, citric acid, succinic acid, coffee acid, fumaric acid, nicotinic acid, o-toluic acid, m-toluic acid, p-toluic acid, capric acid, glucono-delta-lactone, pyruvic acid, sorbic acid, levulinic acid, tartaric acid, gluconic acid, malonic acid, phosphoric acid, 4-hydroxyphenylacetic acid, and mixtures thereof. 31. The aerosolizable formulation or aerosol formulation according to embodiment 28, 29 or 30, wherein the total content of the acid present in the formulation is 1.0 molar equivalent or less based on nicotine. 32. The aerosolizable formulation or aerosol formulation according to any one of embodiments 28 to 31, wherein the total content of the acid present in the solution is 0.1 molar equivalent or more based on nicotine. 33. The aerosolizable formulation according to any one of embodiments 1 to 32, in the form of a solid, semi-solid, or gel. 34. The aerosolizable formulation according to embodiment 33, comprising one or more binders. 35(a) at least one active agent and, (b) an aerosol-forming agent material, and (c) a modulator selected from the group consisting of a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and (d) one or more binders, and an aerosolizable formulation comprising the same. An aerosolizable formulation according to embodiment 33, 34, or 35, comprising one or more binders in an amount of 20 to 40% by weight based on the dry weight of the aerosolizable formulation. 37. The aerosolizable formulation according to any one of embodiments 33 to 36, wherein the one or more binders comprise one or more compounds selected from polysaccharide gelling agents such as alginate, pectin, starch or its derivatives, cellulose or its derivatives, pullulan, carrageenan, agar, and agarose; gelatin; gums such as xanthan gum, guar gum, and acacia gum; silica or silicone compounds such as PDMS and sodium silicate; clays such as kaolin; and polyvinyl alcohol. 38. The aerosolizable formulation according to embodiment 37, wherein the polysaccharide gelling agent is selected from alginate and cellulose derivatives. 39. The aerosolizable formulation according to embodiment 37 or 38, wherein the cellulose derivative is selected from microcrystalline cellulose (MCC), hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate (CA), cellulose acetate butyrate (CAB), and cellulose acetate propionate (CAP). 40. The aerosolizable formulation according to any one of embodiments 33 to 39, wherein the one or more binders are not crosslinked. 41. The aerosolizable formulation according to any one of embodiments 33 to 40, wherein the one or more binders are MCC and / or CMC. 42. The aerosol-forming agent material contains one or more of glycerol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 1,3-butylene glycol, erythritol, meso-erythritol, ethyl vanillate, ethyl laurate, diethyl suberate, triethyl citrate, triacetin, a diacetin mixture, benzyl benzoate, benzyl phenylacetate, tributyrin, lauryl acetate, lauric acid, myristic acid, and propylene carbonate, and is an aerosolizable formulation or aerosol formulation according to any one of Embodiments 1 to 27, or an aerosolizable formulation according to Embodiment 35. 43. The aerosol-forming agent material contains glycerol or a combination of glycerol and propylene glycol, and is an aerosolizable formulation according to Embodiment 42. 44. The modulator is a modulator defined in any one of Embodiments 2 to 24, and is an aerosolizable formulation according to any one of Embodiments 35 to 43. 45. An aerosol-generating composition containing the aerosolizable formulation according to any one of Embodiments 1 to 44. 46. The aerosol-generating composition according to Embodiment 45, containing 50 to 100% by weight (WWB) of an aerosol-generating material. 47. (a) A plant-derived material, (b) An aerosol-forming agent, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and is an aerosol-generating composition. 48. The plant-derived material is a material derived from a plant of the Solanaceae family, and is an aerosol-generating composition according to Embodiment 47. 49. The aerosol-forming composition according to embodiment 47 or 48, wherein the aerosol-forming agent material comprises one or more of glycerol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 1,3-butylene glycol, erythritol, meso-erythritol, ethyl vanillate, ethyl laurate, diethyl suberate, triethyl citrate, triacetin, diacetin mixture, benzyl benzoate, benzyl phenylacetate, tributyrin, lauryl acetate, lauric acid, myristic acid, and propylene carbonate. 50. The aerosol-forming composition according to embodiment 49, wherein the aerosol-forming agent material comprises glycerol or a combination of glycerol and propylene glycol. 51. The aerosol-forming composition according to embodiment 47, wherein the aerosol-forming agent is selected from water, propylene glycol, glycerol, and mixtures thereof. 52. The aerosol-forming composition according to any one of embodiments 47 to 52, wherein the modulator is the modulator defined in any one of embodiments 2 to 24. 53. A consumable for use in a non-combustible aerosol supply device, comprising an aerosolizable formulation or an aerosol-forming composition defined in any one of embodiments 1 to 52. 54. A non-combustible aerosol supply system comprising the consumable according to embodiment 53 and a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device comprises an aerosol generation device arranged to generate an aerosol from the consumable when the consumable is used with the non-combustible aerosol supply device. 55. Use of an aerosolizable formulation or an aerosol-forming composition defined in any one of embodiments 1 to 52 in a consumable for use with a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device comprises an aerosol generation device arranged to generate an aerosol from the consumable when the consumable is used with the non-combustible aerosol supply device. 56. (a) at least one active agent, and (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and A method of forming an aerosol comprising (A) (a) At least one active agent, and (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and A step of aerosolizing an aerosolizable formulation comprising or (B) (a) At least one active agent, and (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and A step of aerosolizing an aerosolizable formulation comprising (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof A step of aerosolizing an aerosolizable formulation comprising A method comprising one of the above. 57. (B) (a) At least one active agent, and (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and A step of aerosolizing an aerosolizable formulation to form an initial aerosol, and the initial aerosol is (c) contacting with a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof The method according to embodiment 56, comprising 58. The method according to embodiment 56 or 57, characterized by the features according to any one of embodiments 2 to 32. 59. (i) a container, and (ii) (a) at least one active agent, (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof an aerosolizable formulation comprising an aerosolizable formulation contained therein. 60. The aerosolizable formulation contained therein according to embodiment 59, wherein the aerosolizable formulation is the aerosolizable formulation defined in any one of embodiments 2 to 32. 61. The aerosolizable formulation contained therein according to embodiment 59 or 60, wherein the container is configured to engage with an aerosol delivery system. 62. The aerosolizable formulation contained therein according to embodiment 59, 60 or 61, wherein the container is configured to engage with an electronic aerosol delivery system. 63. (1) (i) a first container, and (ii) (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof an aerosolizable formulation comprising a first component comprising (2) (i) a second container, and (ii) a modulator formulation comprising a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof a second component comprising a kit comprising. 64. (i) an atomizer for aerosolizing a formulation for inhalation by a user of an electronic aerosol supply system, and (ii) a power source comprising a cell or battery for powering the atomizer, and (iii) at least (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof an aerosolizable formulation comprising, and (iv) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof an electronic aerosol supply system comprising. 65. The electronic aerosol supply system according to embodiment 64, wherein the modulator is present in the aerosolizable formulation. 66. The electronic aerosol supply system according to embodiment 64 or 65, further comprising an acid. 67. The electronic aerosol supply system according to embodiment 66, wherein the acid is present in the aerosolizable formulation. 68. The electronic aerosol supply system according to any one of embodiments 64 to 67, wherein the aerosolizable formulation is the aerosolizable formulation defined in any one of embodiments 2 to 32. 69. Use of a modulator for reducing the unpleasantness upon inhalation of an aerosolized formulation, The modulator is selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, The aerosolized formulation (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof (comprising) for use. 70. The use according to embodiment 69, wherein the aerosolized formulation is formed from an aerosolizable formulation as defined in any one of embodiments 2 to 32. 71. (a) at least one active agent, and (b) an aerosol-forming agent material, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and (d) one or more binders (comprising) an aerosolizable formulation. 72. (a) a plant-based material, and (b) an aerosol-forming agent, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof (comprising) an aerosol-generating composition. 73. The aerosol-generating composition according to embodiment 72, wherein the plant-based material is a material derived from a plant of the Solanaceae family. 74. The aerosol-generating composition according to embodiment 72 or 73, further comprising one or more binders and optionally fillers. 75. The aerosol-generating composition according to embodiment 71 or 74, wherein one or more binders consist of one or more gelling agents. 76. The modulator is at least (iii) One or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist, and (iv) A TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol-generating composition according to any one of Embodiments 71 to 75, comprising 77. The aerosolizable formulation or aerosol-generating composition according to any one of Embodiments 71 to 76, wherein the TRPA1 antagonist or TRPA1 inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity for each of one or more of the receptors of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist. 78. The modulator is at least (iii) A TRPM8 agonist or a TRPV1 agonist, and (iv) A TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol-generating composition according to any one of Embodiments 71 to 77, comprising 79. The modulator is at least (iii) A TRPM8 agonist and a TRPV1 agonist, and (iv) A TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol-generating composition according to any one of Embodiments 71 to 78, comprising 80. The aerosolizable formulation or aerosol-generating composition according to any one of Embodiments 71 to 79, wherein the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof. 81. The aerosolizable formulation or aerosol - generating composition according to any one of embodiments 71 - 80, wherein the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, and combinations thereof. 82. The aerosolizable formulation or aerosol - generating composition according to any one of embodiments 71 - 81, wherein the TRPA1 agonist binds to one or more sites selected from Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof. 83. The aerosolizable formulation or aerosol - generating composition according to any one of embodiments 71 - 82, wherein the TRPM8 agonist binds to one or more sites selected from Arg1007, Arg841, Asn741, Asp781, Ile845, Leu1000, Phe738, Tyr1004, Tyr745, Val848, and combinations thereof. 84. The aerosolizable formulation or aerosol - generating composition according to any one of embodiments 71 - 83, wherein the TRPV1 agonist binds to one or more sites selected from Ala548, Ala568, Ala667, Asn553, Glu572, Ile571, Ile663, Leu517, Leu555, Leu664, Leu671, Met549, Phe518, Phe545, Phe593, Ser514, Thr552, Tyr513, Tyr556, and combinations thereof. 85. The aerosolizable formulation or aerosol - generating composition according to any one of embodiments 71 - 84, wherein the TRPV3 agonist binds to one or more sites selected from Arg693, His430, His426, His417, Leu420, Leu694, Leu429, Trp433, Thr421, and combinations thereof. 86. The aerosolizable formulation or aerosol generating composition according to any one of embodiments 71 to 85, wherein the TRPA1 inhibitor binds to one or more sites selected from Leu867, Leu870, Leu871, Ile946, Ser873, Thr873, Thr874, Phe944, Val948, Phe877, Ile878, Leu880, Leu881, Met912, Phe909, Thr908, Ile906, Ile905, Ile950, Leu956, Val942, Met953, Leu952, Phe884, and combinations thereof. 87. The aerosolizable formulation or aerosol generating composition according to any one of embodiments 71 to 86, wherein the active agent is at least nicotine and / or the aerosolizable formulation or aerosol generating composition further comprises at least one acid. 88. The aerosolizable formulation or aerosol generating composition according to any one of embodiments 71 to 87, wherein the aerosol forming agent material comprises one or more of glycerol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 1,3 - butylene glycol, erythritol, meso - erythritol, ethyl vanillate, ethyl laurate, diethyl suberate, triethyl citrate, triacetin, diacetin mixture, benzyl benzoate, benzyl phenylacetate, tributyrin, lauryl acetate, lauric acid, myristic acid, and propylene carbonate. For example, the aerosol forming agent material comprises glycerol or a combination of glycerol and propylene glycol. 89. A consumable for use in a non - combustible aerosol supply device comprising the aerosolizable formulation or aerosol generating composition defined in any one of embodiments 71 to 88. 90. A non - combustible aerosol supply system comprising the consumable according to embodiment 89 and a non - combustible aerosol supply device, wherein the non - combustible aerosol supply device comprises an aerosol generating device arranged to generate an aerosol from the consumable when the consumable is used with the non - combustible aerosol supply device. Use of an aerosolizable formulation or aerosol generating composition as defined in any one of embodiments 71 to 88 in a consumable for use with a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device comprises an aerosol generating device arranged to generate an aerosol from the consumable when the consumable is used with the non-combustible aerosol supply device. 92. (a) At least one active agent, (b) An aerosol forming agent material, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A method of forming an aerosol comprising: (A) (a) At least one active agent, (b) An aerosol forming agent material, (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, A step of aerosolizing an aerosolizable formulation comprising: Or (B) (a) At least one active agent, (b) A carrier selected from water, propylene glycol, glycerol, and mixtures thereof, A step of aerosolizing an aerosolizable formulation comprising: (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof A step of aerosolizing an aerosolizable formulation comprising: Or (C) (a) At least one active agent, (b) An aerosol - forming agent material, and (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and (d) One or more binders, and The step of aerosolizing an aerosolizable formulation comprising or (D) (a) A plant - based material, and (b) An aerosol - forming agent, and (c) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and The step of aerosolizing an aerosol - generating composition comprising One of the above - mentioned methods. 93. (1) (i) A first container, and (ii) (a) At least one active agent, and (b) An aerosol - forming agent material An aerosolizable formulation comprising A first component comprising (2) (i) A second container, and (ii) A modulator formulation comprising a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof A second component comprising A kit comprising 94. (i) An aerosol generator for aerosolizing a formulation for inhalation by a user of an electronic aerosol supply system, and (ii) A power source comprising a cell or battery for powering the aerosol generator, and (iii) At least (a) At least one active agent, and (b) an aerosol-forming agent material An aerosolizable formulation comprising, and (iv) A modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, and An electronic aerosol supply system comprising. 95. Use of a modulator for reducing the discomfort upon inhalation of an aerosolized formulation, wherein the modulator is selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, the aerosolized formulation comprises (a) At least one active agent, and (b) an aerosol-forming agent material Use comprising. Various modifications and variations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the described embodiments for carrying out the present invention that are obvious to those skilled in the chemical or related arts are intended to be within the scope of the following claims.

Claims

1. (a) at least one active agent; (b) an aerosol-forming agent material; (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof; (d) one or more binders; An aerosolizable formulation comprising.

2. The aerosolizable formulation according to claim 1, wherein the active agent is at least nicotine.

3. The aerosolizable formulation according to claim 1, wherein the active agent is at least a cannabinoid.

4. (a) a plant-derived material; (b) an aerosol-forming agent; (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof; An aerosol-generating composition comprising.

5. The aerosol-generating composition according to claim 4, wherein the plant-derived material is a material derived from a plant of the Solanaceae family.

6. The aerosol-generating composition according to claim 4, wherein the plant-derived material is a material derived from cannabis.

7. The aerosol-generating composition according to claim 4, wherein the plant-derived material is rooibos.

8. The aerosol-generating composition according to any one of claims 4 to 7, further comprising one or more binders and optionally a filler.

9. The aerosol-generating composition according to claim 8, wherein the one or more binders consist of one or more gelling agents.

10. The modulator is at least (v) one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist, and (vi) a TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol-generating composition according to any one of claims 1 to 9, comprising.

11. The modulator is at least (v) a TRPM8 agonist or a TRPV1 agonist, and (vi) a TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol-generating composition according to any one of claims 1 to 10, comprising.

12. The modulator is at least (v) a TRPM8 agonist and a TRPV1 agonist, and (vi)A TRPA1 antagonist or a TRPA1 inhibitor The aerosolizable formulation or aerosol-generating composition according to any one of claims 1 to 11, comprising the same.

13. (1) The TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof. For example, the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, and combinations thereof, and / or (2) The TRPA1 agonist binds to one or more sites selected from Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof, and / or (3) The TRPM8 agonist binds to one or more sites selected from Arg1007, Arg841, Asn741, Asp781, Ile845, Leu1000, Phe738, Tyr1004, Tyr745, Val848, and combinations thereof, and / or (4) The TRPV1 agonist binds to one or more sites selected from Ala548, Ala568, Ala667, Asn553, Glu572, Ile571, Ile663, Leu517, Leu555, Leu664, Leu671, Met549, Phe518, Phe545, Phe593, Ser514, Thr552, Tyr513, Tyr556, and combinations thereof, and / or (5) The TRPV3 agonist binds to one or more sites selected from Arg693, His430, His426, His417, Leu420, Leu694, Leu429, Trp433, Thr421, and combinations thereof, and / or (6) The TRPA1 inhibitor binds to one or more sites selected from Leu867, Leu870, Leu871, Ile946, Ser873, Thr873, Thr874, Phe944, Val948, Phe877, Ile878, Leu880, Leu881, Met912, Phe909, Thr908, Ile906, Ile905, Ile950, Leu956, Val942, Met953, Leu952, Phe884, and combinations thereof. An aerosolizable formulation or aerosol generating composition according to any one of claims 1 to 12.

14. The aerosolizable formulation or aerosol generating composition according to any one of claims 1 to 13, wherein the active agent is at least nicotine and / or the aerosolizable formulation or aerosol generating composition further comprises at least one acid.

15. The aerosolizable formulation or aerosol generating composition according to any one of claims 1 to 9, wherein the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof.

16. The aerosolizable formulation or aerosol generating composition according to any one of claims 1 to 9, wherein the modulator is caryophyllene oxide and benzyl cinnamate.

17. The aerosolizable formulation or aerosol generating composition according to claim 16, comprising caryophyllene oxide in an amount of 0.01 to 20% by weight based on the weight of the aerosolizable formulation or aerosol generating composition, and benzyl cinnamate in an amount of 0.01 to 20% by weight based on the weight of the aerosolizable formulation or aerosol generating composition.

18. A consumable for use in a non-combustible aerosol supply device comprising an aerosolizable formulation or aerosol generating composition according to any one of claims 1 to 17.

19. A non-combustible aerosol supply system comprising the consumable according to claim 18 and a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device is provided with an aerosol generation device arranged to generate an aerosol from the consumable when the consumable is used together with the non-combustible aerosol supply device.

20. Use of an aerosolizable formulation or aerosol generation composition according to any one of claims 1 to 17 in a consumable for use with a non-combustible aerosol supply device, wherein the non-combustible aerosol supply device is provided with an aerosol generation device arranged to generate an aerosol from the consumable when the consumable is used together with the non-combustible aerosol supply device.

21. (a) at least one active agent; (b) an aerosol forming agent material; (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof; A method of forming an aerosol comprising: (A) (a) at least one active agent; (b) an aerosol forming agent material; (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof; aerosolizing an aerosolizable formulation comprising the same; or (B) (a) at least one active agent; (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof; aerosolizing an aerosolizable formulation comprising the same; (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof aerosolizing an aerosolizable formulation comprising the same; or (C) (a) at least one active agent; (b) an aerosol forming agent material; (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof; (d) one or more binders, and a step of aerosolizing an aerosolizable formulation comprising or (D) (a) a plant-based material, (b) an aerosol former, (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof a step of aerosolizing an aerosol-generating composition comprising A method comprising one of the above. **Claim 22** The method according to claim 21, wherein the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof. **Claim 23** （１） (i) a first container, and (ii) (a) at least one active agent, and (b) an aerosol former material an aerosolizable formulation comprising a first component comprising （２） (i) a second container, and (ii) a modulator formulation comprising a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof a second component comprising A kit comprising. **Claim 24** The kit according to claim 23, wherein the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof. **Claim 25** (i) an aerosol generator for aerosolizing a formulation for inhalation by a user of an electronic aerosol supply system, (ii) a power source comprising a cell or battery for supplying power to the aerosol generator, (iii) at least (a) at least one active agent, and (b) an aerosol former material an aerosolizable formulation comprising (iv) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof An electronic aerosol supply system comprising. **Claim 26** The electronic aerosol supply system according to claim 25, wherein the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof. **Claim 27** Use of a modulator to reduce the discomfort upon inhalation of an aerosolized formulation, The modulator is selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof, The aerosolized formulation is, (a) at least one active agent, and (b) an aerosol-forming agent material for use.

28. Use according to claim 25, wherein the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof.

29. (a) at least one active agent, and (b) a carrier selected from water, propylene glycol, glycerol, and mixtures thereof, and (c) a modulator selected from a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, and combinations thereof for an aerosolizable formulation or an aerosol formulation.

30. The aerosolizable formulation or aerosol formulation according to claim 29, wherein the modulator comprises at least one or more of a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist.

31. The aerosolizable formulation or aerosol formulation according to claim 29 or 30, wherein the modulator comprises at least a TRPA1 antagonist or a TRPA1 inhibitor.

32. The modulator is at least (vii) one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist, and (viii) a TRPA1 antagonist or a TRPA1 inhibitor for an aerosolizable formulation or an aerosol formulation according to claim 29, 30, or 31.

33. The aerosolizable formulation or aerosol formulation according to any one of claims 29 to 32, wherein the TRPA1 antagonist or TRPA1 inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity for each of the receptors of one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist.

34. The modulator is at least (vii) a TRPM8 agonist or a TRPV1 agonist, and (viii) a TRPA1 antagonist or a TRPA1 inhibitor An aerosolizable formulation or aerosol formulation according to any one of claims 29 to 33, comprising

35. wherein the modulator is at least (vii) a TRPM8 agonist and a TRPV1 agonist, and (viii) a TRPA1 antagonist or a TRPA1 inhibitor An aerosolizable formulation or aerosol formulation according to any one of claims 29 to 34, comprising

36. (1) The TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof; for example, the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, and combinations thereof, and / or (2) The TRPA1 agonist binds to one or more sites selected from Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof, and / or (3) The TRPM8 agonist binds to one or more sites selected from Arg1007, Arg841, Asn741, Asp781, Ile845, Leu1000, Phe738, Tyr1004, Tyr745, Val848, and combinations thereof, and / or (4) The TRPV1 agonist binds to one or more sites selected from Ala548, Ala568, Ala667, Asn553, Glu572, Ile571, Ile663, Leu517, Leu555, Leu664, Leu671, Met549, Phe518, Phe545, Phe593, Ser514, Thr552, Tyr513, Tyr556, and combinations thereof, and / or (5) The TRPV3 agonist binds to one or more sites selected from Arg693, His430, His426, His417, Leu420, Leu694, Leu429, Trp433, Thr421, and combinations thereof, and / or (6) The TRPA1 inhibitor binds to one or more sites selected from Leu867, Leu870, Leu871, Ile946, Ser873, Thr873, Thr874, Phe944, Val948, Phe877, Ile878, Leu880, Leu881, Met912, Phe909, Thr908, Ile906, Ile905, Ile950, Leu956, Val942, Met953, Leu952, Phe884, and combinations thereof. An aerosolizable formulation or aerosol formulation according to any one of claims 29 to 35.

37. The aerosolizable formulation or aerosol formulation according to any one of claims 29 to 36, wherein the modulator is at least caryophyllene oxide, benzyl cinnamate, or a mixture thereof.

38. The aerosolizable formulation or aerosol formulation according to any one of claims 29 to 37, wherein the modulator is a mixture of caryophyllene oxide and benzyl cinnamate.

39. The aerosolizable formulation or aerosol formulation according to any one of claims 29 to 38, wherein the active agent is at least nicotine.

40. The aerosolizable formulation or aerosol formulation according to any one of claims 29 to 39, wherein the active agent is at least a cannabinoid.

41. The aerosolizable formulation or aerosol formulation according to any one of claims 29 to 40, wherein the active agent is present in an amount of 6% by weight or less based on the aerosolizable formulation or aerosol formulation.

42. The aerosolizable formulation or aerosol formulation according to claim 41, wherein the active agent is present in an amount of 0.01 to 5% by weight based on the aerosolizable formulation or aerosol formulation.

43. The aerosolizable formulation or aerosol formulation according to any one of claims 29 to 42, further comprising at least one acid.

44. The aerosolizable formulation or aerosol formulation according to claim 43, wherein the acid is selected from the group consisting of acetic acid, lactic acid, formic acid, citric acid, benzoic acid, pyruvic acid, levulinic acid, succinic acid, tartaric acid, sorbic acid, propionic acid, phenylacetic acid, salicylic acid, malic acid, caffeic acid, fumaric acid, nicotinic acid, o-toluic acid, m-toluic acid, p-toluic acid, capric acid, glucono-delta-lactone, gluconic acid, malonic acid, phosphoric acid, 4-hydroxyphenylacetic acid, and mixtures thereof.

45. The aerosolizable formulation or aerosol formulation according to claim 43, wherein the acid is selected from the group consisting of salicylic acid, malic acid, citric acid, succinic acid, caffeic acid, fumaric acid, nicotinic acid, o-toluic acid, m-toluic acid, p-toluic acid, capric acid, glucono-delta-lactone, pyruvic acid, sorbic acid, levulinic acid, tartaric acid, gluconic acid, malonic acid, phosphoric acid, 4-hydroxyphenylacetic acid, and mixtures thereof.

46. The aerosolizable formulation or aerosol formulation according to claim 43, 44 or 45, wherein the total content of the acid present in the formulation is 1.0 molar equivalent or less based on the nicotinic acid.

47. The aerosolizable formulation or aerosol formulation according to any one of claims 43 to 46, wherein the total content of the acid present in the solution is 0.1 molar equivalent or more based on the nicotinic acid.

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