EP3364951A1 - Composition de nicotine pour dispositifs de vapotage et dispositifs de vapotage utilisant celle-ci - Google Patents

Composition de nicotine pour dispositifs de vapotage et dispositifs de vapotage utilisant celle-ci

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Publication number
EP3364951A1
EP3364951A1 EP16858466.2A EP16858466A EP3364951A1 EP 3364951 A1 EP3364951 A1 EP 3364951A1 EP 16858466 A EP16858466 A EP 16858466A EP 3364951 A1 EP3364951 A1 EP 3364951A1
Authority
EP
European Patent Office
Prior art keywords
nicotine
synthetic
composition
tobacco
vaping
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16858466.2A
Other languages
German (de)
English (en)
Other versions
EP3364951A4 (fr
Inventor
Michael Arnold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Next Generation Labs LLC
Original Assignee
Next Generation Labs LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Next Generation Labs LLC filed Critical Next Generation Labs LLC
Publication of EP3364951A1 publication Critical patent/EP3364951A1/fr
Publication of EP3364951A4 publication Critical patent/EP3364951A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
    • A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24F—SMOKERS' REQUISITES; MATCH BOXES; SIMULATED SMOKING DEVICES
    • A24F40/00—Electrically operated smoking devices; Component parts thereof; Manufacture thereof; Maintenance or testing thereof; Charging means specially adapted therefor
    • A24F40/10—Devices using liquid inhalable precursors

Definitions

  • compositions currently used in electronic vaping devices generally include nicotine in diluted liquid form.
  • the nicotine used in such compositions is a derived, purified extract of tobacco leaves. These extracts are isolated in semi-pure form along with many contaminants, many of which have been shown to cause serious ailments for the human system, including cancer.
  • tobacco-derived nicotine when purified to levels compliant with the United States Pharmacopeia (USP) monograph for purity still has many contaminants, and these contaminants have a high potential to be problematic for the consumer because many are known carcinogens and agents of addiction. Additionally, these contaminants contribute to the characteristic foul taste and foul smell of commercially available products utilizing tobacco-derived nicotine extracts.
  • USP United States Pharmacopeia
  • vaping products having tobacco-derived nicotine often require relatively large amounts of flavorants, as well as other additional masking chemicals, which are added to the composition to mask the foul taste and/or smell of the tobacco-derived nicotine.
  • These masking chemicals and the large amount of flavorants required to mask the foul taste affect the taste and experience of vaping, and may themselves have a detrimental impact to the user.
  • a composition suitable for vaporizing comprises a nicotine product comprising a synthetic nicotine that 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), nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, nornicotyrine, 2',3-bipyridyl, anabasine, and/or anatabine.
  • the composition may further include one or more pharmaceutically acceptable carriers, additives and/or excipients.
  • FIG. 1 is a schematic representation of a prior art electronic vaping device useable for vaporizing a nicotine composition in accordance with aspects of embodiments of the present invention.
  • a composition suitable for vaporizing (also referred to herein as a "vaping composition” or “vaping solution”) comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of certain contaminants or impurities normally found in tobacco-derived nicotine, such as, for example nicotine-N'-oxide (e.g., nicotine-1 '- N-oxide), nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, nornicotyrine, 2',3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotine-N'-oxide e.g., nicotine-1 '- N-oxide
  • nicotyrine e.g., ⁇ -Nicotyrine
  • cotinine cotinine
  • nornicotyrine 2',3-bipyridyl
  • anabasine N-methyl
  • the composition may include a synthetic nicotine that is free or substantially free of any one or more of nicotine-N'-oxide (e.g., nicotine-1 '-N-oxide), nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, nornicotyrine, 2',3- bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotine-N'-oxide e.g., nicotine-1 '-N-oxide
  • nicotyrine e.g., ⁇ -Nicotyrine
  • cotinine cotinine
  • nornicotyrine 2',3- bipyridyl
  • the composition may include a synthetic nicotine that is free or substantially free of any combination of two or more of nicotine-N'- oxide (e.g., nicotine-1 '-N-oxide), nicotyrine (e.g., ⁇ -Nicotyrine), cotinine,
  • nicotine-N'- oxide e.g., nicotine-1 '-N-oxide
  • nicotyrine e.g., ⁇ -Nicotyrine
  • cotinine e.g., a synthetic nicotine that is free or substantially free of any combination of two or more of nicotine-N'- oxide (e.g., nicotine-1 '-N-oxide), nicotyrine (e.g., ⁇ -Nicotyrine), cotinine,
  • the composition may include a synthetic nicotine that is free or substantially free of all of nicotine-N'-oxide (e.g., nicotine-1 '-N-oxide), nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, nornicotyrine, 2', 3- bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotine-N'-oxide e.g., nicotine-1 '-N-oxide
  • nicotyrine e.g., ⁇ -Nicotyrine
  • cotinine nornicotyrine
  • 2', 3- bipyridyl anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • a composition suitable for vaporizing (also referred to herein as a “vaping composition” or “vaping solution”) comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of nicotyrine (e.g., ⁇ -Nicotyrine), cotinine,
  • nicotyrine e.g., ⁇ -Nicotyrine
  • cotinine e.g., ⁇ -Nicotyrine
  • the composition may include a synthetic nicotine that is free or substantially free of any one or more of nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, nornicotyrine, 2',3-bipyridyl, anabasine, N- methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotyrine e.g., ⁇ -Nicotyrine
  • the composition may include a synthetic nicotine that is free or substantially free of any combination of two or more of nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, nornicotyrine, 2',3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotyrine e.g., ⁇ -Nicotyrine
  • cotinine cotinine
  • nornicotyrine cotinine
  • 2',3-bipyridyl anabasine
  • anabasine e.g., N-methyl anatabine
  • N-methyl anabasine e.g., N-methyl anabasine
  • anabasine e.g., N-Nicotyrine
  • cotinine e.g., cotinine
  • nornicotyrine e.g.,
  • the composition may include a synthetic nicotine that is free or substantially free of all of nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, nornicotyrine, 2',3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotyrine e.g., ⁇ -Nicotyrine
  • cotinine e.g., ⁇ -Nicotyrine
  • nornicotyrine cotinine
  • 2',3-bipyridyl e.g., anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • a vaping composition or vaping solution comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotyrine e.g., ⁇ -Nicotyrine
  • the composition may include a synthetic nicotine that is free or substantially free of any one or more of nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • the composition may include a synthetic nicotine that is free or substantially free of any combination of two or more of nicotyrine (e.g., ⁇ -Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • the composition may include a synthetic nicotine that is free or substantially free of all of nicotyrine (e.g., ⁇ - Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.
  • nicotyrine e.g., ⁇ - Nicotyrine
  • a vaping composition or vaping solution comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of anabasine, N-methyl anatabine, N-methyl anabasine, cotinine and/or anatabine.
  • the composition may include a synthetic nicotine that is free or substantially free of one or more of anabasine, N- methyl anatabine, N-methyl anabasine, cotinine, and/or anatabine.
  • the composition may include a synthetic nicotine that is free or substantially free of two or more of anabasine, N-methyl anatabine, N-methyl anabasine, cotinine and/or anatabine.
  • the composition may include a synthetic nicotine that is free or substantially free of two or more of anabasine, N-methyl anatabine, N-methyl anabasine, cotinine and/or anatabine.
  • one nonlimiting example of a suitable technique for determining whether these impurities are present in a particular composition includes USP-HPLC, i.e., high performance liquid chromatography according to USP standards, which tests for the main impurities in tobacco-derived or natural nicotine (including, e.g., cotinine and anatabine).
  • USP-HPLC high performance liquid chromatography according to USP standards
  • tobacco-derived or natural nicotine including, e.g., cotinine and anatabine
  • the synthetic nicotine according to embodiments of the present invention is distinct and distinguishable from its tobacco-derived or natural counterpart.
  • the synthetic nicotine according to embodiments of the present invention provides an improved overall "vaping" experience that maintains a satisfactorily strong head feel dynamic while also reducing the unpleasant throat feel associated with the "vaping" of tobacco- derived or natural nicotine.
  • the impurities discussed above are one way in which the synthetic nicotine according to embodiments of the present invention may be chemically and physically distinguished from tobacco-derived or natural nicotine. However, additional methods for distinguishing synthetic vs. natural nicotine may also be used.
  • the nicotine obtained from that source will inherently include a measurable amount of radioactive isotopes, e.g., 14 C, 13 C and D. See Randolph A. Culp et al., "Identification of Isotopically Manipulated Cinnamic
  • the 5 13 C and 5D indications refer to the isotopic abundance, i.e., the ratio of the heavier isotope (e.g., 13 C or D) to the lighter isotope (e.g., 12 C or H). As discussed in the Culp references, these ratios are measurably different in
  • the synthetic nicotine has an isotopic abundance (e.g., a 5 13 C and 5D value) and/or 14 C level that is different from that of the natural or tobacco-derived counterpart compound.
  • the synthetic nicotine has an isotopic abundance (e.g., a 5 13 C and 5D value) and/or 14 C level that is lower than that of the natural or tobacco-derived counterpart compound.
  • the synthetic nicotine may have a 14 C level of up to about 10 dpm/gC (distintegrations per minute / grams C).
  • the synthetic nicotine may have 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.
  • the synthetic nicotine may have a 14 C level of about 3.5 to about 7 dpm/gC, or about 4 to about 6 dpm/gC.
  • the 2015 and day 14 C reference standard is 14.0 dpm/gC. Accordingly, the synthetic nicotine according to embodiments of the present invention has a significantly different 14 C level than that of natural nicotine (i.e., based on the 2015 and present day reference standard for 14 C activity).
  • the synthetic nicotine has a 14 C level that is up to about 72% that of natural nicotine, or about 0.5% to about 65% that of natural nicotine. In some embodiments, for example, the synthetic nicotine has a 14 C level that is about 14% to about 58% that of natural nicotine, or about 20% to about 58% that of natural nicotine. For example, in some embodiments, the synthetic nicotine has a 14 C level that is about 25% to about 50% that of natural nicotine, or about 28% to about 43% that of natural nicotine.
  • the unstable radio-isotope of carbon, 14 C has different radioactivity based on its age, e.g., the older it is, the less radioactive it becomes.
  • Comparison of the radioactivity of natural or tobacco-derived nicotine (e.g., the United States Phamacopeia (USP)) standard to that of a synthetic sample provides an avenue for identifying the source of the nicotine. For example, if the nicotine is petroleum based, then the radioactivity will be significantly lower than if the nicotine is natural or tobacco-derived.
  • some synthetic nicotine may be produced from chemicals that originate from living plants, e.g., sugar cane or corn.
  • the amounts of the stable isotope of carbon is determined. Since sugar cane and corn are in a different class of plant than tobacco, they metabolize the heavy isotopes of carbon (C 13 ) and water (D2O) at different magnitudes than the tobacco plant. As such, if the comparative measurement data for these stable isotopes is different, then it can be determined that the nicotine is not from tobacco; and if the comparative measurement data is similar, then it can be determined that the nicotine is from tobacco. For example, natural nicotine has a 5 13 C ( 13 C/ 12 C) around -30 to -32 parts per mil relative to the international standard PDB ( ⁇ ). In contrast, according to embodiments of the present invention, the synthetic nicotine may have a 5 13 C of about -20 to about -29 parts per mil relative to the international standard PDB ( ⁇ ), or about -23 to about -29 parts per mil relative to the
  • the synthetic nicotine may have a 5 13 C of about -25 to about -28.5 parts per mil relative to the international standard PDB ( ⁇ ), or about -26 to about -28.5 parts per mil relative to the international standard PDB ( ⁇ ).
  • the synthetic nicotine according to embodiments of the present invention may have a 5 13 C that is about 66% to about 97% that of natural nicotine, or about 76% to about 97% that of nicotine.
  • the synthetic nicotine according to embodiments of the present invention may have a 5 13 C that is about 83% to about 95% that of natural nicotine, or about 87% to about 95% that of nicotine.
  • natural nicotine has a 5D (D/H) around -170 to -171 parts per mil relative to the international standard V-SMOW ( ⁇ ).
  • the synthetic nicotine may have a 5D of about -140 to about -160 parts per mil relative to the international standard V-SMOW ( ⁇ ), or about -145 to about -160 parts per mil relative to the international V-SMOW ( ⁇ ).
  • the synthetic nicotine may have a 5D of about -150 to about -160 parts per mil relative to the international standard V- SMOW ( ⁇ ), or about -152 to about -158 parts per mil relative to the international standard V-SMOW ( ⁇ ).
  • the synthetic nicotine according to embodiments of the present invention may have a 5D that is about 82% to about 95% that of natural nicotine, or about 85% to about 95% that of nicotine.
  • the synthetic nicotine according to embodiments of the present invention may have a 5D that is about 88% to about 95% that of natural nicotine, or about 89% to about 93% that of nicotine.
  • compositions may further include one or more pharmaceutically acceptable excipients, additives and/or carriers.
  • pharmaceutically acceptable excipients such as sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium bicarbonate, sodium bicarbonate
  • the term “substantially free of the listed compounds refers to a composition that does not include added amounts of the listed
  • the composition for use in an electronic vaping device may comprise nicotine.
  • the composition may be a solid or liquid mixture, for example liquid, and may comprise about 0.001 wt% to about 0.50 wt%, for example about 0.1 wt% to about 0.40 wt%, or about 0.2 wt% to about 0.35 wt% nicotine based on the total weight of the composition.
  • the composition may comprise about 0.3 wt% nicotine.
  • the composition may comprise about 0.1 mg/ml to about 50mg/ml, for example about 1 mg/ml to about 40 mg/ml, or about 2 mg/ml to about 35 mg/ml of the nicotine, based on the total volume of the composition.
  • the composition may comprise about 30 mg/ml of the nicotine.
  • At least a portion of the nicotine present in the composition is synthetic.
  • synthetic means that the identified compound (e.g., nicotine) is prepared through a chemical process that does not include
  • tobacco derived and “non-synthetic” are used interchangeably herein, and refer to the identified compound or composition that is derived from or extracted from a natural source (such as, for example, tobacco).
  • tobacco derived nicotine or “non-synthetic nicotine” refers to nicotine derived from or extracted from tobacco leaves, and does not encompass nicotine produced from independent chemical synthesis.
  • the relative portion of the nicotine that is synthetic may be any amount that is sufficient to provide a similar or better taste, impact, and sensation to the user as compared to conventional electronic vaping device compositions that have only tobacco derived nicotine.
  • the synthetic nicotine may be present in an amount of about 1 wt% or greater, for example about 5 wt% or greater, about 10 wt% or greater, about 20 wt% or greater, 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 wt % or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or in a positive amount (i.e., greater than 0%) up to about 100 wt%.
  • the remaining portion of the nicotine may be tobacco-derived nicotine.
  • the synthetic nicotine in the composition may be prepared by any suitable process, nonlimiting examples of which include the processes disclosed in U.S. Patent Nos. 8,367,837, 8,378,1 10 and 8,389,733 and European Patent No. EP 2487172, the entire contents of all of which are
  • 1 -(but-1 -enyl)pyrrolidin-2-one may be condensed with nicotinic acid ester to give 1 (but-1 -enyl)-3-nicotinoylpyrrolidin-2-one, which may then be treated with an acid and base to give myosamine, which, in turn, is converted to (R,S)-nicotine by reduction and subsequent N-methylation.
  • An example of this reaction scheme is shown below, reproduced from U.S. Patent Nos. 8,367,837, 8,378,1 10 and 8,389,733 and European Patent No. EP 2487172 to Divi, et al.
  • the synthetic nicotine in the composition may be prepared by the synthetic route outlined in Scheme 1 :
  • a carbon-carbon bond forming condensation is first performed under anhydrous conditions.
  • an appropriate nicotinate ester (1 ) is condensed with a suitable N- vinylogous-2-pyrrolidinone (2) under mild conditions, utilizing a suitable dry solvent combination with a suitable strong base, for example a metal hydride.
  • a suitable strong base for example a metal hydride.
  • the condensation reaction mixture utilizes alkyl esters of nicotinic acid in combination with N-vinyl-2-pyrrolidinone, and a metal hydride base in a suitable dry solvent.
  • the nicotinate alkyl ester comprises short chain alkyl groups (for example, R1 in compound (1 ) may be Ci -3, or in some embodiments C 2 ).
  • the N-vinylogous-2- pyrrolidinone may comprise a vinyl substituent with a short chain alkyl group.
  • R2 in compound (2) may be a short chain (e.g., Ci.
  • N-vinylogous-2-pyrrolidinone is n-vinyl-2-pyrrolidinone.
  • condensation reaction mixture with respect to 1 part nicotinate ester is about 0.1 part to about 2.5 parts, for example about 1.2 parts to about 2.1 parts, or about 1.8 parts to about 2 parts.
  • the mole ratio of metal hydride to nicotinate ester is about 1 to 4, for example about 1 : 2 to about 1.6: 2, or about 2:2.
  • the metal in the metal hydride may be lithium, potassium or sodium, for example potassium or sodium, or in some embodiments, sodium.
  • the amount of N-vinylogous-2-pyrolidinone with respect to the amount (in mole equivalents) of nicotinate ester utilized in the condensation reaction mixture may be about 0.1 parts to about 10 parts, for example about 0.5 parts to about 3 parts, or about 1.0 part to about 1.2 parts.
  • the amount of solvent utilized in the condensation reaction mixture with respect to 1 part (in mole equivalents) nicotinate ester may be about 1 parts to about 15 parts, for example about 3 parts to about 10 parts, about 4 parts to about 8 parts, or about 5 parts to about 7 parts.
  • the solvent may be anhydrous.
  • suitable solvents include aromatic hydrocarbon or hydrocarbon solvents, dipolar aprotic solvents (such as, for example,
  • DMF dimethylformamide
  • ethers such as, for example, ethyl ether
  • tetrahydrofuran THF or tetrahydrofuran derivatives
  • polyethers such as, for example, "glyme” or "diglyme”
  • suitable aromatic hydrocarbons or hydrocarbon solvents include alcohols, toluene, xylenes, benzene, and the like.
  • the solvent is an alcohol, or an alcohol and ether combination.
  • the solvent may be THF, or a mixture of DMF and ether, and/or a mixture of DMF and a hydrocarbon or aromatic hydrocarbon.
  • the solvent may be toluene (or benzene).
  • Alcohols such as ethanol, methanol, and/or propanol may be added to help catalyze the condensation, or the alcohol(s) may be used as the only solvent. If an alcohol is to be used as a solvent or co-solvent in the condensation, then the metals sodium, potassium or lithium may be employed in less than or equal to stoichiometric amounts with respect to the nicotinate ester. In some
  • the time of solvent addition is such that a mild effervescence is maintained, and an internal temperature of between 50°C and 80°C is maintained throughout the addition process.
  • the time of addition varies with volume, but may take place within a matter of minutes to hours.
  • the condensation reaction mixture becomes greenish.
  • This greenish condensation reaction mixture may be stirred, in some embodiments, under an inert atmosphere for an appropriate amount of time in order to complete the reaction.
  • the greenish condensation reaction mixture may be heated to an internal temperature of about 40°C to about 110°C, for example about 60°C to about 100°C, or about 80°C to about 95°C.
  • the condensation reaction mixture may contain a reaction product mixture that includes some unreacted starting material (i.e., nicotinate ester, n-vinylogous-2- pyrrolidinone, sodium hydride) as well as the desired reaction products, i.e., the main condensation product which is the nicotinate-n-vinylogous-2-pyrrolidinone adduct
  • the condensation adduct an organic bicyclic compound as the metal salt, e.g., 1 -(1 - alkenyl)-3-nicotinoylpyrrolidine-2-one, where the alkenyl may be ethenyl in some embodiments
  • the alcohol as the metal salt, and some alcohol that is displaced from the nicotinate ester as the alcohol.
  • the reaction product mixture may be either injected (or poured) directly into a solution of acid to form an acid reaction mixture.
  • the acid solution may be a boiling acid solution, or a cold acid aqueous solution.
  • the acid is an aqueous hydrochloric acid solution.
  • the normality of the acid solution may be about 3 to about 12, for example about 4 to about 7, or about 5 to about 6.
  • 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 a cold solution of acid.
  • the amount of the acid may be about 0.25 parts to about 5 parts, for example about 0.5 parts to about 2 parts, or about 0.75 parts to about 1.5 parts with respect to one part of the condensation reaction mixture.
  • the reaction of the acid reaction mixture yields a biphasic mixture in which the protonated bicyclic pyridine-pyrrolidinone adduct (i.e., protonated condensation adduct) which is soluble in water and insoluble in the organic solvent is present in the aqueous phase (or layer), and any unreacted pyrrolidinone starting material is in the organic phase (or layer).
  • the reaction is allowed to settle without agitation, two distinct layers are formed, aqueous and organic (non-aqueous), and the product of the reaction is in the aqueous layer, which aqueous layer is then separated and subjected to further reaction or processing.
  • aqueous and organic (non-aqueous) layers are separated, a concentrated acid is 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 separated aqueous layer to form the aqueous reaction mixture may be about 0.15 parts to about 1.5 part, for example about 0.2 part to about 0.5 part, or about 0.25 part to about 0.5 part with respect to 1 part of the separated aqueous layer.
  • the concentrated acid may be 12N hydrochloric acid (concentrated hydrochloric acid [ca37%]).
  • the aqueous reaction mixture is comprised of water, acid, and product (i.e., the protonated acyclic amine salt, e.g., protonated 3-(4-aminobutanyl-1 -one)-pyridine).
  • product i.e., the protonated acyclic amine salt, e.g., protonated 3-(4-aminobutanyl-1 -one)-pyridine.
  • the aqueous reaction mixture may be cooled to -10°C to 5°C. Then the acidic aqueous reaction mixture (or solution) may be made strongly basic (e.g., having a pH greater than 9) while keeping the temperature at an appropriate level to maintain the reaction.
  • the result of this reaction is the myosamine reaction mixture, which is comprised of myosamine, base, water, and any remaining unreacted materials from the aqueous reaction mixture, as well as any contaminants natural to the reaction.
  • the resulting basic aqueous reaction mixture is extracted with organic solvent, and then the solvent is distilled off to yield crude myosamine.
  • the organic solvent may be dichloromethane.
  • the amount of organic solvent may be about 1 part to about 10 parts with respect to the amount of the basic aqueous reaction mixture, for example about 1.5 parts to about 5 parts, or about 2 parts to about 4 parts with respect to the basic aqueous reaction mixture.
  • the completed condensation reaction may be injected directly into a hot solution of hydrochloric acid (instead of the cold acid solution described above), resulting in a heterogeneous acid reaction mixture.
  • the heterogeneous acid reaction mixture may be heated using an external bath to enable vigorous reflux, and the vigorous reflux may be continued until the reaction is complete.
  • condensation reaction mixture may be toluene or xylene, or a high boiling point solvent such as diglyme.
  • a suitable hydrogenation catalyst is added in a suitable amount to the crude myosamine (3) in solution with an appropriate solvent to form a myosamine reaction mixture.
  • the myosamine reaction mixture is submitted to an atmosphere of hydrogen gas at a pressure greater than or equal to ambient pressure, but not high enough to reduce the carbons in the pyridine ring.
  • the solvent for the myosamine reaction mixture may be an alcoholic solvent, for example, ethanol or isopropanol, although other solvents known in the art of hydrogenation can also be employed.
  • the amount of solvent may be about 3 parts to about 98 parts, for example about 4 parts to about 60 parts, or about 5 parts to about 20 parts solvent with respect to 1 part crude myosamine.
  • the suitable hydrogenation catalyst may include 10% palladium on carbon, but other catalysts common to the art of catalytic hydrogenation may also be employed, either as a co-catalyst, or as the sole catalyst.
  • the pressure of the hydrogen gas can be about ambient pressure to about 100 atmospheres, for example about ambient pressure to about 75 atmospheres, or about 10 to about 50 atmospheres.
  • the myosamine reaction mixture may include a borohydride salt as the reducing agent rather than a hydrogenation catalyst, and the myosamine reaction mixture may undergo different reaction conditions suitable to effect reduction of the myosamine to nornicotine using the borohydride salt.
  • the resulting mixture contains crude RS-Nicotine product, solvent (water), and any unreacted starting material 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
  • the synthetic nicotine produced according to the above-described chemical synthesis is substantially free or completely free of certain contaminants typically found in the natural nicotine derived from tobacco leaves.
  • the synthetic nicotine may be substantially free of these contaminants, such that the combined amount of these contaminants in the synthetic nicotine may be more than 0 wt% but less than 0.5 wt%, for example less than 0.2 wt%, less than 0.01 wt%, less than 0.001 wt%, less than 0.0001 wt%, or less than 0.00001 wt% based on the total weight of the synthetic nicotine.
  • completely free or free of these contaminants means that the synthetic nicotine includes no measurable amount of these contaminants, i.e., 0 wt% (or none).
  • the synthetic nicotine is substantially free or completely free of contaminants such as alkaloid compounds, which may be found in nicotine derived from tobacco.
  • the synthetic nicotine may be substantially free or completely free of one or more or all of nicotine-1 '-N-oxide, nicotyrine, nornicotyrine, 2',3-bipyridyl, anabasine, and anatabine. While these contaminants may be 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 substantially free or completely free of those contaminants and impurities as well.
  • the synthetic nicotine may include certain other impurities or contaminants resulting from the synthetic route. Although such contaminants and impurities may be present in the synthetic nicotine according to embodiments of the present invention, these impurities are not generally present in tobacco-derived or naturally sourced nicotine. Indeed, the contaminants/impurities found in naturally sourced (or tobacco-derived) nicotine are significantly different than those potentially found in the synthetic nicotine according to embodiments of the present invention. For example, the contaminants or impurities present in the synthetic nicotine according to
  • embodiments of the present invention may include one or more or all of myosamine, nornicotine, water, and the solvents (discussed above) used in the various reactions of the synthesis scheme. Additionally, in some embodiments, the contaminants or impurities present in the synthetic nicotine may include one or more or all of 1 -keto- 5-methylamino, or 1 -hydroxy-5-methylamino-2-pyridine. As used herein, the terms "synthetic contaminants,” “synthetic impurities,” and like terms, are used herein.
  • the synthetic nicotine may include about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 5 wt%, for example about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 1 wt%, about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 0.5 wt% myosamine.
  • the synthetic nicotine may include about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 5 wt%, for example about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 3 wt%, or about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 1 wt% nornicotine.
  • the synthetic nicotine may include about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 5 wt%, for example about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 5 wt%, for example about 0 wt% (i.e., an
  • the synthetic nicotine may include about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 5 wt%, for example about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 3 wt%, or about 0 wt% (i.e., an undetectable, or unmeasurable amount) to about 1 wt% water.
  • the synthetic nicotine includes a ratio of the R-isomer to the S-isomer of 1 :1.
  • the ratio of the R-isomer to the S-isomer can be manipulated through further resolution of the synthetic nicotine.
  • the synthetic nicotine may have a ratio of the R-isomer to the S-isomer of 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 :5 to about 1 :7.
  • the synthetic nicotine may include a ratio of the R-isomer to the S-isomer of about 1 : 1 to about 1000: 1 , about 1.1 :1 to about 100:1 , about 2:1 to about 5:1 , about 4:1 to about 9:1 , or about 5:1 to about 7:1.
  • the synthetic nicotine includes a ratio of the S-isomer to the R-isomer of less than 50:1 , for example 45:1 or lower, 40:1 or lower, or 35:1 or lower.
  • the synthetic nicotine may include a ratio of the R-isomer to the S-isomer of less than 50:1 , for example 45:1 or lower, 40:1 or lower, or 35:1 or lower.
  • the synthetic nicotine may include the R-isomer in an amount greater than 5 wt%, for example, greater than 7 wt%, or greater than 10 wt%.
  • the synthetic nicotine may include the S-isomer in an amount greater than 5 wt%, for example, greater than 7 wt%, or greater than 10 wt%. In some embodiments, the synthetic nicotine includes more R-isomer than S-isomer, and in some embodiments, the synthetic nicotine includes more S-isomer than R-isomer.
  • Techniques for determining chirality or optical rotation of a sample are known to those of ordinary skill in the art, and the ordinary artisan would be readily capable of selecting an appropriate technique and carrying out that technique to determine chirality or optical rotation.
  • One nonlimiting example of such a technique is high performance liquid chromatography (HPLC) using a chiral column.
  • HPLC high performance liquid chromatography
  • the optical rotation of the sample may first be
  • the sample may be run through the chiral column and the results compared to the USP standard for tobacco-derived or natural nicotine.
  • the synthetic nicotine containing the racemic mixture of R and S isomers may be resolved to have these relative amounts of the R and S isomers by any suitable resolution techniques, which techniques are known to those skilled in the art (e.g., crystallization, chromatography, etc.). Additionally, in some embodiments, the synthesized nicotine may be fully resolved to yield either pure R-isomer or pure S- isomer.
  • the term "pure" as used in defining the isomeric composition of the synthetic nicotine refers to a percentage of the identified isomer of greater than 97%, for example greater than 98%, and in some embodiments greater than
  • a "pure S isomer” synthetic nicotine includes a synthetic nicotine that has been resolved to include a ratio of S isomer to R isomer of greater than 97:3, for example greater than 98:2, and in some embodiments, greater than 99:1.
  • a "pure R isomer” synthetic nicotine includes a synthetic nicotine that has been resolved to include a ratio of R isomer to S isomer of greater than 97:3, for example greater than 98:2, and in some embodiments, greater than 99:1.
  • a pure R isomer may include 100% R isomer with 0% S isomer
  • a pure S isomer may include 100% S isomer with 0% R isomer.
  • any suitable resolution technique may be used to resolve the synthetic nicotine composition, which techniques are known to those of ordinary skill in the art.
  • resolution techniques include those described in Divi et al., U.S. Patent Publication No. 2012/0197022, filed April 6, 201 1 , Aceto, et al., J. Med. Chem., "Optically Pure (+)-Nicotine from ( ⁇ )-Nicotine and Biological Comparisons with (-)-Nicotine vol. 22, pgs.
  • resolution of the racemic mixture may be accomplished using D-tartaric acid, and as described in DeTraglia et al., resolution can be accomplished using pseudomonas putida.
  • resolution of the racemic mixture may be accomplished using (+)-0,0'-di-p-toluoyl-D-tartaric acid.
  • resolution of the racemic mixture may be accomplished by diastereomeric salt formation using dibenzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid to achieve separation.
  • the racemic mixture may be blended or mixed with suitable added amounts of pure R isomer or pure S isomer, which pure isomers would typically be prepared via enantioselective synthetic pathways.
  • naturally sourced nicotine i.e., that derived from tobacco leaves
  • naturally sourced tobacco generally has an undetectable or small amount of the R isomer
  • typically the naturally sourced tobacco mainly includes the S isomer.
  • naturally sourced tobacco typically has an S to R isomer ratio of greater than 50:1.
  • the synthetic nicotine may include a mixture of the R and S isomers, whether racemic or otherwise.
  • tobacco-derived (or naturally sourced) nicotine typically has greater than 95 wt% of the S isomer, and therefore is optically active. Indeed, when measured using a standard polarimeter, the tobacco-derived nicotine (having 95 wt% or greater S nicotine isomer) registers a negative optical rotation which is typically greater than 125°.
  • the synthetic nicotine may include a racemic (or 1 :1 ) mixture of the R and S isomers, yielding a nicotine having no optical rotation.
  • the synthetic product will register an optical rotation that is different from the optical rotation of tobacco-derived nicotine (i.e., due to the presence of the R isomer, which generally has an opposite optical rotation than that of the S isomer).
  • tobacco-derived (or naturally sourced) nicotine may include one or more or all of the following impurities: nicotine-1 '-N-oxide, nicotyrine, nornicotyrine, 2',3-bipyridyl, cotinine, anabasine, anatabine, nornicotine, and myosamine.
  • tobacco derived nicotine may comprise 99.5 wt% nicotine, 0.1 wt% nornicotine, 0.15 wt% myosamine, and 0.1 wt% cotinine.
  • the vaping composition or vaping solution may include both the synthetic nicotine described above and an amount of naturally sourced (or tobacco-derived) nicotine.
  • the portion of the composition making up the tobacco-derived nicotine may include these components (or contaminants) in, e.g., the above amounts.
  • the naturally sourced nicotine or tobacco-derived nicotine
  • the amount of these natural tobacco contaminants in the overall vaping composition is significantly lower than the amounts reported above, and significantly lower than the amounts in comparable vaping compositions or solutions using larger portions of (or all) naturally sourced nicotine.
  • the composition for use in electronic vaping devices may further comprise, consist essentially of, or consist of one or more pharmaceutically acceptable excipients, additives or solvents.
  • excipients, additives and/or solvents include water, organic solvents, sweetening and/or flavoring agents, pH adjusting agents and the like.
  • Nonlimiting examples of solvents that may be used in liquid vaping compositions include water, and alcohols such as 1 ,2-propylene glycol (PG or MPG), ethanol, ethyl acetate, 1 -3 propanediol, glycerin (e.g., vegetable glycerin) and the like.
  • the solvent may include a single solvent or may include a combination of two or more solvents.
  • the amount of solvent present may be about 50 wt% to about 99.99 wt %, for example about 75 wt% to about 99 wt%, or about 85 wt% to about 98 wt% based on the total weight of the composition.
  • the vaping composition may include water as a solvent.
  • the amount of water present in the vaping composition may be about 0.1 to about 10 wt%, for example about 0.5 to about 5 wt %, based on the total weight of the vaping composition.
  • the vaping composition may include glycerin as a solvent, and the glycerin may be a Kosher vegetable glycerin having a purity greater than 99%, for example greater than 99.5%, or greater than 99.9%.
  • the glycerin may be odorless, colorless and have a slightly sweet taste.
  • the vaping composition may include propylene glycol as a solvent, and the propylene glycol may be USP grade and have a purity greater than 99%, for example greater than 99.5%, or greater than 99.99%.
  • the propylene glycol may be odorless and colorless, and essentially tasteless.
  • the vaping composition may include a solvent that comprises, consists essentially of, or consists of glycerin and propylene glycol.
  • the pH of the vaping composition may be adjusted by the addition of pharmacologically or pharmaceutically acceptable acids as pH adjusting agents.
  • the acid pH adjusting agent may be an inorganic acid.
  • suitable inorganic acid pH adjusting agents include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid.
  • the inorganic acid may include hydrochloric acid and/or sulfuric acid (i.e., an inorganic acid or a mixture of inorganic acids).
  • the acid pH adjusting agent may be an organic acid.
  • 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, and the like.
  • the organic acid may be lactic acid, ascorbic acid, fumaric acid and/or citric acid (i.e., an organic acid or a mixture of organic acids).
  • the organic acid includes citric acid and/or lactic acid.
  • the acid pH adjusting agent may be an acid which forms an acid addition salt with the active substance.
  • a single acid pH adjusting agent may be used, or a mixture of two or more acid pH adjusting agents may be used.
  • some acids have additional properties that make them desirable for inclusion in the vaping composition.
  • some acids may have pH adjusting (or acidifying) properties in addition to auxiliary or additional properties, such as, e.g. flavoring properties or antioxidant properties.
  • pH adjusting (or acidifying) properties in addition to auxiliary or additional properties, such as, e.g. flavoring properties or antioxidant properties.
  • Some nonlimiting examples of such dual function acids include citric acid and ascorbic acid.
  • the pH adjusting agent may be basic, or the vaping composition may include an additional pH adjusting agent that is basic (e.g., in addition to the acidic pH adjusting agent).
  • a basic pH adjusting agent may be used or desired to more precisely titrate the pH of the vaping composition.
  • the pH adjusting agent may include (or further include) a basic pH adjusting agent, which may include a pharmacologically acceptable base.
  • suitable such bases include alkali metal hydroxides and alkali metal carbonates.
  • the alkali ion in the alkali metal hydroxides or carbonates may be sodium.
  • the vaping composition may further include a pharmacologically or pharmaceutically acceptable excipient.
  • the excipient may include any of a number of compounds, some nonlimiting examples of which include antioxidants, such as ascorbic acid (which can also be used to adjust the pH as discussed above), vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body.
  • antioxidants such as ascorbic acid (which can also be used to adjust the pH as discussed above), vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body.
  • suitable excipients include preservatives, which can 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.
  • suitable preservatives include benzalkonium chloride, benzoic acid or benzoates such as sodium benzoate.
  • the preservative may include
  • benzalkonium chloride Any suitable amount of the preservative may also be used, which amount (or concentration) would be known to those skilled in the art.
  • the vaping composition may further comprise a sweetening and/or flavoring agent.
  • a sweetening and/or flavoring agent Any suitable such sweetener and/or flavoring agent may be used, some nonlimiting examples of which include peppermint, menthol, wintergreen, spearmint, propolis, eucalyptus, cinnamon, or the like.
  • suitable flavorants or sweeteners include those derived from fruits, tobacco itself, liquor, coffee and confectionaries.
  • the amount of the sweetener and/or flavorant may be about 0 wt% (e.g.
  • the amount of the sweetener and/or flavorant may be about 10 wt% based on the total weight of the vaping composition.
  • a vaping composition may comprise, consist essentially of, or consist of nicotine, propylene glycol, glycerin, nut oils, drinking alcohol (such as vodka), and flavorings (e.g., those designed for use in vaping devices).
  • the amount of nicotine in the vaping composition may be as described above with respect to a wholly synthetic nicotine source, a combination of both synthetic nicotine (e.g., synthetic S-nicotine or synthetic R-nicotine) and tobacco derived (or naturally sourced) nicotine, or an R,S isomeric mixture or blend (e.g., a racemic mixture, or any other mixture of the R and S isomers).
  • the amount of propylene glycol in the vaping composition may be about 0 wt% (i.e., not present at all, or not added) to about 99 wt%, for example about 10 wt% to about 70%, or about 30 wt% to about 50%, based on the total weight of the vaping composition.
  • the amount of glycerin in the vaping composition may be about 0 wt% (i.e., not present at all, or not added) to about 99 wt%, for example about 30 wt% to about 90 wt%, or about 40 wt% to about 70 wt%, based on the total weight of the vaping composition.
  • the amount of nut oil in the vaping composition may be about 0 wt% (i.e., not present at all, or not added) to about 20 wt%, for example about 0.5 wt% to about 10 wt%, or about 1.0 wt% to about 5.0 wt%, based on the total weight of the vaping composition.
  • the amount of drinking alcohol (such as vodka) may be about 0 wt% (i.e., not present at all, or not added) to about 99 wt%, for example about 30 wt% to about 90 wt%, or about 40 wt% to about 70 wt%, based on the total weight of the vaping composition.
  • the amount of flavorings in the vaping composition may be about 0 wt% (i.e., not present at all, or not added) to about 40 wt%, for example about 1.0 wt% to about 30 wt%, about 5 wt% to about 20 wt%, or about 10 wt% to about 15 wt%, based on the total weight of the vaping composition.
  • vaping compositions according to embodiments of the present invention including a portion of synthetic nicotine has suitable and/or enhanced physiological activity on the human system, including neuroactivity, as well as suitable and/or enhanced sensory appeal (e.g., mouthfeel, throatfeel, etc.) as compared to compositions including only nicotine derived from tobacco (or naturally sourced nicotine) as the nicotine component.
  • suitable and/or enhanced sensory appeal e.g., mouthfeel, throatfeel, etc.
  • smoker/vaporizer uses have found that the compositions according to the present invention including at least a portion of synthetic nicotine to be preferable to compositions using only nicotine derived from tobacco (or naturally sourced nicotine) as the nicotine component.
  • vaping compositions described herein have fewer of the contaminants associated with tobacco-derived nicotine, smaller amounts (if any at all) of flavorants are needed in the compositions. In particular, smaller amounts of flavorants are needed to mask the bitterness and smell of comparable compositions comprising only tobacco-derived nicotine as the nicotine component. In some embodiments, the vaping composition is substantially free of flavorants.
  • Using smaller amounts of flavorants provides a mechanical benefit to the electronic vaping device. Specifically, the use of smaller amounts of flavorants leads to less wear on the coil or heating element of the vaporizer. Because flavorants tend to be sticky, oily or more viscous than the other components in the vaping composition, the addition of larger amounts of flavorants causes the coil (or heating element) to work harder to heat the vaping composition. Also, because of the sticky, oily, viscous properties of the flavorants, compositions having larger amounts of flavorants tend to have larger amounts of buildup on the coil, which also increases wear on the coil, and decreases the working life of the coil (and device).
  • vaping compositions according to embodiments of the present invention In contrast, in the vaping compositions according to embodiments of the present invention, smaller amounts of the flavorants are used, reducing the wear on the coil, and the potential for buildup on the coil. As a result, the vaping compositions according to embodiments of the present invention can increase the working life of the coil or heating element, and thus the life of the vaping device.
  • a (1 ) 50-50 RS synthetic nicotine provides the same or better sensory impact as "S” nicotine derived from tobacco.
  • a (2) racemic synthetic nicotine is neurologically effective, and in many cases exhibits superior neurological effect to that of tobacco-derived (“S") nicotine.
  • the above-disclosed blends of synthetic RS nicotine with synthetic or non-synthetic tobacco-derived nicotine have improved sensory impact as well as neurological impact on the user as compared to vaping compositions having only tobacco-derived nicotine as the source of nicotine. Additionally, having fewer tobacco alkaloids in the vaping composition increases the shelf life of the
  • composition and maintains visual clarity of product (e.g., a colorless or transparent appearance).
  • an electronic vaping device utilizes the vaping compositions described above. Any suitable electronic vaping device may use the vaping compositions according to
  • embodiments of the present invention include single-use (or disposable) e-cigarettes, refillable devices that can be refilled with a vaping (e.g., liquid) composition, and/or reusable devices having removable and replaceable cartridges containing a vaping (e.g., liquid) composition.
  • a vaping e.g., liquid
  • reusable devices having removable and replaceable cartridges containing a vaping (e.g., liquid) composition.
  • a vaping device may include the vaping compositions described herein and an atomizer (or a heating coil or other heat source) for vaporizing the composition.
  • an e-cigarette according to embodiments of the present invention is shown in FIG. 1.
  • an external shell 14 has an air inlet 4 and houses an LED 1 , cell 2, electronic circuit board 3, normal pressure cavity 5, sensor 6, vapor-liquid separator 7, atomizer 9, liquid-supplying bottle 11 , mouthpiece 15, microswitch 16, gas vent 17, and air passage 18.
  • the electronic circuit board 3 has an electronic switching circuit and a high frequency generator.
  • the sensor 6 includes a negative pressure cavity 8 separated from the sensor 6 by a ripple film.
  • the atomizer 9 has an atomization cavity 10.
  • a retaining ring 13 locks the liquid-supplying bottle 11 between one side of the liquid-supplying bottle 11 and the shell 14.
  • the other side of the liquid- supplying bottle includes an aerosol passage 12.
  • vaping compositions according to embodiments of the present invention may be used with any known type of electronic vaping device including devices referred in the art as direct coil vaporizers, heated plate vaporizers, ceramic or metal bed/bowl heating vaporizers, ultrasonic agitation vaporizers, and electronic heated nail/spike vaporizers.
  • the heating range of the heating elements during operation of these devices may be about 100°C to about 460 °C.
  • the combined extracts from the separation were dried over sodium sulfate, filtered and the solvent evaporated to give an amorphous material.
  • the amorphous material was taken up in 3 parts ethanol, and then palladium-on-carbon was added (about 10%) and the resulting mixture was subjected to hydrogen pressure for 6 hours (greater than 25 atmospheres).
  • the resulting residue was diluted with more ethanol and filtered through celite.
  • the solvent was evaporated to dryness under vacuum with minimal heat, and then the residue was taken up in a formic acid/formaldehyde solution (1 :1 ).
  • the resulting mixture was heated to an internal temperature of 90 degrees Celsius and maintained at this temperature over a period of 12 hours, and then cooled and neutralized with sodium hydroxide to a pH of greater than 10, and then extracted with
  • dichloromethane was added and the layers were separated.
  • the aqueous layer was extracted twice with excess dichloromethane, and the extracts were combined and washed with water, and then dried over sodium sulfate.
  • the solution was then filtered and the solvent removed using vacuum to yield a brownish solid.
  • This solid was dissolved in ethanol (about 5 to about 10 parts), and then 0.5 parts palladium on carbon was added and the resulting mixture was subjected to hydrogen pressure for 6 hours (greater than 25 atmospheres). The resulting residue was diluted with more ethanol and filtered through celite.
  • the mildly effervescent exothermic reaction mixture turned a light rose color and then a light green precipitant formed as the exothermic reaction maintained itself at about 60 to about 65 °C. After the addition was complete, the reaction mixture was heated to an internal temperature of about 85°C and
  • the reaction mixture was cooled to 0°C, and then neutralized with 50% sodium hydroxide solution while not allowing the internal temperature to go above 35 to 40 degrees centigrade.
  • the pH was made very basic by addition of a sodium hydroxide solution (50%) until the pH reached 1 1 to 13 (as indicated by a blue color change on litmus paper).
  • the resulting solution was extracted 4 times with 15L of dichloromethane, and the combined extracts were subjected to medium vacuum distillation to yield myosamine as a non-viscous brownish oil.
  • COMPOSITION EXAMPLE 1 1 - COMPOSITION FOR USE IN ELECTRONIC VAPING DEVICES
  • the R,S nicotine was produced by the method of Example 10.
  • the composition of the R,S nicotine had an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic nicotine was a racemic mixture of R and S isomers).
  • the synthetic RS- nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • COMPOSITION EXAMPLE 12 COMPOSITION FOR USE IN ELECTRONIC VAPING DEVICES
  • the S-nicotine was produced by resolution of RS nicotine to semi-pure or enantio-pure (i.e., 98% or greater) synthetic S-nicotine using (+)-0,0'-di-p-toluoyl-D- tartaric acid.
  • the synthetic S-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic S-nicotine component does not include other
  • the R,S nicotine was produced by the method of Example 10.
  • the composition of the R,S nicotine had an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic nicotine was a racemic mixture of R and S isomers).
  • the synthetic RS- nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the R,S nicotine was produced by the method of Example 10.
  • the composition of the R, S nicotine had an R isomer to S isomer ratio of 1 :1.
  • the S- nicotine was produced by resolution of R, S-nicotine to semi-pure or enantio-pure (i.e., 98% or greater) S-nicotine using (+)-O,O'-di-p-toluoyl-D-tartaric acid.
  • the nicotine component of the composition includes a mixture (or blend) of racemic RS nicotine and pure S nicotine, both of which are synthetic.
  • the composition of the R,S nicotine had an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic RS nicotine is a racemic mixture of R and S isomers).
  • the synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the synthetic S-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic S-nicotine component also does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • COMPOSITION EXAMPLE 15 COMPOSITION FOR USE IN ELECTRONIC VAPING DEVICES
  • the R,S nicotine was produced by the method of Example 10.
  • the tobacco-derived S-nicotine is off-the-shelf nicotine, such as one of the (-)-Nicotine products available from Sigma-Aldrich Co., LLC.
  • the nicotine component of the composition included a mixture (or blend) of racemic RS nicotine (which is synthetic) and S-nicotine derived from tobacco (naturally sourced).
  • the synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the tobacco-derived nicotine component may contain the contaminants discussed above normally found in tobacco-derived nicotine, and may also contain those contaminants in the amounts described above.
  • the R,S nicotine was produced by the method of Example 10.
  • the tobacco-derived S-nicotine is off-the-shelf nicotine, such as one of the (-)-Nicotine products available from Sigma-Aldrich Co., LLC.
  • the nicotine component of the composition included a mixture (or blend) of racemic RS nicotine (which is synthetic) and S nicotine derived from tobacco (naturally sourced).
  • the synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the tobacco-derived nicotine component may contain the contaminants discussed above normally found in tobacco-derived nicotine, and may also contain those contaminants in the amounts described above.
  • the R,S nicotine was produced by the method of Example 10.
  • the composition of the R,S nicotine had an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers).
  • the synthetic RS- nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt%, or about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the R,S nicotine was produced by the method of Example 10.
  • the composition of the R,S nicotine had an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers).
  • the synthetic RS- nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • COMPOSITION EXAMPLE 19 COMPOSITION FOR USE IN ELECTRONIC VAPING DEVICES
  • the R,S nicotine was produced by the method of Example 10.
  • the composition of the R,S nicotine has an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers).
  • the synthetic RS- nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt%, or about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the flavoring was obtained from Capella Flavors, Inc. (San Marcos, CA).
  • COMPOSITION EXAMPLE 20 COMPOSITION FOR USE IN ELECTRONIC VAPING DEVICES
  • the synthetic S-nicotine was produced by resolution of RS nicotine to semi-pure or enantio-pure (i.e., 98% or greater) S-nicotine using (+)-O,O'-di-p- toluoyl-D-tartaric acid.
  • the synthetic S-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt% or less.
  • the synthetic S-nicotine component also does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the flavoring was obtained from Capella Flavors, Inc. (San Marcos, CA).
  • Flavoring 20.0 The R,S nicotine was produced by the method of Example 10.
  • the composition of the R,S nicotine has an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers).
  • the synthetic RS- nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt%, or about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the flavoring was obtained from Capella Flavors, Inc. (San Marcos, CA).
  • an "open tank” or “open system” vaping device the user may fill and/or refill the tank or cartridge designed to house the vaping liquid.
  • Open tank or open system vaping devices are popular due to their high level of customizability.
  • open tank or open system devices are not limited to the vaping liquids provided with the device, and instead can be customized by the addition of any suitable vaping liquid to the open cartridge of the system.
  • the open tank or open system device was the product marketed as "Sub Tank” by Shenzhen Kanger Technology Co., Ltd. (Shenzhen, China).
  • the R,S nicotine was produced by the method of Example 10.
  • the composition of the R,S nicotine has an R isomer to S isomer ratio of 1 :1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers).
  • the synthetic RS- nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt%, or about 0.5 wt% or less.
  • the synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.
  • the flavoring was obtained from Capella Flavors, Inc. (San Marcos, CA).
  • vaping liquid is pre-charged into a closed container or cartridge mounted in the closed system device.
  • This pre-charged cartridge is not fillable or refillable by the user of the device.
  • most "closed tank” or “closed system” vaping devices are designed as disposable after exhaustion of the vaping liquid in the pre-charged cartridge (e.g., e-cigarettes or so-called “cig-a- likes"). COMPARATIVE TESTING
  • the first composition included 0.3 wt% synthetic nicotine as a racemic mixture, and 99.7 wt% glycerin.
  • the second composition i.e., the comparative composition
  • the only difference between the compositions was that the nicotine in the first composition was purely synthetic nicotine and the nicotine in the second composition was purely tobacco-derived nicotine.
  • the users were not informed whether their electronic vaping devices contained the first composition or the second composition, and the testing was done according to typical sensory evaluation methods including a panel and questionnaire. In every single instance, the user stated that they preferred the sensation provided by the electronic vaping device comprising the first composition having the synthetic nicotine.
  • the users expressed that, with respect to the composition comprising only synthetic nicotine, the flavors were much better, they could not taste or smell the nicotine, there was no tobacco after-taste, and that the nicotine impact was as strong as tobacco-derived nicotine.
  • the flavor blending was much easier because it was not necessary to mask the nicotine taste. Furthermore, the coils (or heating elements) in the vaping devices were found to burn clean all day. In contrast, the tobacco-derived nicotine compositions required large amounts of flavorants, which caused the devices to get dirty after a short period of time, necessitating cleaning the devices a number of times throughout the testing period.
  • the first composition was a 0.3% synthetic S nicotine prepared according to the methods described herein; the second composition was a 0.3% tobacco-derived nicotine; the third composition was a 0.3% synthetic RS nicotine prepared by the methods described herein; the fourth composition was a 0.6% synthetic S nicotine prepared according to the methods described herein; the fifth composition was a 0.6% tobacco-derived nicotine; the third composition was a 0.6% synthetic RS nicotine prepared by the methods described herein.
  • the subjects used the following criteria: Throat Feel Head Feel Dynamics
  • electrophysiology-based HTS assay was used to evaluate and compare the activity of different nicotine forms on two nicotinic ACh receptors (nAChRs), i.e., a7 and ⁇ 4 ⁇ 2.
  • nAChRs nicotinic ACh receptors
  • the nicotinic forms subjected to this assay included an S nicotine available from Sigma-Aldrich Corporation, St.
  • the synthetic R nicotine according to embodiments of the present invention appears to be a full, weak agonist at human a7 nAChRs, but only a partial agonist at human ⁇ 4 ⁇ 2 nAChRs, suggesting a selectivity of the nicotine isomers at different types of nAChRs, which is surprising and unexpected. For example, these results may suggest different
  • neurophysiological responses to the R and S isomers of nicotine and therefore different neurophysiological responses to various mixtures of the R and S isomers. These differences in the neurophysiological response may be responsible for the different sensory experiences reported in Tables 1 and 2 above, and these
  • vaping compositions according to embodiments of the present invention include a synthetic nicotine source that improves the vaping experience by the vaping consumer.
  • a synthetic nicotine source that improves the vaping experience by the vaping consumer.
  • vaping users can typically detect a foul taste in vaping liquids that use tobacco-derived nicotine, the same users typically cannot detect a similar foul taste in vaping liquids according to embodiments of the present invention using synthetic nicotine.
  • vaping liquids using tobacco-derived nicotine typically include large amounts of flavorants to mask the foul taste of the tobacco-derived nicotine
  • the vaping liquids according to embodiments of the present invention need not use so much flavorant. As discussed above, this reduction in the amount of flavorant can improve the lifespan of the vaping device in which the vaping liquid is used.
  • vaping liquids using tobacco-derived nicotine typically have a harsh throat feel when vaporized by the vaping device, and generally have a strong "tobacco" odor.
  • the vaping liquids according to embodiments of the present invention using synthetic nicotine have a smoother throat feel, eliminating (or at least significantly reducing) the harsh feel associated with tobacco-derived nicotine.
  • the vaping liquids according to embodiments of the present invention include synthetic nicotine that is not derived from tobacco, and therefore exhibit significantly fewer "tobacco" odors.
  • a nicotine source that comprises a synthetic nicotine
  • a nicotine source consisting essentially of or consisting of a synthetic nicotine is also within the scope of this disclosure.
  • the nicotine source may consist essentially of the synthetic nicotine.
  • “consisting essentially of” means that any additional components in the nicotine source will not materially affect the user experience in terms of taste or neurological effect.
  • a nicotine source consisting essentially of the synthetic nicotine may exclude any measurable or detectable amount of the contaminants or impurities described herein as normally associated with tobacco-derived nicotine.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne une composition adaptée pour utilisation dans un dispositif de vapotage qui comprend un produit de nicotine qui comprend une nicotine synthétique qui est sensiblement exempte d'un ou plusieurs contaminants et/ou impuretés normalement associés à la nicotine dérivée de tabac. Par exemple, la nicotine synthétique est sensiblement exempte d'un ou plusieurs des 1'-N-oxyde de nicotine, nicotyrine, nornicotyrine, 2',3-bipyridyle, cotinine, anabasine et/ou anatabine. La composition comprend en outre un ou plusieurs excipients, additifs et/ou solvants pharmaceutiquement acceptables.
EP16858466.2A 2015-10-23 2016-10-24 Composition de nicotine pour dispositifs de vapotage et dispositifs de vapotage utilisant celle-ci Withdrawn EP3364951A4 (fr)

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US201562245795P 2015-10-23 2015-10-23
PCT/US2016/058544 WO2017070706A1 (fr) 2015-10-23 2016-10-24 Composition de nicotine pour dispositifs de vapotage et dispositifs de vapotage utilisant celle-ci

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AU2016341443A1 (en) 2018-06-07
CN108697643A (zh) 2018-10-23
EP3364951A4 (fr) 2019-04-17
WO2017070706A1 (fr) 2017-04-27
US20170112182A1 (en) 2017-04-27
CA3041577A1 (fr) 2017-04-27

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