CN108697643A - Nicotine composition for electronic cigarette device and the electronic cigarette device using the composition - Google Patents

Abstract

A kind of composition suitable for electronic cigarette device, it includes nicotine product, which includes synthesis nicotine, the synthesis nicotine substantially free of usually with the relevant one or more pollutants of nicotine and/or impurity from tobacco.For example, the synthesis nicotine is substantially free of nicotine -1';- N- oxides, remove first nicotyrine, 2' at nicotyrine;, one or more in 3- bipyridyls, cotinine, neonicotine and/or anatabine.The composition further includes one or more pharmaceutically acceptable excipient, additive and/or solvent.

Description

Nicotine composition for electronic cigarette device and electronic cigarette using same device

Background technique

Compositions currently used in e-cigarette devices (also referred to herein as "vaping devices" or "vaping devices") typically contain nicotine in dilute liquid form. The nicotine used in this composition is derived from a purified extract of tobacco leaves. These extracts are isolated in a semi-purified form along with many contaminants, many of which have been shown to cause serious disease in serious human systems, including cancer. For example, when tobacco-derived nicotine is purified to a level consistent with the monograph for purity set forth in the United States Pharmacopeia (USP) monograph, tobacco-derived nicotine still contains many contaminants, and since many contaminants are known carcinogens and addictive agents, so these pollutants are likely to cause problems for consumers. In addition, these contaminants contribute to the particular unpleasant taste and odor of commercially available products using tobacco-derived nicotine extracts. Notably, e-cigarette products that use tobacco-derived nicotine typically require relatively large amounts of flavoring agents, as well as other additional masking chemicals, that are added to the composition to mask the difficulty of tobacco-derived nicotine. Smell and/or smell. These masking chemicals and the high volume of flavorings required to mask the unpleasant taste can affect the taste and experience of vaping products and may themselves adversely affect users.

Contents of the invention

According to aspects of various embodiments of the present invention, a composition suitable for vaporization comprising a nicotine product comprising synthetic nicotine free or substantially free of nicotine derived from tobacco typically found in The presence of certain contaminants or impurities such as, for example, nicotine-N'-oxide (e.g. nicotine-1'-N-oxide), diene nicotine (e.g. beta-diene nicotine), cotinine, Nornicotine, 2',3-bipyridine, anabaxine, and/or anatapine. In some embodiments, the composition may further comprise one or more pharmaceutically acceptable carriers, additives and/or excipients.

Other advantages and novel features of the various aspects of various embodiments of the invention will be set forth in part in the following description, and in part will become apparent to those skilled in the art through examination of the following or through practical study.

Description of drawings

Figure 1 is a schematic diagram of a prior art electronic cigarette device that may be used to vaporize a nicotine composition according to aspects of various embodiments of the present invention.

Detailed ways

The following description of certain example embodiments of the invention described below should not be taken to limit the scope of the invention. From the following description, other examples, features, aspects, embodiments, advantages, and one of the best modes considered for implementing the present invention will become apparent to those skilled in the art from the following description, which is provided for the purpose only illustrative, and in no way intended to limit the scope of the invention. It will be appreciated that various modifications may be made to the described embodiments of the invention without departing from the scope of the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive.

According to various aspects of various embodiments of the present invention, a composition suitable for vaporization (also referred to herein as "e-cigarette composition" or "e-cigarette solution") comprising a nicotine product comprising a synthetic Nicotine, said synthetic nicotine is free or substantially free of certain contaminants or impurities normally present in tobacco-derived nicotine, such as, for example, nicotine-N'-oxide (e.g., nicotine-1'-N-oxide ), diene nicotine (such as β-diene nicotine), cotinine, nordiene nicotine, 2',3-bipyridyl, anabaxine, N-methyl anatapine, N - Methylanabaxine, N-methylanabaxine, anabaxine and/or anatapine. For example, in some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of nicotine-N'-oxide (e.g., nicotine-1'-N-oxide), diene smoke Bases (e.g. beta-diene nicotine), cotinine, nordiene nicotine, 2',3-bipyridine, anabaxine, N-methylanastatine, N-methylanastatine Any one or more of Baxin, Anabaxin and/or Anatapine. In some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of nicotine-N'-oxide (e.g., nicotine-1'-N-oxide), diene nicotine (e.g. beta-diene nicotine), cotinine, nordiene nicotine, 2',3-dipyridine, anabaxine, N-methylanastatine, N-methylanaba Combination of any two or more of Xin, Anabaxine and/or Anatapine. In some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of nicotine-N'-oxide (e.g., nicotine-1'-N-oxide), diene smoke Bases (e.g. beta-diene nicotine), cotinine, nordiene nicotine, 2',3-bipyridine, anabaxine, N-methylanastatine, N-methylanastatine All of Baxin, Anabaxin, and/or Anatapine.

According to aspects of various embodiments of the present invention, a composition suitable for vaporization (also referred to herein as "e-cigarette composition" or "e-cigarette solution") comprises a nicotine product comprising synthetic nicotine that is not Contains or is substantially free of diene nicotine (e.g. beta-diene nicotine), cotinine, nordiene nicotine, 2',3-bipyridine, anabacin, N-methylanana Tarapine, N-methylanabaxine, Anabaxine and/or Anatapine. For example, in some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of diene nicotine (e.g., beta-diene nicotine), cotinine, nordiene nicotine, Any one or more of 2',3-bipyridine, anabaxine, N-methylanabaxine, N-methylanabaxine, anabaxine and/or anatapine . In some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of diene nicotine (e.g., beta-diene nicotine), cotinine, nordiene nicotine, 2' , Combination of any two or more of 3-bipyridine, anatabaxine, N-methylanabaxine, N-methylanabaxine, ananabaxine and/or anatapine . In some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of diene nicotine (e.g., beta-diene nicotine), cotinine, nordiene nicotine, 2' , All of 3-bipyridine, Anabaxine, N-methylanabaxine, N-methylanabaxine, Anabaxine and/or Anatapine.

For example, in some embodiments, the e-cigarette composition or e-cigarette solution comprises a nicotine product comprising synthetic nicotine that is free or substantially free of diene nicotine (e.g., beta-diene nicotine), Cotinine, Anabaxine, N-Methylanabaxine, N-Methylanabaxine, Anabaxine, and/or Anatapine. For example, in some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of diene nicotine (e.g., beta-diene nicotine), cotinine, anabacin, N- Any one or more of methylanabaxine, N-methylanabaxine, anatabaxine and/or anatapine. In some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of diene nicotine (e.g., beta-diene nicotine), cotinine, anabacin, N-methyl Combination of any two or more of anatapine, N-methylanabaxine, ananabaxine and/or anatapine. In some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of diene nicotine (e.g., beta-diene nicotine), cotinine, anabacin, N-methyl Anatapine, N-methylanabaxine, all of anabaxine and/or anatapine.

For example, in some embodiments, the e-cigarette composition or e-cigarette solution comprises a nicotine product comprising synthetic nicotine free or substantially free of anabaxin, N-methylanastatine, N-methylanabaxine, cotinine, and/or anatapine. For example, in some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of anabaxine, N-methylanastatine, N-methylanabaxine, alternative One or more of Ning and/or Anatapine. In some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of anabaxine, N-methylanastatine, N-methylanabaxine, cotinine, and and/or two or more of anatarine. For example, in some embodiments, the composition may comprise synthetic nicotine that is free or substantially free of anabaxine, N-methylanastatine, N-methylanabaxine, alternative Two or more of Ninglin and/or Anatapine.

Those of ordinary skill in the art will be aware of known methods for determining the presence of the compounds and impurities discussed herein. However, a non-limiting example of a suitable method for determining the presence or absence of these impurities in a particular composition includes USP-HPLC, High Performance Liquid Chromatography according to USP standards, which is capable of testing nicotine derived from tobacco or the major Impurities (including, for example, cotinine and anatapine). One of ordinary skill in the art should be able to readily practice this method and will recognize that measurable amounts of any impurities or contaminants present in the tobacco-derived nicotine indicate that the composition is natural or tobacco-derived. nicotine.

Synthetic nicotine according to embodiments of the present invention is distinct from and distinguishable from its tobacco-derived or natural counterparts. Specifically, as discussed further in the Examples section herein, synthetic nicotine according to embodiments of the present invention provides an improved overall "vaping" experience that maintains a satisfactorily strong brain impact It also reduces the uncomfortable throat sensation that accompanies smoking "vapes" with tobacco-derived nicotine or natural nicotine. The impurities discussed above are one way to physically and chemically distinguish synthetic nicotine according to embodiments of the present invention from tobacco-derived or natural nicotine. However, other methods can be used to differentiate synthetic nicotine from natural nicotine. For example, since natural nicotine is derived or extracted from living tobacco plants, nicotine obtained from this source will inherently contain measurable amounts of radioactive isotopes such ^as14C , ^13C and D. See Randolph A. Culp et al., "Identification of Isotopically Manipulated Cinnamic Aldehyde and Benzaldehyde," J. Agric. Food Chem., 1990, 38, 1249-1255; and Randolph A. Culp et al., "Determination of Synthetic Components in Flavors by Deuterium /Hydrogen Isotopic Ratios", collectively referred to herein as the "Culp Reference", the entire contents of both are incorporated herein by reference. As noted in the Culp reference, compounds of natural (or plant-derived) origin can be determined by isotopic analysis for ¹⁴ C levels and the isotopic abundances of ¹³ C and D (commonly denoted δ ¹³ C and δD, respectively). δ ¹³ C and δD readings refer to isotopic abundance, ie the ratio of heavy isotopes (eg ¹³ C or D) to light isotopes (eg ¹² C or H). As discussed in the Culp reference, these ratios differ significantly in the corresponding synthetic compounds and compounds of natural or plant origin. Thus, in some embodiments of the invention, synthetic nicotine has a different isotopic abundance (eg, δ ¹³ C and δD values) and/or ¹⁴ C levels than natural or tobacco-derived nicotine. For example, in some embodiments, synthetic nicotine has lower isotopic abundance (eg, δ ¹³ C and δD values) and/or ¹⁴ C levels than natural or tobacco-derived nicotine. For example, in some embodiments, synthetic nicotine may ^have14C levels of up to about 10 dpm/gC (decays per gram of carbon per minute). For example, in some embodiments, synthetic nicotine may have a ¹⁴ C level of about 0.1 to about 9 dpm/gC, or in some embodiments about 2 to about 8 dpm/gC, or about 3 to about ⁸ dpm/gC. ¹⁴ C levels of gC. For example, in some embodiments, synthetic nicotine may have a14C level of about 3.5 to about 7dpm/gC, or ^a14C level of about 4 to about ^6dpm /gC. This compares to 14.0dpm/gC in 2015 and the current reference standard. Thus, synthetic nicotine according to embodiments of the present invention has significantly different14C levels than natural ^nicotine (ie based on 2015 and current reference standards ^for14C activity). For example, in some embodiments, the synthetic nicotine has ^a14C level of up to about 72% of natural nicotine, or has ^a14C level of about 0.5% to about 65% of natural nicotine. For example, in some embodiments, the synthetic nicotine has a14C level of about ¹⁴ % to about 58% of natural nicotine, or ^a14C level of about 20% to about 58% of natural nicotine. For example, in some embodiments, the synthetic nicotine has ^a14C level of about 25% to about 50% of natural nicotine, or ^a14C level of about 28% to about 43% of natural nicotine.

As mentioned above, ¹⁴ C, an unstable radioactive isotope of carbon, has different radioactivity depending on its age, for example, the older it is, the less radioactive it is. Comparing the radioactivity of natural or tobacco-derived nicotine (eg, United States Pharmacopeia (USP)) standards with those of synthetic samples provides a way to determine the source of nicotine. For example, if nicotine is petroleum-based, it will be significantly less radioactive than natural or tobacco-derived nicotine. However, some synthetic nicotine can be made from chemicals derived from living plants such as sugar cane or corn. In order to differentiate nicotine derived from tobacco from nicotine derived from sugar crops or from maize, the amount of stable isotopes of carbon can be determined. Since sugarcane and maize are plants of a different class than tobacco, they metabolize heavy isotopes of carbon (C ¹³ ) and water (D ₂ O) to a different extent than tobacco plants. Therefore, if the comparative measurements of these stable isotopes are different, then the nicotine can be determined not to come from tobacco; and if the comparative measurements are similar, then the nicotine can be determined to be from tobacco. For example, natural nicotine has a δ ¹³ C ( ¹³ C/ ¹² C) of about -30 to -32 ppm relative to the international standard PDB (±σ). In contrast, synthetic nicotine may have from about -20 to about -29 ppm relative to International Standard PDB (±σ), or from about -23 to about -29 ppm relative to International Standard PDB (±σ) according to embodiments of the present invention δ ¹³ C. For example, in some embodiments, the synthetic nicotine may have a δ13C of about -25 to about ^-28.5 ppm relative to the International Standard PDB (±σ), or about -26 to about - 28.5 ppm of δ ¹³ C. Thus, synthetic nicotine according to embodiments of the present invention may have a δ ¹³ C of about 66% to about 97% of natural nicotine, or a δ ¹³ C of about 76% to about 97% of nicotine. For example, in some embodiments, synthetic nicotine according to embodiments of the invention may have a δ ¹³ C of about 83% to about 95% of natural nicotine, or a δ ¹³ C of about 87% to about 95% of nicotine.

In addition, natural nicotine has a δD(D/H) of about -170 to -171 ppm relative to the international standard V-SMOW (±σ). In contrast, according to embodiments of the present invention, synthetic nicotine may have a δD of about -140 to about -160 ppm relative to the international standard V-SMOW (±σ), or about Delta D of -145 to about -160 ppm. For example, in some embodiments, the synthetic nicotine may have a δD of about -150 to about -160 ppm relative to the International Standard V-SMOW (±σ), or about -152 to about Delta D of -158ppm. Thus, synthetic nicotine according to embodiments of the present invention may have a delta D of about 82% to about 95% of natural nicotine, or a delta D of about 85% to about 95% of nicotine. For example, in some embodiments, synthetic nicotine according to embodiments of the invention may have a delta D of about 88% to about 95% of natural nicotine, or about 89% to about 93% of nicotine.

The composition may further comprise one or more pharmaceutically acceptable excipients, additives and/or carriers. As used herein, the term "substantially" is used as a term of approximation, rather than a term of degree, and is intended to account for the possibility of incidental impurities in the listed components. For example, the term "substantially free" of a listed compound means that the composition does not include added amounts of the listed compound, and that any such component is included in the composition only as an accompanying impurity in negligible amounts, which does not contribute to The function or property of the composition contributes. In contrast, a composition that is "free" or "completely free" of a listed compound does not contain measurable amounts of the listed components.

In various aspects of various embodiments of the invention, compositions for use in electronic smoking devices may include nicotine. The composition may be a solid or a liquid mixture, such as a liquid, and may comprise from about 0.001 wt% to about 0.50 wt% nicotine, such as from about 0.1 wt% to about 0.40 wt% nicotine, or about 0.2 wt% to about 0.35 wt% nicotine. In some embodiments, the composition may comprise about 0.3 wt% nicotine. On a weight per volume basis, the composition may comprise nicotine from about 0.1 mg/ml to about 50 mg/ml of the total volume of the composition, for example from about 1 mg/ml to about 40 mg/ml of nicotine, or from about 2 mg/ml to about 35mg/ml of nicotine. For example, in some embodiments, the composition may comprise about 30 mg/ml nicotine.

At least a portion of the nicotine present in the composition is synthetic. As used herein, the term "synthetic" means that the referenced compound (eg, nicotine) is prepared by chemical methods that do not include making/extracting nicotine from naturally occurring sources (eg, tobacco leaves). The terms "tobacco-derived" and "non-synthetic" are used interchangeably herein and mean that the referenced compound or composition is prepared or extracted from a natural source such as, for example, tobacco. For example, as used herein, "nicotine derived from tobacco" or "non-synthetic nicotine" refers to nicotine made or extracted from tobacco leaves and does not include nicotine prepared by separate chemical synthesis. In various aspects of the various embodiments of the invention, the corresponding fraction of synthetic nicotine may be in any amount sufficient to provide the user with similar or better Taste, function and feeling. For example, synthetic nicotine may be present in an amount of about 1% by weight or greater, such as about 5% by weight or greater, about 10% by weight or greater, about 20% by weight or greater, as part of the total amount of nicotine present in the composition , about 30 wt% or greater, about 40 wt% or greater, about 50 wt% or greater, about 60 wt% or greater, about 70 wt% or greater, about 80 wt% or greater, about 90 wt% or greater, About 95% by weight or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or positive amounts up to about 100% by weight (ie, greater than 0%). When less than 100% by weight of the nicotine in the composition is synthetic, the remainder of the nicotine may be tobacco derived nicotine.

According to some embodiments, the synthetic nicotine in the composition may be prepared by any suitable method, non-limiting examples of which include the methods disclosed in U.S. Patent Nos. 8,367,837, 8,378,110, and 8,389,733, and European Patent No. EP 2487172, all of which are incorporated in their entirety by Incorporated herein by reference. For example, in some embodiments, 1-(butyl-1-enyl)pyrrolidin-2-one as generally described in U.S. Pat. It can be condensed with nicotinic acid ester to give 1(butyl-1-enyl)-3-nicotinoylpyrrolidin-2-one, which can then be treated with acid and base to give mioxamine, followed by reduction and Subsequent N-methylation converts it to (R,S)-nicotine. An example of this reaction scheme is shown below, reproduced from US Patent Nos. 8,367,837, 8,378,110 and 8,389,733 and European Patent No. EP 2487172 to Divi et al.

In some embodiments, the synthetic nicotine in the composition can be prepared by the synthetic route given in Scheme 1:

In the synthetic route described in Scheme 1, the condensation reaction to form carbon-carbon bonds is first carried out under anhydrous conditions. In this condensation reaction, an appropriate amount of nicotinic acid ester (1) is combined with a suitable N-vinylogous-2-pyrrolidone (2) using a suitable dry solvent and a suitable strong base (such as metal hydride). Condenses under mild conditions. The condensation reaction gave good yields of the condensation adduct as its metal salt.

In some embodiments, the condensation reaction mixture employs an alkyl ester of nicotinic acid and N-vinyl-2-pyrrolidone and a metal hydride base in a suitable dry solvent. In some embodiments, the nicotinic acid alkyl ester comprises a short chain alkyl group (eg, R1 in compound (1) can be C _1-3 , or in some embodiments can be C ₂ ). In some embodiments, the N-alkenyl-2-pyrrolidone may comprise a vinyl substituent with a short chain alkyl group. In some embodiments, R2 in compound ( ₂ ) can be a short chain (eg, C _1-10 ) alkyl group (such as (eg,) methyl, isopropyl, etc.), or in some embodiments, R2 is Hydrogen (H). In some embodiments, the N-alkenyl-2-pyrrolidone is n-vinyl-2-pyrrolidone.

The amount (in relative moles) of the metal hydride employed in the condensation reaction mixture is from about 0.1 parts to about 2.5 parts, such as from about 1.2 parts to about 2.1 parts, or from about 1.8 parts to about 2 parts, relative to 1 part nicotinic acid ester. share. In some embodiments, the molar ratio of metal hydride to nicotinate is about 1 to 4, eg, about 1:2 to about 1.6:2, or about 2:2. In some embodiments, the metal in the metal hydride may be lithium, potassium or sodium, such as potassium or sodium, or in some embodiments sodium.

The amount of N-alkenyl-2-pyrrolidone may be from about 0.1 parts to about 10 parts, such as from about 0.5 parts to about 3 parts, relative to the amount (in molar equivalents) of nicotinic acid ester used in the condensation reaction mixture, or From about 1.0 parts to about 1.2 parts.

The amount of solvent employed in the condensation reaction mixture may be from about 1 part to about 15 parts, such as from about 3 parts to about 10 parts, from about 4 parts to about 8 parts, relative to 1 part (in molar equivalents) of nicotinic acid ester, or About 5 servings to about 7 servings. In some embodiments, the solvent can be anhydrous. Non-limiting examples of suitable solvents include aromatic hydrocarbons or hydrocarbon solvents, dipolar aprotic solvents such as, for example, dimethylformamide (DMF), ethers such as, for example, diethyl ether, tetrahydrofuran (THF) or tetrahydrofuran derivatives), polyethers (such as (for example) "glyme" or "diglyme"), and combinations thereof. Non-limiting examples of suitable aromatic hydrocarbons or hydrocarbon solvents include alcohols, toluene, xylenes, benzene, and the like. For example, in some embodiments, the solvent is alcohol, or a mixture of alcohol and ether. In some embodiments, the solvent may be THF, or a mixture of DMF and ether, and/or a mixture of DMF and a hydrocarbon or aromatic hydrocarbon. In some embodiments, the solvent may be toluene (or benzene). Alcohols, such as ethanol, methanol, and/or propanol, can be added to help catalyze the condensation reaction, or alcohols can be used as the sole solvent. If an alcohol is used as a solvent or co-solvent in the condensation reaction, then less than or equal to the stoichiometric amount relative to nicotinic acid ester, metal sodium, potassium or lithium can be used. In some embodiments, the solvent is added at such a time that mild effervescence is maintained throughout the addition and an internal temperature of between 50°C and 80°C is maintained. Addition time varies with volume, but can occur on the order of minutes to hours.

The condensation reaction mixture turned green after the solvent was added to the nicotinate and N-alkenyl-pyrrolidone. In some embodiments, the green condensation reaction mixture can be stirred under an inert atmosphere for a suitable amount of time to complete the reaction. In some embodiments, the green condensation reaction mixture is heated to an internal temperature of from about 40°C to about 110°C, such as from about 60°C to about 100°C, or from about 80°C to about 95°C.

Following the reaction of nicotinate with N-alkenyl-2-pyrrolidone, the condensation reaction mixture may contain a reaction product mixture comprising some unreacted starting materials (i.e. nicotinate, n-alkenyl-2-pyrrolidone, hydrogenated sodium), and the target reaction product, the main condensation reaction product, which is nicotinate-n-alkenyl-2-pyrrolidone adduct (the condensation reaction adduct, which is a metal Salts such as 1-(1-alkenyl)-3-nicotinoylpyrrolidin-2-one, wherein in some embodiments the alkenyl group may be vinyl), metal salts of alcohols, and Some alcohols replaced by alcohols.

After the reaction is completed due to the effect of the condensation reaction mixture, the reaction product mixture may be directly injected (or poured) into the acid solution to form an acid reaction mixture. The acid solution may be a boiling acid solution, or a cold aqueous acid solution. In some embodiments, the acid is aqueous hydrochloric acid. In some embodiments, the acid solution may have a normality of about 3 to about 12, such as about 4 to about 7 or about 5 to about 6.

According to some embodiments, the acid reaction mixture may be prepared by cooling the completed condensation reaction mixture to ambient temperature and then injecting the cooled condensation reaction mixture into the cold acid solution. The amount of acid may be from about 0.25 parts to about 5 parts, such as from about 0.5 parts to about 2 parts or from about 0.75 parts to about 1.5 parts, relative to 1 part of the condensation reaction mixture.

The reaction of the acid reaction mixture produces a biphasic mixture in which a protonated bicyclic pyridine-pyrrolidone adduct (ie, a protonated condensation reaction adduct) soluble in water but insoluble in organic solvents is present in the aqueous phase (or layer) , while any unreacted pyrrolidone starting material is in the organic phase (or layer). When the reaction is allowed to stand without stirring, two distinct layers are formed, an aqueous layer and an organic layer (non-aqueous layer), and the reaction product is in the aqueous layer, which is then separated and subjected to further reaction or processing.

After acid addition, the aqueous and organic (non-aqueous) layers were separated, and concentrated acid was added to the separated aqueous layer to form an aqueous reaction mixture. The aqueous reaction mixture is then heated to reflux for an appropriate period of time to complete the reaction.

The amount of concentrated acid added to the separated aqueous layer to form the aqueous reaction mixture may be from about 0.15 parts to about 1.5 parts, such as from about 0.2 parts to about 0.5 parts or from about 0.25 parts to about 0.5 parts, relative to 1 part of the separated aqueous layer . In some embodiments, the concentrated acid may be 12N hydrochloric acid (concentrated hydrochloric acid [approximately 37%]).

Aqueous Reaction Mixture After the reaction is complete, the aqueous reaction mixture consists of water, acid and product (ie protonated acyclic amine salt, eg protonated 3-(4-aminobutanyl-1-one)-pyridine).

After the reaction of the aqueous reaction mixture is complete, the aqueous reaction mixture can be cooled to -10°C to 5°C. The acidic aqueous reaction mixture (or solution) can then be made strongly alkaline (eg, pH greater than 9) while maintaining the temperature at an appropriate level to sustain the reaction. The product of this reaction is a meoxamine reaction mixture consisting of meoxamine, base, water, and any remaining unreacted material from the aqueous reaction mixture and any contaminants inherent to the reaction. The obtained alkaline aqueous reaction mixture is extracted with an organic solvent, and then the solvent is distilled off to obtain crude mioxamine. In some embodiments, the organic solvent can be dichloromethane. In some embodiments, the amount of organic solvent may be from about 1 part to about 10 parts relative to the amount of the basic aqueous reaction mixture, such as from about 1.5 parts to about 5 parts or about 2 parts relative to the basic aqueous reaction mixture to about 4 servings.

In some embodiments, the reacted condensation reactants can be injected directly into the hot hydrochloric acid solution (instead of the cold acid solution described above), resulting in a heterogeneous acid reaction mixture. The heterogeneous acid reaction mixture can be heated using an external bath such that vigorous reflux is effected and continued until the reaction is complete. In this hot acid alternative embodiment, the solvent used for the condensation reaction mixture may be toluene or xylene, or a high boiling point solvent such as diglyme.

To reduce the crude mioxamine product to the crude nornicotine product, a suitable amount of a suitable hydrogenation catalyst is added to a solution of crude mioxamine (3) with a suitable solvent to form a misoxamine reaction mixture. To accomplish the reduction of the meoxamine to nornicotine, the meoxamine reaction mixture is subjected to an atmosphere of hydrogen at a pressure greater than or equal to ambient pressure (but not high enough to reduce the carbon in the pyridine ring).

In some embodiments, the solvent used in the mioxamine reaction mixture can be an alcoholic solvent, such as ethanol or isopropanol, although other hydrogenation solvents known in the art can also be used. The amount of solvent may be from about 3 parts to about 98 parts, such as from about 4 parts to about 60 parts, or from about 5 parts to about 20 parts of solvent relative to 1 part of crude mioxamine. In some embodiments, a suitable hydrogenation catalyst may include 10% palladium on carbon, but other catalytic hydrogenation catalysts conventional in the art may also be used, either as a cocatalyst, or as the sole catalyst. The hydrogen pressure may be from about ambient pressure to about 100 atmospheres, such as from about ambient pressure to about 75 atmospheres, or from about 10 to about 50 atmospheres.

In some embodiments, the mioxamine reaction mixture can include a borohydride salt as a reducing agent instead of a hydrogenation catalyst, and the mioxamine reaction mixture can be subjected to a reaction suitable for reducing the mioxamine to normethoxamine using a borohydride salt. Different reaction conditions of nicotine.

Completion of the Mioxamine Reaction Mixture Reaction produces a Crude Nornicotine Reaction Mixture which includes Nornicotine (reduction product), catalyst and solvent, as well as any unreacted starting material (crude Mioxamine) and unwanted reaction contamination things. The crude nornicotine product (4) is extracted from the crude nornicotine reaction mixture using known extraction methods.

Water, formic acid and formaldehyde are added to the crude nornicotine (4) product to form a crude nicotine reaction mixture. The crude nicotine reaction mixture is heated to a suitable temperature for a period of time to allow the methylation reaction to complete to give crude nicotine in good yield.

Crude Nicotine Reaction Mixture When the reaction is complete, the resulting mixture contains crude RS-nicotine product, solvent (water), and any unreacted starting materials (including formaldehyde and formic acid), as well as reaction contaminating by-products.

The product of the crude nicotine reaction mixture, i.e. crude RS-nicotine, may be subjected to at least one high vacuum distillation in order to obtain pure (i.e. greater than 95% pure, e.g. greater than 97% pure, greater than 99% pure, or greater than 99.5% pure) RS-nicotine as a clear colorless and non-viscous liquid.

Synthetic nicotine produced according to the chemical synthesis described above is substantially free or completely free of certain contaminants normally present in natural nicotine derived from tobacco leaves. In some embodiments, the synthetic nicotine can be substantially free of these contaminants such that the combined amount of these contaminants in the synthetic nicotine can be greater than 0 wt % but less than 0.5 wt %, such as less than 0.2 wt %, based on the total weight of the synthetic nicotine , less than 0.01 wt%, less than 0.001 wt%, less than 0.0001 wt%, or less than 0.00001 wt%. As discussed above, completely free or free of these contaminants means that the synthetic nicotine does not contain measurable amounts of these contaminants, ie 0 wt% (or none). In some embodiments, the synthetic nicotine is substantially free or completely free of contaminants, such as alkaloid compounds, which may be found in tobacco-derived nicotine. For example, synthetic nicotine may be substantially free or completely free of nicotine-1'-N-oxide, nicotine diene, nornicotine nordiene, 2',3-bipyridine, anabaxine, and anabacin One or more or all of the other drugs Although these contaminants may be included among the most common impurities or contaminants in tobacco-derived nicotine, other naturally occurring contaminants or impurities may be present in tobacco-derived nicotine , and the synthetic nicotine according to embodiments of the present invention is also substantially free or completely free of those contaminants and impurities.

However, while synthetic nicotine according to embodiments of the present invention may be substantially free or completely free of certain contaminants commonly found in tobacco-derived nicotine, as discussed above, synthetic nicotine may contain Certain other impurities or contaminants. While such contaminants and impurities may be present in synthetic nicotine according to embodiments of the present invention, these impurities are generally absent in nicotine derived from tobacco or derived from natural sources. In fact, the contaminants/impurities present in nicotine derived from natural sources (or tobacco derived) are significantly different from those that may be present in synthetic nicotine according to embodiments of the present invention. For example, contaminants or impurities present in the synthesis of nicotine according to embodiments of the present invention may include one of the solvents (discussed above) used in the various reactions of the synthetic scheme (discussed above) one or more or all. Additionally, in some embodiments, contaminants or impurities present in synthetic nicotine may include one or more of 1-keto-5-methylamino, or 1-hydroxy-5-methylamino-2-pyridine species or all. As used herein, the terms "synthetic contaminants," "synthetic impurities," and similar terms are used interchangeably and refer to synthetic nicotine present in but derived from natural sources (or derived from tobacco) according to embodiments of the present invention. These contaminants and/or impurities are not normally present in nicotine.

For example, the synthetic nicotine may comprise from about 0% by weight (i.e., no appreciable or measurable amount) to about 5% by weight of meoxamine, based on the total weight of the synthetic nicotine, such as about 0% by weight (i.e., no appreciable or measurable amount). amount) to about 1 wt%, about 0 wt% (ie no detectable or measurable amount) to about 0.5 wt% of mioxamine. In some embodiments, the synthetic nicotine may comprise from about 0 wt % (i.e., no detectable or measurable amount) to about 5 wt % nornicotine, based on the total weight of the synthetic nicotine, such as about 0 wt % (i.e., no detectable amount) or immeasurable amount) to about 3 wt%, or about 0 wt% (ie, no detectable or measurable amount) to about 1 wt% of nornicotine. In some embodiments, the synthetic nicotine may comprise from about 0 wt % (i.e., no appreciable or measurable amount) to about 5 wt % solvent, such as about 0 wt % (i.e., no appreciable or non-measurable amount), based on the total weight of the synthetic nicotine. measured amount) to about 3 wt%, or about 0 wt% (ie, no appreciable or measurable amount) to about 1 wt% solvent. Additionally, in some embodiments, the synthetic nicotine may comprise from about 0 wt % (i.e., no appreciable or measurable amount) to about 5 wt % water, such as about 0 wt % (i.e., no appreciable amount), based on the total weight of the synthetic nicotine. or immeasurable amount) to about 3 wt%, or about 0 wt% (ie, no appreciable or immeasurable amount) to about 1 wt% of water.

The synthesis of nicotine as described above produces a racemic mixture, ie a 50-50 mixture of the R and S isomers of nicotine. Thus, in some embodiments, the synthetic nicotine comprises a 1:1 R-isomer/S-isomer ratio. However, in some embodiments, the R-isomer/S-isomer ratio can be manipulated by further resolution of synthetic nicotine. For example, synthetic nicotine can have about 1:1 to about 1:1000, about 1:1.1 to about 1:100, about 1:2 to about 1:5, about 1:4 to about 1:9, or about 1:1:1. R-isomer/S-isomer ratio of 5 to about 1:7. In some embodiments, synthetic nicotine may comprise from about 1:1 to about 1000:1, from about 1.1:1 to about 100:1, from about 2:1 to about 5:1, from about 4:1 to about 9:1, Or an R-isomer/S-isomer ratio of about 5:1 to about 7:1.

For example, in some exemplary embodiments, the synthetic nicotine comprises an S-isomer/R-isomer ratio of less than 50:1, such as 45:1 or less, 40:1 or less, or 35:1 or lower S-isomer/R-isomer ratio. In some embodiments, synthetic nicotine may comprise an R-isomer/S-isomer ratio of less than 50:1, such as 45:1 or less, 40:1 or less, or 35:1 or less The R-isomer/S-isomer ratio. Additionally, in some embodiments, the synthetic nicotine may comprise the R-isomer in an amount greater than 5 wt%, such as greater than 7 wt%, or in an amount greater than 10 wt%. In some embodiments, the synthetic nicotine may comprise the S-isomer in an amount greater than 5 wt%, eg, the S-isomer in an amount greater than 7 wt%, or greater than 10 wt%. In some embodiments, the synthetic nicotine comprises more R-isomer than S-isomer, and in some embodiments, synthetic nicotine comprises more S-isomer than R-isomer.

This R/S isomer ratio in the synthetic product is yet another feature that distinguishes synthetic nicotine according to embodiments of the present invention from natural or tobacco-derived nicotine. In fact, a simple test to determine the chirality of a sample can be performed to determine whether the sample contains natural nicotine or synthetic nicotine according to embodiments of the present invention. Techniques for determining the chirality or optical rotation of a sample are known to those of ordinary skill in the art, and one of ordinary skill will be able to readily select an appropriate technique and implement the technique to determine chirality or optical rotation. A non-limiting example of such a technique is high performance liquid chromatography (HPLC) using a chiral column. For example, the optical activity of a sample can first be determined by any suitable technique (which is known to those of ordinary skill in the art), the sample can then be passed through a chiral column, and the results compared to those used for tobacco-derived nicotine or USP standards for natural nicotine for comparison.

Synthetic nicotine containing a racemic mixture of R and S isomers may be resolved by any suitable resolution technique that yields the relative amounts of these R and S isomers Known to those skilled in the art (eg crystallization, chromatography, etc.). Additionally, in some embodiments, synthetic nicotine can be completely resolved to yield either a pure R-isomer or a pure S-isomer. As used herein, the term "pure" used to define the isomeric composition of synthetic nicotine means that the percentage of the mentioned isomer is greater than 97%, such as greater than 98%, and in some embodiments greater than 99%. %. For example, "pure S isomer" synthetic nicotine comprises an S isomer/R isomer that is resolved to comprise greater than 97:3, such as greater than 98:2, and in some embodiments greater than 99:1 than synthetic nicotine. Similarly, "pure R isomer" synthetic nicotine comprises an R isomer/S isomer resolved to comprise greater than 97:3 (e.g. greater than 98:2, and in some embodiments greater than 99:1) body ratio of synthetic nicotine. However, in some embodiments, a pure R isomer may comprise 100% of the R isomer and 0% of the S isomer, while a pure S isomer may comprise 100% of the S isomer and 0% R isomer.

As noted above, the synthetic nicotine composition may be resolved using any suitable resolution technique, known to those of ordinary skill in the art. Some non-limiting examples of resolution techniques include those described in: Divi et al., U.S. Patent Publication No. 2012/0197022, filed April 6, 2011, J. Med. Chem., Aceto et al., " Optically Pure(+)-Nicotine from(±)-Nicotine and BiologicalComparisons with(-)-Nicotine" , Vol. 22, pp. 174-177 (1979), and DeTraglia et al., "Separation of D-(+)-Nicotine from a Racemic Mixture by Stereospecific Degradation of the L-(-)Isomer with Pseudomonas putida (using malodorous fake Stereospecific Degradation of the L-(-) Isomer by Monastridia Separation of D-(+)-Nicotine from a Racemic Mixture), Applied and Environmental Microbiology, Volume 39, Pages 1067-1069 (1980) , the entire contents of which are incorporated herein by reference. For example, resolution of racemic mixtures can be accomplished using D-tartaric acid as described by Aceto et al., and using Pseudomonas putida as described by DeTraglia et al. Additionally, in some embodiments, resolution of the racemic mixture can be accomplished using (+)-O,O'-di-p-toluoyl-D-tartaric acid. Alternatively, as described by Divi et al., resolution of racemic mixtures can be accomplished by using dibenzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid to form diastereomeric salts to achieve separate.

However, in some embodiments, the racemic mixture can be blended or mixed with a suitable additional amount of the pure R isomer or the pure S isomer, where the pure isomer is usually determined by enantioselective prepared by synthetic route. In particular, nicotine derived from natural sources (ie nicotine derived from tobacco leaves) usually has no detectable or small amounts of the R isomer, whereas tobacco derived from natural sources usually contains mainly the S isomer. Indeed, tobacco derived from natural sources typically has an S/R isomer ratio greater than 50:1.

As discussed above, according to some embodiments of the invention, synthetic nicotine may comprise a mixture of R and S isomers, whether racemic or otherwise. Those of ordinary skill in the art will appreciate that nicotine derived from tobacco (or derived from natural sources) typically has greater than 95% by weight of the S isomer and is therefore optically active. Indeed, tobacco-derived nicotine (with 95% by weight or more of the S nicotine isomer) has a negative optical rotation, typically greater than 125°, when measured using a standard polarimeter. In contrast, according to embodiments of the present invention, synthetic nicotine may comprise a racemic (or 1:1) mixture of the R and S isomers, resulting in nicotine that is not optically active. Additionally, in embodiments of the invention where nicotine is synthesized comprising a non-racemic mixture of R and S isomers, the synthetic product has an optical activity different from that of tobacco-derived nicotine (i.e. due to the presence of R isomer, which generally has the opposite optical activity to the S isomer).

As discussed above, nicotine derived from tobacco (or derived from natural sources) may contain one or more or all of the following impurities: nicotine-1'-N-oxide, nicotine diene, nor Diene nicotine, 2',3-bipyridine, cotinine, anabaxine, anatapine, nornicotine, and methoxamine. For example, tobacco-derived nicotine may comprise 99.5 wt% nicotine, 0.1 wt% nornicotine, 0.15 wt% meoxamine and 0.1 wt% cotinine. As mentioned above, according to some embodiments of the present invention, the electronic cigarette composition or electronic cigarette solution may contain both the above-mentioned synthetic nicotine and a certain amount of natural source (or tobacco derived) nicotine. In these embodiments of the e-cigarette composition comprising naturally derived nicotine, the portion of the composition that makes up the tobacco derived nicotine may comprise, for example, the above amounts of these components (or contaminants). However, those of ordinary skill in the art will understand that since nicotine derived from natural sources (or nicotine derived from tobacco) only constitutes a part of the electronic cigarette composition or electronic cigarette solution, these natural tobacco pollutants in the entire electronic cigarette composition The amount is significantly lower than the amounts listed above, and is significantly lower than the amount in similar electronic cigarette compositions or solutions that use a larger proportion (or all use) of nicotine derived from natural sources.

In addition to the above-discussed synthetic nicotine and/or nicotine derived from natural sources, compositions for use in electronic cigarette devices (i.e., electronic cigarette compositions or electronic cigarette solutions) may further comprise one or more pharmaceutically acceptable Acceptable excipients, additives or solvents consisting essentially of one or more pharmaceutically acceptable excipients, additives or solvents, or consisting of one or more pharmaceutically acceptable excipients, additives or solvents Solvent composition. Non-limiting examples of such excipients, additives and/or solvents include water, organic solvents, sweetening and/or flavoring agents, pH adjusters, and the like. Non-limiting examples of solvents that can be used in liquid e-cigarette compositions include water, and alcohols such as 1,2-propanediol (PG or MPG), ethanol, ethyl acetate, 1-3 propylene glycol, glycerin (such as vegetable glycerin), etc. Wait. The solvent may include a single solvent, or may include a combination of two or more solvents. The solvent may be present in an amount from about 50 wt% to about 99.99 wt%, such as from about 75 wt% to about 99 wt%, or from about 85 wt% to about 98 wt%, based on the total weight of the composition.

In some embodiments, the e-cigarette composition may include water as a solvent. The amount of water present in the e-cigarette composition may be from about 0.1 to about 10 wt%, such as from about 0.5 to about 5 wt%, based on the total weight of the e-cigarette composition.

In some embodiments, the e-cigarette composition may include glycerin as a solvent, and the glycerin may be Kosher vegetable glycerin having a purity greater than 99%, such as greater than 99.5% or greater than 99.9%. Glycerin can be odorless, colorless and has a slightly sweet taste.

In some embodiments, the e-cigarette composition may include propylene glycol as a solvent, which may be USP grade and have a purity greater than 99%, such as greater than 99.5% or greater than 99.99%. Propylene glycol can be odorless, colorless, and essentially odorless. In some embodiments, the e-cigarette composition may comprise a solvent comprising, consisting essentially of, or consisting of glycerin and propylene glycol.

In some embodiments, the pH of the electronic cigarette composition can be adjusted by adding a pharmacologically or pharmaceutically acceptable acid as a pH adjusting agent. In some embodiments, the acidic pH adjuster can be a mineral acid. Non-limiting examples of suitable inorganic acid pH adjusters include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and/or phosphoric acid. In some embodiments, the mineral acid may include hydrochloric acid and/or sulfuric acid (ie, a mineral acid or a mixture of mineral acids).

In some embodiments, the acid pH adjuster can be an organic acid. Non-limiting examples of suitable organic acids include: lactic acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid, among others. For example, in some embodiments, the organic acid may be lactic acid, ascorbic acid, fumaric acid, and/or citric acid (ie, an organic acid or a mixture of organic acids). For example, in some embodiments, the organic acid includes citric acid and/or lactic acid.

In some embodiments, the acidic pH adjusting agent may be an acid capable of forming an acid addition salt with the active material. In addition, a single acid pH adjuster may be used, or a mixture of two or more acid pH adjusters may be used, if desired. Indeed, some acids have other properties that make them desirable for inclusion in e-cigarette compositions. For example, some acids may have pH adjusting (or acidifying) properties in addition to auxiliary properties or other properties such as, for example, flavoring properties or antioxidant properties. Some non-limiting examples of such bifunctional acids include citric acid and ascorbic acid.

In some embodiments, the pH adjusting agent can be alkaline, or the e-cigarette composition can include an additional alkaline pH adjusting agent (eg, in addition to an acidic pH adjusting agent). For example, alkaline pH adjusters may be used or desired to more accurately titrate the pH of the e-cigarette composition. Thus, in some embodiments, the pH adjusting agent may comprise (or further comprise) an alkaline pH adjusting agent, which may comprise a pharmacologically acceptable base. Non-limiting examples of suitable such bases include alkali metal hydroxides and alkali metal carbonates. In some embodiments, the alkali ion in the alkali metal hydroxide or carbonate may be sodium. In embodiments where such basic pH adjusting agents are used, one of ordinary skill in the art will appreciate that care must be taken to ensure that the resulting salt (which will then be included in the finished pharmaceutical formulation) is pharmacologically compatible with the acids described above. Acid compatibility of pH adjusters.

Those skilled in the art will appreciate that the amount of pH adjusting agent (whether acid or base) will depend on the desired target and starting pH of the composition. Indeed, pH adjustment and titration techniques and amounts added are well within the knowledge and ability of those of ordinary skill in the art.

In some embodiments, as discussed above, the e-cigarette composition may further comprise a pharmacologically or pharmaceutically acceptable excipient. Excipients can include any of a number of compounds, some non-limiting examples of which include antioxidants such as ascorbic acid found in the human body (which can also be used to adjust pH as discussed above), vitamin A, vitamin E, tocopherols and similar vitamins or provitamins. Other non-limiting examples of suitable excipients include preservatives, which may be added to protect the formulation from contamination by, for example, pathogenic bacteria. Any suitable preservative may be used, including those known in the art. Some non-limiting examples of suitable preservatives include benzalkonium chloride, benzoic acid or a salt of benzoate (such as sodium benzoate). In some embodiments, preservatives may include benzalkonium chloride. Any suitable amount of preservative can also be used, the amount (or concentration) of which will be known to those skilled in the art.

In some embodiments, the electronic cigarette composition may further include sweeteners and/or flavoring agents. Any suitable sweetening and/or flavoring agent may be used, some non-limiting examples of which include peppermint, menthol, oil of wintergreen, spearmint, propolis wax, eucalyptus, cinnamon essential oil, and the like. Some additional non-limiting examples of suitable flavoring or sweetening agents include those derived from fruit, tobacco itself, spirits, coffee and candies. The amount of sweetener and/or flavoring agent may be from about 0 wt% (for example, no flavoring agent is present, or no flavoring agent is added) to about 40 wt%, such as about 1 wt% to about 30 wt%, based on the total weight of the electronic cigarette composition , about 5 wt % to about 20 wt %, or about 10 wt % to about 15 wt %. In some embodiments, the sweetener and/or flavoring agent may be present in an amount of about 10 wt%, based on the total weight of the e-cigarette composition.

In some embodiments, the e-cigarette composition may comprise, consist essentially of, or consist of They make up. Relative to a completely synthetic nicotine source, a combination of synthetic nicotine (such as synthetic S-nicotine or synthetic R-nicotine) and tobacco-derived (or naturally derived) nicotine or a mixture or blend of R, S isomers ( For example a racemic mixture of R and S isomers or any other mixture), the amount of nicotine in the e-cigarette composition may be as described above. The amount of propylene glycol in the electronic cigarette composition may be from about 0 wt% (i.e. not present at all, or not added) to about 99 wt%, such as from about 10 wt% to about 70% or from about 30 wt% to the total weight of the electronic cigarette composition. About 50%. The amount of glycerin in the e-cigarette composition may be from about 0 wt % (ie, not present at all, or not added) to about 99 wt %, such as about 30 wt % to about 90 wt % or about 40 wt % to about 90 wt %, based on the total weight of the e-cigarette composition. About 70 wt%. The amount of nut oil in the e-cigarette composition may be from about 0 wt % (ie, not present at all, or not added) to about 20 wt %, such as about 0.5 wt % to about 10 wt % or about 1.0 wt %, based on the total weight of the e-cigarette composition. wt% to about 5.0 wt%. The amount of drinking alcohol (such as vodka) may be about 0 wt% (ie, not present at all, or not added) to about 99 wt%, such as about 30 wt% to about 90 wt%, or about 40 wt% to about 90 wt% based on the total weight of the electronic cigarette composition. About 70 wt%. The amount of flavoring agent in the electronic cigarette composition can be about 0wt% (that is, not present at all, or not added) to about 40wt%, such as about 1.0wt% to about 30wt%, about 5wt% based on the total weight of the electronic cigarette composition % to about 20 wt%, or about 10 wt% to about 15 wt%.

We have surprisingly found that, compared with compositions containing only nicotine derived from tobacco (or nicotine of natural origin) as the nicotine component, the electronic cigarette composition according to the embodiments of the present invention containing a part of synthetic nicotine has a positive effect on the human body system. Suitable and/or enhanced physiological activity, including neural activity, and suitable and/or enhanced sensory appeal (eg mouthfeel, throat sensation, etc.). In fact, smoker/vaporizer use has shown that compositions according to the invention comprising at least a portion of synthetic nicotine are more satisfactory than compositions using only nicotine derived from tobacco (or nicotine of natural origin) as the nicotine component .

Since the e-cigarette compositions described herein have fewer contaminants associated with tobacco-derived nicotine, less, if any, flavoring is required in the composition. In particular, smaller amounts of flavoring agents are required to mask the bitter taste and odor of similar compositions containing only tobacco-derived nicotine as the nicotine component. In some embodiments, the e-cigarette composition is substantially free of flavorants.

The use of smaller amounts of flavorants (or substantially no flavorants) provides mechanical benefits to electronic smoking devices. Specifically, using a smaller amount of flavoring causes less wear and tear on the coils or heating elements of the vaporizer. Since flavorants tend to be viscous, oily, or more viscous than other components in the e-cigarette composition, adding larger amounts of flavorant causes the coil (or heating element) to work harder to heat the e-cigarette composition thing. Additionally, due to the viscous, oily, viscous nature of flavoring, compositions with larger amounts of flavoring tend to have a greater buildup on the coils, which also increases wear on the coils and reduces coil The working life of the pipe (and device). In contrast, smaller amounts of flavoring are used in e-cigarette compositions according to embodiments of the present invention, thereby reducing wear on the coil and the likelihood of buildup on the coil. Thus, e-cigarette compositions according to embodiments of the present invention may increase the working life of the coil or heating element, and thus increase the life of the e-cigarette device.

According to various aspects of various embodiments of the present invention, (1) 50-50RS synthetic nicotine can provide the same or better sensory effects than tobacco-derived "S" nicotine. Similarly, (2) racemic synthetic nicotine is neuroactive and in many cases exhibits better neurological effects than tobacco-derived ("S") nicotine. In addition, according to the embodiments of the present invention, compared with the e-cigarette composition having only tobacco-derived nicotine as the nicotine source, the synthetic RS nicotine containing synthetic or non-synthetic tobacco-derived nicotine disclosed above has a co- The blend has an improved sensory and neurological effect on the user. In addition, having less tobacco alkaloid in the electronic cigarette composition can increase the service life of the composition and maintain the visual transparency (eg, colorless or transparent appearance) of the product.

According to some embodiments of the present invention, the electronic cigarette device uses the electronic cigarette composition described above. Any suitable e-cigarette device may use an e-cigarette composition according to embodiments of the present invention, some non-limiting examples of which include single-use (or disposable) e-cigarettes, refillable e-cigarettes such as liquid) composition refillable device and/or has a removable cartridge and a replaceable cartridge containing the e-cigarette (eg liquid) composition reusable device.

According to an embodiment of the present invention, an electronic cigarette device may include the electronic cigarette composition described herein and an atomizer (or a heating coil or other heat source) for vaporizing the composition. For example, Fig. 1 shows an electronic cigarette according to an embodiment of the present invention. As shown in Figure 1, housing 14 has air inlet 4 and houses LED 1, battery 2, electronic circuit board 3, atmospheric pressure chamber 5, sensor 6, smoke-liquid separator 7, atomizer 9, liquid supply bottle 11 , Cigarette holder 15, micro switch 16, ventilation hole 17 and ventilation channel 18. The electronic circuit board 3 has an electronic switching circuit and a high-frequency generator. The sensor 6 comprises a negative pressure chamber 8 separated from the sensor 6 by a corrugated membrane. The atomizer 9 has an atomization chamber 10 . The positioning ring 13 fixes the liquid supply bottle 11 between one side of the liquid supply bottle 11 and the shell 14 . The other side of the liquid supply bottle includes an aerosol channel 12 . The construction, function, and operation of e-cigarettes and vaping devices are known to those skilled in the art, and additional details of these devices are described in U.S. Patent No. 7,832,410 B2 to Hon, the entire contents of which are incorporated by reference This article. E-cigarette compositions according to embodiments of the present invention may be used with any known type of e-cigarette device, including what are known in the art as direct coil vaporizers, hot plate vaporizers, ceramic or metal bed/bowl heated vaporizers, ultra raw agitated vaporizers and electronically heated spike/tip vaporizer. The heating element may heat in the range of about 100°C to about 460°C during operation of these devices.

example

The following examples are provided for illustrative purposes only and are not intended to limit the scope of any embodiments of the invention.

Synthesis example 1——R, the synthesis of S nicotine

To a stirred solution of 1-vinyl-2-pyrrolidone (2) in dry THF was added 1 equivalent of potassium hydride under nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equiv) was added, and the resulting mixture was stirred at 65 degrees Celsius for 24 hours. The reaction was cooled, then acidified using 5% HCl, then concentrated hydrochloric acid was added, and the resulting solution was refluxed for 48 hours. The pH was adjusted to 13 using sodium hydroxide, and the aqueous and organic layers of the resulting biphasic solution were separated 3 times using the same volume of dichloromethane. The separated combined extracts were dried over sodium sulfate, filtered and the solvent was evaporated to give an amorphous material. The amorphous material was dissolved in 3 parts of ethanol, then palladium on carbon (about 10%) was added, and the resulting mixture was subjected to hydrogen pressure (greater than 25 atmospheres) for 6 hours. The resulting residue was diluted with more ethanol and filtered through celite. The solvent was evaporated to dryness under vacuum with minimal heating, and the residue was dissolved in formic acid/formaldehyde solution (1:1). The resulting mixture was heated to an internal temperature of 90 degrees Celsius and held at this temperature for a period of 12 hours, then cooled and neutralized to a pH greater than 10 using sodium hydroxide, then extracted with dichloromethane and dried over sodium sulfate, filtered and concentrated , to obtain a brown oil. Vacuum distillation of this oil yields pure RS nicotine.

Synthesis Example 2——Synthesis of R,S Nicotine

To a stirred solution of 1-vinyl-2-pyrrolidone (2) in dry THF/DMF (3/1 ) was added 1.2 equivalents of sodium hydride under nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equiv) was added, and the resulting mixture was stirred at 65 degrees Celsius for 24 hours. The reaction was cooled, then acidified using 5% HCl, then concentrated hydrochloric acid was added, and the resulting mixture was refluxed for 48 hours. The pH was adjusted to 6 using sodium hydroxide, then excess dichloromethane was added and the layers were separated. The aqueous layer was extracted twice with excess dichloromethane, the extracts were combined and washed with water, then dried over sodium sulfate. The solution was then filtered and the solvent was removed using vacuum to give a brown solid. This solid was dissolved in ethanol (about 5 to about 10 parts), then 0.5 parts of palladium on carbon was added, and the resulting mixture was subjected to hydrogen pressure (greater than 25 atmospheres) for 6 hours. The resulting residue was diluted with more ethanol and filtered through celite. The solvent was evaporated to dryness under vacuum using minimal heating, then the residue was dissolved in 3 parts formic acid and 3 parts formaldehyde, and the resulting solution was heated to an internal temperature of about 90 to about 95 degrees Celsius, and at that temperature Hold for a 24-hour period. The reaction was cooled and then vacuum distilled to yield pure RS nicotine as a clear, colorless and non-viscous oil.

Synthesis Example 3——Synthesis of R, S Nicotine

To a stirred solution of 1-vinyl-2-pyrrolidone (2) in dry DMF was added 1 equivalent of potassium hydride under nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equiv) was added, and the resulting mixture was stirred at 65 degrees Celsius for 24 hours. The reaction was cooled, then acidified using 5% HCl, then refluxed for 48 hours. The pH was adjusted to 6 using sodium hydroxide, then an excess of sodium borohydride suspension in isopropanol was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then acidified to a pH of about 3 using 5% HCl and then stirred for about 15 minutes. 10 parts of dichloromethane were added and the layers were separated. The organic layer was dried over sodium sulfate and filtered, then 1.1 equivalents of potassium carbonate was added, followed by 1.1 equivalents of methyl iodide, the reaction mixture was stirred for 24 hours and filtered, and the solvent was removed to give an oil which was vacuum distilled to give pure RS nicotine .

Synthesis example 4——R, the synthesis of S nicotine

To a stirred solution of 1-vinyl-2-pyrrolidone (2) in dry THF was added 1 equivalent of potassium hydride under nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equiv) was added, and the resulting mixture was stirred at 65 degrees Celsius for 24 hours. The reaction was cooled, then acidified using 5% HCl, then concentrated hydrochloric acid was added and the resulting mixture was refluxed for 48 hours. The pH was adjusted to 6 using sodium hydroxide, then an excess of sodium borohydride suspension in isopropanol was added and the reaction mixture was stirred at room temperature for 24 hours. About 10 parts of formic acid and about 10 parts of formaldehyde are then added, and the resulting solution is stirred at about 100 degrees Celsius for 24 hours, cooled, and then the pH is adjusted to about 12 by adding sodium hydroxide solution. The layers were then separated and the aqueous layer was washed several times with dichloromethane. The organic extract was dried over sodium sulfate and the solvent was removed. The resulting crude oil was vacuum distilled to yield pure RS nicotine as a clear, colorless, non-viscous liquid.

Synthesis example 5——R, the synthesis of S nicotine

To a stirred solution of 1-vinyl-2-pyrrolidone (2) in toluene was added 1.2 equivalents of sodium hydride (60% dispersion in oil), followed by the dropwise addition of ethyl nicotinate (1 equivalent ) toluene concentrated solution. The resulting mixture was heated to reflux for 3 hours. The crude reaction mixture was cooled in an ice bath, excess concentrated hydrochloric acid was added, and the resulting solution was heated to an internal temperature of about 85 to about 110 degrees Celsius and maintained at this temperature for a period of 12 hours. The reaction mixture was then cooled to room temperature, and the upper toluene layer was removed. Sodium hydroxide was added to the acidic aqueous layer until the pH was greater than 12, then the pH was adjusted to about 8 using HCl. To the stirred solution was added 2.5 equivalents of sodium borohydride in isopropanol (stabilized with sodium hydroxide), and the resulting mixture was stirred for 6 hours (until the reaction was complete). Excess formic acid and formaldehyde were then added, and the resulting mixture was refluxed for 10 hours, then adjusted to neutral or slightly basic pH using sodium hydroxide, then the solvent was removed by vacuum, and the remaining residue was vacuum distilled to give pure R , S Nicotine (boiling point = 74 to 76 degrees Celsius at 0.5mmHg).

Synthesis Example 6——Synthesis of Mioxamine

To a stirred solution of toluene (10 L) was added sodium hydride (1.25 Kg, 31.2 moles) under an inert atmosphere (dry nitrogen or argon) and stirred at room temperature for about 15 minutes. A solution of n-vinylpyrrolidone (2 kg, 18.02 mol) in 1 L of toluene was then added via funnel over 15 minutes and the resulting mixture was stirred at ambient temperature for about 15 minutes. A solution of ethyl nicotinate (2.5 Kg, 16.56 moles) in 2 L of toluene was then added in portions over a period of 2 hours. The moderately effervescent exothermic reaction mixture turned pale rose in color and then maintained itself at about 60 to about 65°C as the exothermic reaction formed a pale green precipitate. After the addition was complete, the reaction mixture was heated to an internal temperature of about 85°C and held at that temperature for about 16 hours, then cooled to room temperature to give a green heterogeneous mixture. The green heterogeneous mixture is fluid and can be pumped through 1/2" polyethylene tubing using a diaphragm pump. Add the green heterogeneous mixture to 25 L of boiling 6N HCl solution in approximately 250 mL portions. Proceed with vigorous effervescence Addition, vigorous effervescence subsided within minutes after adding an aliquot of the reaction mixture to hot HCl. After all of the reaction mixture had been added, the resulting dark brown biphasic mixture was stirred at reflux for an additional 1 hour. Then The reaction mixture was cooled, and the layers were separated. The aqueous layer was cooled, made basic (i.e., pH greater than 10) using NaOH (50%), and then extracted 3 times with 8 L of dichloromethane. Then vacuum distillation (bath The liquid temperature is about 45 degrees Celsius) and the solvent is removed to give crude mioxamine as a dark brown non-viscous oil.

Synthesis example 7 - the synthesis of nornicotine

All of the crude Mioxamine of Synthesis Example 6 was dissolved in 16 L of ethanol. 250 g of 10% palladium on carbon was added, and the resulting mixture was stirred under a hydrogen atmosphere for 12 hours, then filtered using celite, and washed with ethanol. Ethanol was removed by vacuum to give crude nornicotine as a dark brown non-viscous oil.

Synthesis example 8——R, the synthesis of S nicotine

To the crude nornicotine of Synthesis Example 7, 2.0 Kg of formaldehyde (37%) and 1.5 Kg of formic acid (85%) were added. The resulting brown solution was heated to an internal temperature of 85 degrees Celsius and held at this temperature for 15 hours, then cooled to ambient temperature. The resulting solution was cooled to about 5 °C and then made basic by the addition of NaOH. The resulting solution was then extracted three times with 8 L of dichloromethane, and the solvent was removed by vacuum. Pure R,S-nicotine was obtained using high vacuum distillation (ie, 75 to 76 at 0.5 mmHg) as a clear, colorless, non-viscous oil (approximately 31% overall yield from ethyl nicotinate).

Synthesis example 9 - the synthesis of nornicotine

All of the crude Mioxamine of Synthesis Example 6 was dissolved in 16 L of methanol and 4 L of acetic acid. The resulting solution was cooled to an internal temperature of -40°C, and then 700 g of sodium borohydride (granular) was added in portions over 1 hour. The reaction mixture was allowed to warm to room temperature with stirring, then vacuum distilled to remove most of the solvent. The resulting liquid was added to 25 L of water, and the resulting solution was adjusted to a pH greater than 10 using NaOH. The resulting solution was extracted 3 times with 15 L of dichloromethane and the combined extracts were subjected to medium vacuum distillation to yield crude nornicotine as a crude non-viscous dark brown oil.

Synthesis example 10——R, the synthesis of S nicotine

A solution of N-vinylpyrrolidone (4.5 kg) in 2.5 Kg of toluene was added to a stirred suspension of 2.5 Kg of sodium hydride (60% dispersion in mineral oil) in 20 L of toluene. The resulting mixture was stirred at room temperature for about 15 minutes. 5 Kg of ethyl nicotinate in 10 Kg of toluene was added to the resulting mixture batchwise and via a constant slow liquid stream (pale golden color). The exothermic reaction was controlled to an internal temperature of about 60°C by controlling the rate of addition of the ethyl nicotinate-toluene solution. After adding about one-third of the ethyl nicotinate, a green precipitate formed. After the addition was complete, the green heterogeneous mixture was heated to an internal temperature of about 85°C and held at this temperature for about 12 hours. The resulting solution was poured into pre-cooled 30 L of 4N HCl solution at 0° C., followed by vigorous stirring for about 5 minutes. The layers were separated, and the toluene layer was washed once with 2.5 Kg of 4N HCl. 8 L of concentrated hydrochloric acid was added to the combined acidic aqueous layers, and the reaction mixture was heated to boiling and maintained at this temperature for about 3 hours (or until the reaction was complete as determined by thin layer chromatography (TLC)). The reaction mixture was cooled to 0°C and then neutralized with 50% sodium hydroxide solution while allowing the internal temperature not to rise above 35 to 40°C. The pH was made strongly alkaline by adding sodium hydroxide solution (50%) until the pH reached 11 to 13 (as indicated by the blue change on litmus paper). The resulting solution was extracted 4 times with 15 L of dichloromethane, and the combined extracts were subjected to moderate vacuum distillation to afford meoxamine as a non-viscous brown oil.

40 L of absolute ethanol was added to the crude mioxamine product, and 2 Kg of 10% palladium on carbon was added to the resulting solution. The resulting mixture was subjected to a hydrogen pressure of 50 atm. The reaction was complete within 12 hours. The resulting heterogeneous mixture was filtered through celite and washed twice with 10 L of ethanol. The combined ethanolic solution of the crude nornicotine product was vacuum distilled below 50°C (29 inches Hg) and the crude dark brown oil was dissolved in 10 L of water. To the resulting solution was added a solution of 5 L of formaldehyde solution (37%) and 4 L of formic acid (85%), and the mixture was heated to an internal temperature of 90° C. and maintained at this temperature for 20 hours. The reaction mixture was cooled to -5°C and then made basic (ie pH greater than 10) by addition of sodium hydroxide solution (50%). The basic liquid was then extracted 3 times with 15 L of dichloromethane and the combined extracts were distilled under moderate vacuum to give the crude RS-nicotine product as a dark brown oil. The dark brown oil was distilled twice under high vacuum to obtain RS-nicotine whose purity meets the requirements of the USP purity test.

Composition Example 11 - Composition for Use in Electronic Cigarette Devices

Component Content (wt%)

Synthetic RS-Nicotine 0.3%

Glycerin 99.7%

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie the synthetic nicotine is a racemic mixture of the R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine.

Composition Example 12 - Composition for Use in Electronic Cigarette Devices

Component Content (wt%)

S-nicotine (synthetic) 0.3

Glycerin 99.7

S-nicotine was synthesized by resolution of RS nicotine to semi-pure or enantiomerically pure (i.e., 98% or greater) using (+)-O,O'-di-p-toluoyl-D-tartaric acid to generate S -nicotine. The synthetic S-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic S-nicotine component is free of other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine.

Composition Example 13 - Composition for Use in Electronic Cigarette Devices

Component Content (wt%)

RS Nicotine (Synthetic) 0.6

Vegetable glycerin 99.4

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie the synthetic nicotine is a racemic mixture of the R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5% by weight or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine.

Composition Example 14 - Composition for use in electronic cigarette devices

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has an R isomer/S isomer ratio of 1:1. R,S-nicotine is resolved into semi-pure or enantiomerically pure (i.e. 98% or greater) S-nicotine by using (+)-O,O'-di-p-toluoyl-D-tartaric acid, Produces S-nicotine.

As set forth herein, the nicotine component of the composition comprises a mixture (or blend) of racemic RS nicotine and pure S nicotine, both of which are synthetic nicotines. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie synthetic RS nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine. Similarly, the synthetic S-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic S-nicotine component also does not contain other contaminants such as those commonly associated with naturally derived (or tobacco derived) nicotine.

Composition Example 15 - Composition for Use in Electronic Cigarette Devices

R,S nicotine was produced by the method of Example 10. Tobacco-derived S-nicotine is off-the-shelf nicotine, such as a (-)-nicotine product available from Sigma-Aldrich Co., LLC (Sigma-Aldrich Co., LLC).

As set forth herein, the nicotine component of the composition comprises a mixture (or blend) of racemic RS nicotine (which is synthetic nicotine) and tobacco-derived (naturally sourced) S-nicotine. The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine. The tobacco-derived nicotine component may contain the contaminants discussed above that are typically present in tobacco-derived nicotine, and may also contain those contaminants in the amounts recited above.

Composition Example 16 - Composition for Use in Electronic Cigarette Devices

R,S nicotine was produced by the method of Example 10. Tobacco-derived S-nicotine is off-the-shelf nicotine, such as a (-)-nicotine product available from Sigma-Aldrich Co., LLC (Sigma-Aldrich Co., LLC).

As set forth herein, the nicotine component of the composition comprises a mixture (or blend) of racemic RS nicotine (which is synthetic nicotine) and tobacco-derived (naturally sourced) S nicotine. The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine. The tobacco-derived nicotine component may contain the contaminants discussed above that are typically present in tobacco-derived nicotine, and may also contain those contaminants in the amounts recited above.

Composition Example 17 - Composition for use in electronic cigarette devices

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of less than 1 wt%, or less than about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine.

Composition Example 18 - Composition for Use in Electronic Cigarette Devices

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine.

Composition Example 19 - Composition for use in electronic cigarette devices

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of less than 1 wt%, or less than about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine. Flavors were purchased from Capella Flavors, Inc. (San Marcos, CA).

Composition Example 20 - Composition for use in electronic cigarette devices

Synthetic S-nicotine was produced by resolving RS nicotine into semi-pure or enantiomerically pure (i.e., 98% or greater) S-nicotine using (+)-O,O'-di-p-toluoyl-D-tartaric acid. -nicotine. The synthetic S-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of about 0.5 wt% or less. The synthetic S-nicotine component also does not contain other contaminants such as those commonly associated with naturally derived (or tobacco derived) nicotine. Flavors were purchased from Capella Flavors, Inc. (San Marcos, CA).

Device Example 1 - Liquid Compositions in "Open Pot" or "Open System" Electronic Cigarette Devices

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of less than 1 wt%, or less than about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine. Flavors were purchased from Capella Flavors, Inc. (San Marcos, CA).

In an "open tank" or "open system" e-cigarette device, a user fills and/or refills a tank or cartridge designed to hold e-cigarette liquid. Open can or open system vaping devices are popular due to their high degree of customizability. For example, an open tank or open system device is not limited to the e-liquid supplied with the device, but can be customized by adding any suitable e-liquid to the open pod of the system. In this example, the open tank or open system device is a product sold under the name "Sub Tank" by "Shenzhen Kanger Technology Co., Ltd." (Shenzhen Kanger Technology Co., Ltd.) (Shenzhen, China).

Device Example 2 - Liquid Compositions in "Closed Pot" or "Closed System" Electronic Cigarette Devices

R,S nicotine was produced by the method of Example 10. The R,S nicotine composition has a 1:1 R isomer/S isomer ratio (ie synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component contains synthetic contaminants or synthetic impurities (those terms are defined above) in an amount of less than 1 wt%, or less than about 0.5 wt% or less. The synthetic RS-nicotine component does not contain other contaminants, such as those commonly associated with naturally-derived (or tobacco-derived) nicotine. Flavors were purchased from Capella Flavors, Inc. (San Marcos, CA).

Unlike "open tank" or "open system" vaping devices, in "closed tank" or "closed system" vaping devices, e-cigarette liquid is prefilled in a closed container or cartridge that fits into the closed system device. The prepackaged cartridge cannot be filled or refilled by the device user. In fact, most "closed can" or "closed system" e-cigarette devices are designed to deplete the e-cigarettes in prefilled cartridges such as e-cigarettes or so-called "cig-a-likes" (e-cigarette analogs) The smoke liquid can then be discarded.

comparison test

A double-blind pilot study of more than 250 people was conducted on several vaping liquid manufacturers. Each person is provided with an electronic cigarette device to vaporize and inhale the liquid nicotine composition. Each device contains one of two possible liquid nicotine compositions. The first composition contained 0.3% by weight of synthetic nicotine as a racemic mixture, and 99.7% by weight of glycerin. The second composition, the comparative composition, contained 0.3 wt% tobacco-derived nicotine (commercially available from Alltech Associates Inc., a division of W. R. Grace & Co.) and 99.7 wt% glycerin. Thus, the only difference between the compositions is that the nicotine in the first composition is entirely synthetic nicotine, while the nicotine in the second composition is entirely tobacco-derived nicotine. Users were not informed whether their vaping device contained the first or second composition, and testing was performed according to typical sensory evaluation methods, including registers and questionnaires. In each individual instance, users stated that they preferred the sensations provided by the e-cigarette device including the first composition containing synthetic nicotine. In particular, users indicated that the smell was much better with respect to compositions containing only synthetic nicotine, that they could not taste or smell nicotine, that there was no aftertaste of tobacco, and that the nicotine effect was as strong as nicotine derived from tobacco.

From a manufacturer's perspective, blending flavors is much easier since there is no need to mask the taste of nicotine. Additionally, the coils (or heating elements) in vaping devices have been found to burn cleanly throughout the day. In contrast, tobacco-derived nicotine compositions required large amounts of flavoring, which caused the device to become dirty after a short time, necessitating cleaning the device many times throughout the test period.

In another study, 10 subjects were asked to "vape" 3 different nicotine compositions (each provided at two different concentrations of nicotine, for a total of 6 compositions), and each combination was compared The brain shock and throat sensation of food. The first composition is 0.3% synthetic S-nicotine prepared according to the method described herein; the second composition is 0.3% nicotine derived from tobacco; the third composition is 0.3% prepared according to the method described herein synthetic RS nicotine; the fourth composition is 0.6% synthetic S nicotine prepared according to the method described herein; the fifth composition is 0.6% nicotine derived from tobacco; the third composition is prepared by the method described herein Method prepared 0.6% synthetic RS nicotine. In evaluating the brain impact and throat sensation of the different compositions, the following criteria were used by each subject:

Tables 1 and 2 below set forth the results for compositions of 0.3% and 0.6%, respectively, of synthetic S nicotine, synthetic RS nicotine, and tobacco-derived nicotine.

Table 1 - Compositions at 0.3%

Table 2 - 0.6% Composition

As can be seen from Tables 1 and 2 above, at a loading level of 0.3%, the synthetic "S" isomer had the same (within experimental error) "brain shock" as its tobacco-derived counterpart; and The "RS" synthetic nicotine formulation has slightly less effect. The 'throat feel' results show that the difference is noticeable and probably predictable, with the synthetic nicotine formulation providing a smaller effect and thus a more pleasant throat experience.

Also as shown in Tables 1 and 2, a loading level of 0.6% produced stronger results. Similar to the lower concentration version, but to a greater extent, the synthetic "S" isomer acts with the same (within experimental error) "brain shock" as its tobacco-derived counterpart; and the "RS" synthetic Nicotine formulations have slightly less effect. However, in complete contrast, the "throat feel" results for the e-liquid formulation with 0.6% nicotine showed significant differences and were easily perceivable by all subjects. These results show, for example, that synthetic nicotine e-liquid formulations provide a substantially different and significantly different "throat feel" compared to their tobacco-derived counterparts, while maintaining a similar "brain hit".

In another study of the difference between synthetic nicotine and tobacco-derived nicotine according to an embodiment of the present invention, electrophysiology-based HTS assays for two nicotinic ACh receptors (nAChRs) (i.e., α7 and α4β2 ) to evaluate and compare the activity of different forms of nicotine. The nicotine form for this analysis comprised S nicotine commercially available from Sigma-Aldrich Company of St. Louis, MO, a synthetic RS racemic mixture of the R and S isomers according to embodiments of the present Synthetic S nicotine of an example of the invention, a synthetic RS mixture comprising 75% of the S isomer according to an example of the invention and 25% of the R isomer according to an example of the invention, an example according to the invention Synthetic R nicotine of , a synthetic RS mixture comprising 25% of the S isomer and 75% of the R isomer according to an embodiment of the invention, S nicotine available from Alchem Laboratories, Alachua, Florida, and Reference nicotine available from Sigma-Aldrich. Tables 3 and 4 below present the results of the analysis showing the obtained _EC50 , _IC50 , _Emax and Hillslope values for receptor activation and inhibition.

Table 3—Activation and inhibition of α4β2 nAChRs

Table 4—Activation and inhibition of α7 nAChRs

As can be seen from the above Tables 3 and 4, the synthetic R nicotine according to the embodiment of the present invention seems to be a complete weak agonist on human α7 nAChRs, but only a partial agonist on human α4β2 nAChRs, indicating that it is effective in different types of The selectivity of nicotine isomers on nAChRs was surprising and unexpected. For example, these results may indicate different neurophysiological responses to the R and S isomers of nicotine, and thus different neurophysiological responses to various mixtures of the R and S isomers. These differences in neurophysiological responses may be responsible for the different sensory experiences listed in Tables 1 and 2 above, and these differences in the cell membrane receptor binding properties of the R and S isomers may also affect psychological Active neuronal pathways and addiction responses.

As discussed above, e-cigarette compositions according to embodiments of the present invention include a synthetic nicotine source that can improve the e-cigarette experience for e-cigarette users. For example, while an e-cigarette user can often perceive an unpleasant taste in e-liquids using tobacco-derived nicotine, the same user typically does not perceive an unpleasant taste in e-liquids using synthetic nicotine according to embodiments of the present invention. similar to the unpleasant taste.

In addition, although e-cigarette liquids using tobacco-derived nicotine generally contain a large amount of flavoring agents to mask the unpleasant taste of tobacco-derived nicotine, the e-cigarette liquids according to the embodiments of the present invention do not need to use so much flavoring agents . As discussed above, this reduction in the amount of flavoring agent may improve the life of an vaping device in which e-cigarette liquid is used.

Additionally, e-liquids that use tobacco-derived nicotine often have a pungent throat sensation when vaporized by an e-cigarette device, and often have a strong "tobacco" taste. In contrast, e-cigarette liquids according to embodiments of the present invention using synthetic nicotine have a smoother throat feel, thereby eliminating (or at least significantly reducing) the irritating sensation associated with tobacco-derived nicotine. Additionally, e-liquids according to embodiments of the present invention contain synthetic nicotine that is not derived from tobacco, and thus exhibit significantly less "tobacco" odor.

While certain exemplary embodiments of the present disclosure have been illustrated and described, those of ordinary skill in the art will recognize that the invention can be implemented without departing from the spirit and scope of the present invention as defined in the appended claims and their equivalents. Various changes and modifications can be made to the described embodiments without exception. For example, although certain components may be described in the singular, ie, "a" flavoring agent, "a" solvent, etc., one or more of these components in any combination may be used in accordance with the present disclosure.

Additionally, although certain embodiments are described as "comprising" or "including" the recited components, "consisting essentially of" or "consisting of" the listed components " embodiments are also within the scope of the present disclosure. For example, while embodiments of the present invention are described as nicotine sources comprising synthetic nicotine, nicotine sources consisting essentially of or consisting of synthetic nicotine are also within the scope of the present disclosure. Thus, the nicotine source may consist essentially of synthetic nicotine. In this context, "consisting essentially of" means that any additional components of the nicotine source do not materially affect the user's experience in terms of taste or neurological effects. For example, a nicotine source consisting essentially of synthetic nicotine may be free of any measurable or detectable amounts of the contaminants or impurities described herein generally associated with tobacco-derived nicotine.

As used herein, unless expressly stated otherwise, all numbers (eg, those expressing values, ranges, amounts, or percentages) can be read as if preceded by the word "about," even if that term does not explicitly appear. Additionally, the word "about" is used as a term of approximation, rather than a term of degree, and reflects limits of variables associated with measurements, significant figures, and substitutability, all as understood by those of ordinary skill in the art to which this disclosure pertains. Any reference herein to a numerical range is intended to include all subranges subsumed therein. The plural includes the singular and vice versa. For example, although this disclosure may describe "a" flavor or "a" solvent, mixtures of such flavors or solvents may be used. Where ranges are given, any endpoints of those ranges and/or within those ranges are encompassed within the scope of the disclosure. The term "including" and similar terms mean "including but not limited to", unless expressly stated to the contrary.

Notwithstanding that the numerical ranges and parameters set forth herein may be approximations, the numerical values set forth in the examples are reported as practical as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. As used in the specification and claims the word "comprising" and variations thereof do not limit the disclosure to the exclusion of any variation or addition.

Claims (20)

1. A composition suitable for electronic cigarette devices, said composition comprising: Nicotine products comprising synthetic nicotine substantially free of nicotine-1'-N-oxide, diene nicotine, nordiene nicotine, cotinine, 2',3-bipyridine, arginine One or more of Nabaxin, N-methylanabaxine, N-methylanabaxine, Anabaxime and/or Anatapine, and One or more pharmaceutically acceptable excipients, additives and/or solvents. 2. The composition of claim 1, wherein the synthetic nicotine comprises pure S-nicotine, or a mixture of R-nicotine and S-nicotine. 3. The composition of claim 2, wherein the mixture of R-nicotine and S-nicotine comprises a racemic mixture of R-nicotine and S-nicotine. 4. The composition of claim 2, wherein the mixture of R-nicotine and S-nicotine comprises more R-nicotine than S-nicotine. 5. The composition of claim 1, wherein the synthetic nicotine comprises greater than 5 wt% R-nicotine, based on the total weight of the synthetic nicotine. 6. The composition of claim 1, wherein the nicotine product further comprises tobacco-derived nicotine. 7. The composition of claim 6, wherein the nicotine product comprises from about 10 wt% to about 90 wt% synthetic nicotine based on the total weight of the nicotine product, and the remainder of the nicotine product is from the source Nicotine from tobacco. 8. The composition of claim 1, further comprising a flavoring agent. 9. The composition of claim 1, wherein the composition is substantially free of flavoring agents. 10. The composition of claim 1, wherein the nicotine product comprises 100 wt% synthetic nicotine. 11. The composition according to claim 1, wherein nicotine-1'-N-oxide, diene nicotine, nordiene nicotine, 2', 3-bipyridine, anabacin, N- One or more of methylanabaxine, N-methylanabaxine, cotinine, ananabaxine and/or anatapine are present in the composition, and the Their combined content is less than 0.5% by weight based on the total weight of the composition. 12. The composition of claim 1, wherein the one or more pharmaceutically acceptable excipients, additives and/or solvents comprise glycerol and/or propylene glycol. 13. An electronic cigarette device comprising: The composition according to claim 1; and A nebulizer for vaporizing the composition. 14. The electronic cigarette device according to claim 13, wherein the synthetic nicotine comprises pure S-nicotine, or a mixture of R-nicotine and S-nicotine. 15. The electronic cigarette device of claim 14, wherein the mixture of R-nicotine and S-nicotine comprises a racemic mixture of R-nicotine and S-nicotine. 16. The electronic cigarette device of claim 14, wherein the mixture of R-nicotine and S-nicotine comprises more R-nicotine than S-nicotine. 17. The electronic cigarette device of claim 13, wherein the synthetic nicotine comprises greater than 5 wt% R-nicotine based on the total weight of the synthetic nicotine. 18. The electronic smoking device of claim 13, wherein the nicotine product further comprises tobacco-derived nicotine. 19. The electronic smoking device of claim 13, wherein the nicotine product comprises 100 wt% synthetic nicotine. 20. The electronic cigarette device according to claim 13, wherein nicotine-1'-N-oxide, diene nicotine, nordiene nicotine, 2',3-bipyridine, anabacin, N - one or more of methylanabaxine, N-methylanabaxine, cotinine, ananabaxine and/or anatapine are present in said composition, and in said composition The combined content is less than 0.5wt% based on the total weight of the composition.