WO2021220018A1 - Composition et utilisation correspondante - Google Patents

Composition et utilisation correspondante Download PDF

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Publication number
WO2021220018A1
WO2021220018A1 PCT/GB2021/051055 GB2021051055W WO2021220018A1 WO 2021220018 A1 WO2021220018 A1 WO 2021220018A1 GB 2021051055 W GB2021051055 W GB 2021051055W WO 2021220018 A1 WO2021220018 A1 WO 2021220018A1
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WIPO (PCT)
Prior art keywords
approximately
weight
composition
alkaloid
acid
Prior art date
Application number
PCT/GB2021/051055
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English (en)
Inventor
Michael Richard LOVEDALE
Original Assignee
Exhale Technologies Ltd
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Publication date
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Publication of WO2021220018A1 publication Critical patent/WO2021220018A1/fr

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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
    • 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
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B13/00—Tobacco for pipes, for cigars, e.g. cigar inserts, or for cigarettes; Chewing tobacco; Snuff
    • 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
    • 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
    • A24F40/20—Devices using solid inhalable precursors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse

Definitions

  • the present invention relates to a composition and use thereof.
  • the present invention relates to an alkaloid composition for use in the preparation of a composition for mammalian or human administration.
  • the composition for mammalian or human administration is a vaping composition, vaping liquid, e-liquid, or the like.
  • tobacco cigarette smoking is one of the biggest causes of death and illness in the UK, and worldwide.
  • smoking has serious health risks and can increase the risk of developing diseases such as cancer, coronary heart disease, pneumonia, and bronchitis.
  • These health risks are primarily due to the smoke produced by burning the tobacco leaf, which comprises a number of toxins.
  • tobacco smoke comprises tar, carbon monoxide, metals, radioactive compounds, and other carcinogenic compounds.
  • a pharmacological substance is an ingredient in a medicine that causes the desired effect of the medicine. It may also be called an active pharmaceutical ingredient or drug substance.
  • a psychoactive substance is a drug or other substance that affects how the brain works and causes changes in mood, awareness, thoughts, feelings, or behaviour (NCI Dictionary of Cancer Terms).
  • Tobacco comprises a class of organic compounds known as alkaloids, which are responsible for the pharmacological and psychoactive effects of smoking. Nicotine is the most abundant alkaloid in tobacco. It is well known that nicotine is a mild stimulant, which provides a psychoactive effect to the user and contributes to the addictive properties of tobacco. However, there are also several minor alkaloids present in tobacco that are considered to be addictive and contribute to the psychoactive effects of smoking.
  • tobacco extracts comprising nicotine and all minor alkaloids present in tobacco provide the user with a complete tobacco-analogous psychoactive effect.
  • Harris et al. Drug Alcohol Depend., 2015, Volume 153, pages 330-334, doi: 10.1016/j.drugalcdep.2015.06.005
  • the minor alkaloids may also contribute to tobacco addiction by mimicking or enhancing the effects of nicotine to the user.
  • Nicotine and anabatine have been found to have anti-depressant drug-like effects, and ferulic acid a nootropic effect (i.e. an effect which enhances memory or other cognitive functions) in rodents (Xia et al, European Journal of Pharmacology 865 (2019) 172809).
  • Vaping liquids typically comprise only one psychoactive ingredient (pure nicotine), a liquid carrier such as propylene glycol, and a flavouring agent.
  • the nicotine content aids in reducing nicotine cravings experienced by smokers.
  • vaping liquid users often revert back to using traditional cigarettes. This is because vaping products do not comprise all the psychoactive chemicals (i.e. , nicotine and minor alkaloids) present in tobacco.
  • cigarette substitutes that provide the same or substantially the same psychoactive effect as traditional cigarettes are highly desirable to overcome some of the limitations of current cigarette substitutes. It is envisaged by the Applicant that a cigarette substitute that provides the same or substantially the same psychoactive effect as traditional cigarettes would assist a smoker to more successfully quit hazardous tobacco products without relapsing back to their use.
  • a further object of the invention is to provide a composition (such as a vaping composition), which will enable the user to obtain the same or substantially the same psychoactive effect as provided by traditional tobacco cigarettes.
  • an alkaloid composition for use in the preparation of a composition for mammalian or human administration, the alkaloid composition comprising: (i) nicotine, and
  • alkaloid composition comprises from approximately 70% by weight to approximately 98%, such as approximately 70% by weight to approximately 95%, by weight nicotine.
  • the alkaloid composition is a non-tobacco alkaloid composition.
  • the alkaloid composition is free or substantially free of tobacco plant tissue.
  • the alkaloid composition may be an extract of tobacco leaves, stems and/or dust which have not been cured, for example, fresh tobacco leaves, stems and/or dust.
  • tobacco incorporated into cigarettes is typically cured by methods such as air-, fire-, flue-, or sun-curing.
  • the alkaloid composition may be a full spectrum tobacco extract in that its alkaloid profile is similar to the alkaloid profile of uncured tobacco.
  • the alkaloid composition may be a distillate of a tobacco extract. It may be the distillate of a single fractional distillation, two fractional distillations (double distillate), or three fractional distillations (triple distillate). Nicotine may contain residual solvents used during its extraction process. These solvents include but are not limited to hexane and chloroform.
  • NIOSH National Institute for Occupational Safety and Health
  • REL recommended exposure level
  • TWA 40-hour workweek
  • NIOSH considers chloroform to be a potential occupational carcinogen with a short-term exposure limit (ST) of 2 ppm over 60 minutes.
  • the alkaloid composition of the present invention therefore may comprise no or substantially no extraction solvent, including but not limited to hexane and/or chloroform.
  • the alkaloid composition comprises minor alkaloids i.e. more than one minor alkaloid.
  • the alkaloid composition may comprise two, three, four, five, six, seven or more minor alkaloids, for example, five, six, or seven minor alkaloids, such as five minor alkaloids.
  • the alkaloid composition may comprise from approximately 70% by weight to approximately 98% by weight nicotine and from approximately 2% by weight to approximately 30% by weight minor alkaloids.
  • the alkaloid composition may comprise from approximately 70% by weight to approximately 95% by weight nicotine and from approximately 5% by weight to approximately 30% by weight minor alkaloids.
  • the alkaloid composition may comprise from approximately 78% by weight to approximately 95% by weight nicotine and from approximately 5% by weight to approximately 22% by weight minor alkaloids.
  • the alkaloid composition may comprise from approximately 78% by weight to approximately 94% by weight nicotine and from approximately 6% by weight to approximately 22% by weight minor alkaloids.
  • the alkaloid composition may comprise from approximately 82% by weight to approximately 94% by weight nicotine and from approximately 6% by weight to approximately 18% by weight minor alkaloids.
  • the alkaloid composition may comprise approximately 90% by weight nicotine and approximately 10% by weight minor alkaloids.
  • the alkaloid composition may comprise approximately 95% by weight nicotine and approximately 5% by weight minor alkaloids.
  • the alkaloid composition may comprise approximately 94% by weight nicotine and approximately 6% by weight minor alkaloids.
  • the alkaloid composition has an alkaloid profile that is similar to the profile of traditional tobacco cigarettes, which provides the user with psychoactive effects similar to those obtained from tobacco cigarettes. Therefore, the user experiences the psychoactive effects of smoking, such as the cessation of cravings and other positive psychoactive effects, without being exposed to the harmful chemicals found in tobacco smoke.
  • TSNA tobacco-specific nitrosamine
  • NCI Dictionary of Cancer Terms A tobacco-specific nitrosamine (TSNA) is a type of harmful, cancer- causing chemical found in tobacco and tobacco smoke (NCI Dictionary of Cancer Terms).
  • TSNAs are formed primarily by growing tobacco in over fertilised soil and/or during tobacco curing, fermentation, and ageing.
  • the alkaloid composition of the present invention may comprise no or substantially no TSNA.
  • no or substantially no TSNA we mean the amount of TSNA present in the alkaloid composition is below the level of detection using the analytical method set out in the Examples below. Without wishing to be bound by theory, it is believed that the present alkaloid composition may have no or substantially no quantities of TSNA because it may be an extract of tobacco leaves, stems and/or dust which have not been cured.
  • the alkaloid composition may comprise no or substantially no TSNA selected from the group consisting of N'-nitrosonornicotine (NNN), 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and a mixture thereof.
  • NNN N'-nitrosonornicotine
  • NNK 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone
  • the alkaloid composition may comprise less than 0.0002% of NNN as determined by the UHPLC-MS method described below.
  • the alkaloid composition may comprise less than 0.0001% of NNK as determined by the UHPLC-MS method described below.
  • Tobacco smoke contains polycyclic aromatic hydrocarbons (PAHs), which are a class of compounds containing two or more fused aromatic carbocyclic rings.
  • PAHs in tobacco smoke are known for their carcinogenic and mutagenic properties, and include but are not limited to naphthalene, acenaphthylene, acenaphthene, fluorene, anthracene, phenanthrene, fluoranthene, pyrene, benz[a]anthracene, chrysene, benzo[b]fluoroanthene, benzo[e]pyrene, benzo[k]fluoranthene and benzo[a]pyrene.
  • PAHs are combustion products and originate from two sources - the wood burnt during the fire-curing of tobacco leaves, and from tobacco itself when burnt.
  • the alkaloid composition of the present invention does not comprise PAHs.
  • alkaloid is meant any class of nitrogenous organic compounds of plant origin which have pronounced physiological actions on humans. Alkaloids include, but are not limited to, nicotine, myosmine, anabasine, b-nicotyrine, anatabine, nornicotine and cotinine.
  • the alkaloids may be nicotinic alkaloids.
  • nicotinic alkaloid an alkaloid that: i. binds to nicotinic receptors in human, insect and other metabolisms; ii. is structurally related to nicotine; and/or iii. may be obtained from the same source as nicotine, in particular tobacco.
  • a nictonic alkaloid which may be obtained from the same source as nicotine includes uncured tobacco leaves, stems and/or dust.
  • the term “nicotine” includes, but is not limited to, (S)-nicotine, (R)-nicotine and a mixture comprising (S)-nicotine and (R)-nicotine.
  • the term “nicotine” may comprise all or substantially all (S)-nicotine. The ratio of
  • (S)-nicotine to (R)-nicotine in the mixture may be 1 :0.
  • the mixture may be a racemic mixture, that is the ratio of (S)-nicotine to (R)-nicotine in the mixture may be 1:1.
  • the ratio of (S)-nicotine to (R)-nicotine in the mixture may be 7:3, optionally 7:2, preferably 6.3:2.7.
  • the mixture may comprise any suitable ratio of (S)-nicotine to (R)-nicotine.
  • (S)-nicotine is considered to provide a greater psychoactive effect to the user than (R)-nicotine.
  • administration is meant the path by which a substance enters the human body.
  • the alkaloid composition may comprise from approximately 70% by weight to approximately 98% by weight nicotine, optionally from approximately 78% by weight to approximately 94% by weight nicotine, optionally from approximately 82% by weight to approximately 94% by weight nicotine.
  • the alkaloid composition may comprise approximately 90% by weight nicotine.
  • the alkaloid composition may comprise from approximately 2% to approximately 30% by weight minor alkaloids.
  • the alkaloid composition may comprise from approximately 5% to approximately 30% by weight minor alkaloids.
  • the alkaloid composition may comprise approximately 5% by weight to approximately 22% by weight minor alkaloids, optionally from approximately 5% by weight to approximately 18% by weight minor alkaloids.
  • the alkaloid composition may comprise approximately 6% by weight to approximately 22% by weight minor alkaloids, optionally from approximately 6% by weight to approximately 18% by weight minor alkaloids.
  • the alkaloid composition may comprise approximately 10% by weight minor alkaloids.
  • the minor alkaloids may be a mixture of minor alkaloids selected from one or more (e.g. 2, 3, 4, 5, 6, or more) of the group consisting of: myosmine, anabasine, b-nicotyrine, anatabine, nornicotine, cotinine, and other minor alkaloids.
  • the minor alkaloids may be a mixture of minor alkaloids comprising at least one or more (e.g. 2, 3, 4, 5, or 6) of the group consisting of: myosmine, anabasine, b-nicotyrine, anatabine, nornicotine and cotinine.
  • the minor alkaloids may be a mixture of minor alkaloids comprising at least one or more (e.g.
  • the minor alkaloids may be a mixture of minor alkaloids comprising at least one or more (e.g. 2, or 3) of the group consisting of: myosmine, anabasine and cotinine.
  • the alkaloid composition may comprise from approximately 0.02% by weight to approximately 1.9% by weight myosmine, optionally from approximately 0.04% by weight to approximately 0.9% by weight myosmine, optionally from approximately 0.1% by weight to approximately 0.7% by weight myosmine, optionally from approximately 0.2% by weight to approximately 0.4% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.3% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.45% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.61% by weight myosmine.
  • the alkaloid composition may comprise from approximately 0.25% by weight to approximately 0.37% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.31% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.35% by weight myosmine.
  • the alkaloid composition may comprise from approximately 0.3% by weight to approximately 0.75% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.45% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.61% by weight myosmine.
  • the alkaloid composition may comprise approximately 0.62% by weight myosmine.
  • the alkaloid composition may comprise from approximately 0.05% by weight to approximately 5.2% by weight anabasine, optionally from approximately 0.10% by weight to approximately 2.6% by weight anabasine, optionally from approximately 0.5% by weight to approximately 2% by weight anabasine, optionally from approximately 0.7% by weight to approximately 1% by weight anabasine.
  • the alkaloid composition may comprise approximately 0.9% anabasine.
  • the alkaloid composition may comprise from approximately 0.69% by weight to approximately 1.04% by weight anabasine.
  • the alkaloid composition may comprise approximately 0.86% by weight anabasine.
  • the alkaloid composition may comprise from approximately 0.5% by weight to approximately 2.5% by weight anabasine, optionally from approximately 0.6% by weight to approximately 2% by weight anabasine, optionally from approximately 0.7% by weight to approximately 1.8% by weight anabasine.
  • the alkaloid composition may comprise approximately 0.955% anabasine.
  • the alkaloid composition may comprise approximately 1.16% anabasine.
  • the alkaloid composition may comprise approximately 1.62% anabasine.
  • the alkaloid composition may comprise approximately 1.68% anabasine.
  • the alkaloid composition may comprise from approximately 0.5% by weight to approximately 1.5% by weight anabasine, optionally from approximately 0.9% by weight to approximately 1.2% by weight anabasine.
  • the alkaloid composition may comprise approximately 1.16% anabasine.
  • the alkaloid composition may comprise approximately 0.96% anabasine.
  • the alkaloid composition may comprise from approximately 0% by weight to approximately 0.4% by weight b-nicotyrine, optionally from approximately 0.01% by weight to approximately 0.2% by weight b- nicotyrine, optionally from approximately 0.05% by weight to approximately 0.1% by weight b-nicotyrine.
  • the alkaloid composition may comprise approximately 0.1% by weight b-nicotyrine.
  • the alkaloid composition may comprise from approximately 0% by weight to approximately 0.15% by weight b-nicotyrine, optionally from approximately 0.01 % by weight to approximately 0.1 % by weight b- nicotyrine, optionally from approximately 0.02% by weight to approximately 0.09% by weight b-nicotyrine.
  • the alkaloid composition may comprise approximately 0.033% by weight b-nicotyrine.
  • the alkaloid composition may comprise approximately 0.04% by weight b-nicotyrine.
  • the alkaloid composition may comprise approximately 0.05% by weight b- nicotyrine.
  • the alkaloid composition may comprise from approximately 0.05% by weight to approximately 0.07% by weight b-nicotyrine.
  • the alkaloid composition may comprise approximately 0.06% by weight b-nicotyrine.
  • the alkaloid composition may comprise from approximately 0.07% by weight to approximately 1.8% by weight anatabine, optionally from approximately 0.14% by weight to approximately 0.9% by weight anatabine, optionally from approximately 0.2% by weight to approximately 0.4% by weight anatabine.
  • the alkaloid composition may comprise approximately 0.3% by weight anatabine.
  • the alkaloid composition may comprise from approximately 0.01 % by weight to approximately 3% by weight anatabine, optionally from approximately 0.02% by weight to approximately 2.7% by weight anatabine, optionally from approximately 0.03% by weight to approximately 2.6% by weight anatabine.
  • the alkaloid composition may comprise approximately 0.04% by weight anatabine.
  • the alkaloid composition may comprise approximately 0.09% by weight anatabine.
  • the alkaloid composition may comprise approximately 2.46% by weight anatabine.
  • the alkaloid composition may comprise approximately 2.53% by weight anatabine.
  • the alkaloid composition may comprise from approximately 0.01% by weight to approximately 0.15% by weight anatabine, optionally from approximately 0.02% by weight to approximately 0.13% by weight anatabine, optionally from approximately 0.03% by weight to approximately 0.1% by weight anatabine.
  • the alkaloid composition may comprise approximately 0.04% by weight anatabine.
  • the alkaloid composition may comprise approximately 0.09% by weight anatabine.
  • the alkaloid composition may comprise from approximately 0.24% by weight to approximately 0.37% by weight anatabine.
  • the alkaloid composition may comprise approximately 0.30% by weight anatabine.
  • the alkaloid composition may comprise from approximately 0% by weight to approximately 0.7% by weight nornicotine, optionally from approximately 0.01 % by weight to approximately 0.4% by weight nornicotine, optionally from approximately 0.05% by weight to approximately 0.2% by weight nornicotine.
  • the alkaloid composition may comprise approximately 0.1% by weight nornicotine.
  • the alkaloid composition may comprise from approximately 0.001 % by weight to approximately 3.5% by weight nornicotine, optionally from approximately 0.01% by weight to approximately 3% by weight nornicotine, optionally from approximately 0.05% by weight to approximately 2.9% by weight nornicotine.
  • the alkaloid composition may comprise approximately 0.1 % by weight nornicotine.
  • the alkaloid composition may comprise approximately 0.165% by weight nornicotine.
  • the alkaloid composition may comprise approximately 2.2% by weight nornicotine.
  • the alkaloid composition may comprise approximately 2.71% by weight nornicotine.
  • the alkaloid composition may comprise from approximately 1% by weight to approximately 3.5% by weight nornicotine, optionally from approximately 1.3% by weight to approximately 3% by weight nornicotine, optionally from approximately 1.5% by weight to approximately 2.9% by weight nornicotine.
  • the alkaloid composition may comprise from approximately 0.001% by weight to approximately 1% by weight nornicotine, optionally from approximately 0.01% by weight to approximately 0.5% by weight nornicotine, optionally from approximately 0.05% by weight to approximately 0.3% by weight nornicotine.
  • the alkaloid composition may comprise from approximately 0.09% by weight to approximately 0.14% by weight nornicotine.
  • the alkaloid composition may comprise approximately 0.12% by weight nornicotine.
  • the alkaloid composition may comprise from approximately 0.03% by weight to approximately 1.2% by weight cotinine, optionally from approximately 0.05% by weight to approximately 0.6% by weight cotinine, optionally from approximately 0.1% by weight to approximately 0.3% by weight cotinine.
  • the alkaloid composition may comprise approximately 0.2% by weight cotinine.
  • the alkaloid composition may comprise from approximately 0.01% by weight to approximately 1 % by weight cotinine, optionally from approximately 0.03% by weight to approximately 0.8% by weight cotinine, optionally from approximately 0.05% by weight to approximately 0.5% by weight cotinine.
  • the alkaloid composition may comprise approximately 0.08% by weight cotinine.
  • the alkaloid composition may comprise approximately 0.14% by weight cotinine.
  • the alkaloid composition may comprise approximately 0.29% by weight cotinine.
  • the alkaloid composition may comprise approximately 0.35% by weight cotinine.
  • the alkaloid composition may comprise from approximately 0.16% by weight to approximately 0.23% by weight cotinine.
  • the alkaloid composition may comprise approximately 0.20% by weight cotinine.
  • minor alkaloids any alkaloid derived from tobacco, except nicotine, myosmine, anabasine, b-nicotyrine, anatabine, nornicotine and cotinine.
  • Other minor alkaloids include, but are not limited to, one or more of the following: nicotyrine, (R,S)-anatabine, a-Nicotine (o- Nicotine), n-methyl anabasine, 2,3’-dipyridyl, N(2- carbomethoxyvinyl)methylamine, N-ethyl-3-methyl-benzenamine, methyl nicotinate, isopropyl toluidine, 2-methoxy benzenamine, N-methyl-3- pyridinecarboxamide, pentyl pyridine, 1 -methyl-3, 4-dihydro-1 H-quinolin-2- one, 1 ,2, 3, 6-tetrahydro-2, 3-bipyridine, 2-(2,2,3,4-tetramethyl-4-
  • the alkaloid composition may comprise from approximately 0.5% by weight to approximately 25% by weight other minor alkaloids.
  • the alkaloid composition may comprise from approximately 5% by weight to approximately 10% by weight other minor alkaloids.
  • the alkaloid composition may comprise from approximately 7% by weight to approximately 10% by weight other minor alkaloids.
  • the alkaloid composition may comprise from approximately 8% by weight to approximately 9% by weight other minor alkaloids.
  • the alkaloid composition may comprise approximately 8% by weight other minor alkaloids.
  • the alkaloid composition may comprise other alkaloid compounds, for example, nitrogen-containing C10-12 and Ci 8-22-aromatics.
  • the alkaloid composition may comprise from approximately 0.5% by weight to approximately 2.5% by weight other alkaloid compounds, optionally from approximately 0.6% by weight to approximately 2.3% by weight other alkaloid compounds, optionally from approximately 0.7% by weight to approximately 2% by weight other alkaloid compounds.
  • the alkaloid composition may comprise approximately 0.85% by weight other alkaloid compounds.
  • the alkaloid composition may comprise approximately 1.89% by weight other alkaloid compounds.
  • the alkaloid composition typically comprises 100 wt% of alkaloids. A major portion of the alkaloid composition comprises nicotine, and the minor alkaloids. The balance typically comprises other minor alkaloids, and other alkaloid compounds (if any).
  • the alkaloid composition may be as described for Example 9 below.
  • the alkaloid composition may be as described for Example 10 below.
  • the alkaloid composition may comprise a standardising agent. This can be added to standardise the nicotine to minor alkaloid ratio within the desired range.
  • the standardising agent may be a high purity alkaloid.
  • the high purity alkaloid may be a synthetic or naturally derived alkaloid.
  • the high purity alkaloid may be selected from one or more of the group consisting of: high purity nicotine, high purity anatabine, high purity myosmine, high purity anabasine, high purity nornicotine and high purity cotinine.
  • Nicotine, anabasine, anatabine, nornicotine, and cotinine each contain a chiral centre. Racemates, and enantiomers are within the scope of the invention for nicotine, the minor alkaloids listed above and where appropriate, the other minor alkaloids. It is typically desirable that the enantiomeric and/or racemic forms present in the alkaloid composition are those which are naturally produced by tobacco plants and are extractable therefrom. According to a second aspect of the invention, there is provided a composition for mammalian or human administration, the composition comprising:
  • an alkaloid composition comprising: (a) nicotine, and
  • composition comprises from approximately 0.3% weight by volume to approximately 20% weight by volume of the alkaloid composition.
  • the mammalian or human administration may be by inhalation, buccal administration, transdermal administration, intranasal administration or oral administration.
  • the administration may be by inhalation.
  • the diluent may be a liquid diluent, and may be selected from one or more of the group consisting of: water, a flavouring agent and a solvent. In certain embodiments, the diluent is not saline.
  • flavouring agent any food grade compounds that provide a distinctive taste to the composition.
  • Flavouring agents may include any flavouring agents known in the art, for example, any flavouring agents typically used in vaping products.
  • the solvent may be an alcohol.
  • the solvent may be selected from one or more of the group consisting of: propylene glycol, vegetable glycerine (glycerol), polyethylene glycol 400 (PEG 400), polyethylene glycol 300 (PEG 300), ethanol, or any suitable alcohol.
  • the alcohol may be propylene glycol.
  • the alcohol may be vegetable glycerine (glycerol).
  • the alcohol may be mixture of propylene glycol and vegetable glycerine.
  • any combination of suitable alcohols may be used.
  • the ratio of propylene glycol to vegetable glycerine may 1:1.
  • the ratio of propylene glycol to vegetable glycerine may be 1 :4.
  • the ratio of propylene glycol to vegetable glycerine may be 4:1.
  • the ratio of propylene glycol to vegetable glycerine may be 6:4.
  • the ratio of propylene glycol to vegetable glycerine may be 4:6.
  • any suitable ratio may be used.
  • the alkaloids in the alkaloid composition may be in the free base form.
  • the composition may further comprise at least one organic acid, optionally the organic acid may be selected from one or more of the group consisting of: salicylic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, citric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, phenylacetic acid, benzoic acid, pyruvic acid, levulinic acid, tartaric acid, lactic acid, malonic acid, succinic acid, fumaric acid, finnaric acid, gluconic acid, saccharic acid, sorbic acid, malonic acid and malic acid.
  • the organic acid may be selected from one or more of the group consisting of: salicylic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid
  • the organic acid may be salicylic acid.
  • the organic acid may be tartaric acid.
  • the organic acid may be pyruvic acid.
  • the organic acid may be levulinic acid.
  • the alkaloids in the alkaloid composition may be alkaloid salts.
  • the nicotine may be nicotine salt.
  • the salt may be a bitartrate or ditartrate salt, such as the bitartrate dihydrate.
  • alkaloid salt is meant that the alkaloids are protonated.
  • the composition may contain a mixture (e.g. 2, 3, 4, 5 or more) of alkaloid salts.
  • the composition may contain alkaloid salts in which approximately 30% are levulinate salts, approximately 60% are bitartrate hemihydrate salts, and approximately 10% are pyruvate salts.
  • the composition may contain alkaloid salts in which approximately 30% are levulinate salts, and approximately 70% are bitartrate hemihydrate salts.
  • the acid utilised in the salt of the alkaloid composition may be an active acid, inactive acid or a combination of both.
  • active acid we mean that the acid has a pharmacological or psychoactive effect in its own right.
  • An alkaloid salt composition with an active salt therefore will impart a pharmacological or psychoactive effect by virtue of the alkaloid composition, and a pharmacological or psychoactive effect by virtue of the active acid.
  • the pharmacological or psychoactive effect produced by the active acid may be the same or different to that produced by the alkaloid composition.
  • the active acid may be ferulic acid, which has a nootropic effect. Ferulic acid may be used to form ferulate alkaloid salts.
  • inactive acid we mean that the acid has no pharmacological or psychoactive effect in its own right.
  • An alkaloid salt composition with an inactive salt therefore will impart a pharmacological or psychoactive effect by virtue of the alkaloid composition alone.
  • the acid utilised in the alkaloid salt is an inactive acid
  • the acid may be selected from the organic acids described above.
  • the alkaloid composition may be a mixture of alkaloids in free base form and one or more (e.g. 1 , 2, 3, 4, 5 or more) alkaloid salts.
  • the free base form and salts (which may be active salts , inactive salts, or both) are as described above.
  • the composition may be a liquid solution, optionally the liquid solution may be in a form suitable for inhalation as a vapour.
  • the composition may be a liquid solution.
  • the liquid solution may be suitable for inhalation, transdermal administration or intranasal administration.
  • the liquid solution may be inhaled as a vapour, or applied as a spray, patch, cream, lotion, or the like.
  • the composition may exist in any suitable form, and for any suitable route of administration.
  • the composition is not for intravenous administration.
  • the composition may be for use in an electronic cigarette, or vaping device. However, it should be appreciated that the composition may be suitable for use in any nicotine replacement therapy products.
  • nicotine replacement therapy is meant a product, such as gums, powders, patches, inhalators, or sprays, that administers nicotine into the body.
  • the composition may be a vaping composition, an e-liquid, a vaping liquid, or the like for use in an e-cigarette.
  • vaping liquid is meant an e-liquid or nicotine solution for use inside electronic cigarettes.
  • the composition may comprise no or substantially no TSNA as determined using the method described in the Examples below.
  • NNN may be below the level of detection using method described in the Examples below.
  • NNK may be below the level of detection using the using method described in the Examples below.
  • the alkaloid salts may be prepared by methods known in the art.
  • the alkaloid composition and acid may be combined in a solvent, for example, the acid may be dissolved in a solvent and the alkaloid composition added to the acidic solution.
  • the solvent may be any suitable protic solvent or combination of protic solvents.
  • protic solvents include one or more alcohols, such as methanol, ethanol, propanol (n- or i) and butanol (n-, i- or t-).
  • the alcohol solvent may be ethanol.
  • the concentration of the alkaloid composition to solvent may be any suitable concentration, such as approximately 0.001 mol/L to approximately 1 mol/L.
  • any suitable quantity of acid may be used, although it is desirable that the molar ratio of acid : alkaloid composition is from approximately 0.90 : approximately 1 moles to approximately 0.99 : approximately 1 moles, such as approximately 0.95 : approximately 1 moles. In this instance, a slightly less than stoichiometric amount of acid is used to prevent the undesirable presence of residual free acid in the final composition.
  • the process for preparing the alkaloid salt composition may be carried out at a temperature in the range of about -10°C to about 120°C, such as about 0°C to about 100°C. In certain embodiments, the process can be carried out at about room temperature (i.e. about 20°C to about 30°C). It is desirable that the temperature is maintained below the decomposition temperature and so when the alkaloid composition or acid are known to decompose within the temperature ranges given above, the temperature should be maintained below the decomposition temperature.
  • the method may be carried out under an inert atmosphere, for example, under a nitrogen or argon atmosphere.
  • the inert atmosphere reduces or eliminates the potential for the alkaloid composition to undergo oxidative degradation.
  • the reaction mixture may be performed in an environment which reduces or eliminates the potential for light to photodegrade the alkaloid composition.
  • the reaction may be carried out for a period of from about several minutes to about 24 hours.
  • a proportion of the solvent may be evaporated if desired prior to recovery of the alkaloid salts.
  • an anti-solvent may be used to precipitate the alkaloid salts from the solvent.
  • the alkaloid salts may be recovered directly by filtering, decanting or centrifuging.
  • the separated alkaloid salts may be washed (e.g. with ethanol) and then dried. Drying may be performed using known methods, for example at temperatures in the range 10-60°C and preferably 20-40°C under 1-30 mbar vacuum for 1 hour to 5 days. Alternatively or in addition, the alkaloid salts may be dried without the active application of vacuum.
  • the alkaloids salts may be stored in containers suitable for the storage of photosensitive products.
  • vaping composition comprising:
  • vaping composition comprises from approximately 0.3% weight by volume to approximately 20% weight by volume of the alkaloid composition.
  • vaping composition comprising: (i) an alkaloid composition comprising:
  • vaping composition comprising:
  • vaping composition comprises from approximately 0.3% weight by volume to approximately 20% weight by volume of the alkaloid composition.
  • composition for mammalian or human administration comprising:
  • composition comprises from approximately 0.2% by weight to approximately 20% by weight of the alkaloid composition.
  • the mammalian or human administration may be by inhalation, buccal administration, transdermal administration, intranasal administration or oral administration.
  • the administration may be by buccal administration.
  • facial administration is meant applying a substance to the cheek or gums to allow the substance to diffuse through the oral mucosa into the bloodstream.
  • the composition may be in the form of a solid.
  • the solid may be suitable for oral administration or buccal administration.
  • the solid may be administered as a gum, powder, lozenge, capsule, film, or the like.
  • the composition may exist in any suitable form, and for any suitable route of administration.
  • the composition may be a powder suitable for buccal administration.
  • the composition may be a buccal pouch composition, or the like.
  • the composition may be an immediate, sustained, or modified-release (e.g. a delayed-release) composition.
  • the composition may be for use in a nicotine replacement gum.
  • the composition may be for use in a nicotine replacement powder, such as a buccal pouch.
  • the composition may be suitable for use in any nicotine replacement therapy products.
  • excipient is meant an inactive substance that is used to dilute the active substance in a solid composition.
  • the excipient may be selected from one or more of the group consisting of: a humectant, a flavouring agent, water, a resin and a bulking agent.
  • the excipient may be a bulking agent.
  • heating agent any compound that is added to increase the weight of the composition without affecting the other properties.
  • the bulking agent may be a plant-derived material.
  • the plant-derived material may be selected from one or more of the group consisting of: natural polysaccharides, natural polyalcohols, mint leaves and plant fibres.
  • the bulking agent may be mint leaves.
  • the bulking agent may be a gel, or gelling agent.
  • the bulking agent may be microcrystalline cellulose, polyvinylpyrrolidone (PVP), xylitol, magnesium stearate and/or maltitol.
  • humectant any compound that retains or preserves moisture in the composition.
  • flavouring agent any food grade compounds that provide a distinctive taste to the composition.
  • Flavouring agents may include any flavouring agents known in the art, for example, any flavouring agents typically used in buccal pouch products.
  • the resin may be an ion-exchange resin, such as Amberlite IRP64, Purolite C115HMR, Doshion P551 , or any other suitable resins known in the art.
  • a resin is used, the resulting composition may be described as resinate, poliacrex or resinate poliacrex.
  • the composition may further comprise a preservative.
  • the preservative may be a salt.
  • the salt may be selected from one of more of the group consisting of: sodium chloride, sodium bicarbonate, bitartrate salts, ditartrate salts and sodium carbonate.
  • the composition may further comprise an acidity regulator.
  • acidity regulator any compound that controls the pH of the composition.
  • a buccal pouch composition comprising:
  • an alkaloid composition comprising: (a) nicotine, and
  • buccal pouch composition comprises from approximately 0.2% by weight to approximately 20% by weight of the alkaloid composition.
  • the composition of any one of the first to the seventh aspects of the invention for use in treatment of respiratory diseases that respond to nicotinic alkaloids may be caused by a coronavirus, optionally wherein the coronavirus is 8ARS-CoV ⁇ 2 and the respiratory disease that is caused is COVID-19.
  • % by weight values used throughout the specification are based on the total weight of the alkaloids in the composition. The total % by weight adds up to approximately 100 % by weight.
  • Current cigarette substitutes, such as vaping liquids, comprise nicotine.
  • the nicotine in current cigarette substitutes can be produced synthetically, but is typically extracted from the tobacco plant. Typically, the extraction process removes all other impurities, such as minor alkaloids, from the tobacco to provide pure nicotine. The pure nicotine is then diluted for use in current vaping liquids, patches, gums, or the like.
  • the alkaloid composition of the present invention comprises a combination of nicotine and minor alkaloids.
  • compositions of the present invention were prepared as follows.
  • Nicotine and minor alkaloids were extracted from tobacco leaves.
  • the minor alkaloids are isolated by fractional distillation and added to the nicotine to provide the desired alkaloid profile of the alkaloid composition.
  • This provides an alkaloid composition with an alkaloid profile similar to that of traditional tobacco cigarettes.
  • synthetic minor alkaloids may be added to nicotine extracted from tobacco or nicotine prepared synthetically to provide the desired alkaloid profile of the alkaloid composition. More specifically, tobacco leaves, stems and dust are macerated with sulphuric acid. This converts the nicotine to nicotine sulphate which is soluble in water. The aqueous solution of nicotine sulphate is then filtered to remove organic matter.
  • the aqueous solution of nicotine sulphate is then treated with a base to increase the pH of the aqueous solution to above pH 9 which creates the free base of nicotine which itself is soluble in organic solvent.
  • the aqueous solution of nicotine is extracted with a non water miscible solvent whereby the nicotine is concentrated in the organic solvent Separation of the two layers - organic and aqueous gives an organic solution of nicotine and other alkaloids. Removal of the organic solvent gives a 90% concentrate of nicotine.
  • reference to the extraction of nicotine also refers to the concomitant extraction of the other components in the alkaloid composition.
  • This extraction process provides an alkaloid composition, at approximately 100% by weight alkaloids.
  • the ratio of alkaloids, in particular minor alkaloids, within the composition depends on the type of tobacco leaf used and can vary seasonally.
  • Example compositions at 99.99% by weight total alkaloid content are provided in Table 1 below. It should be noted that the named minor alkaloids in combination with nicotine contribute significantly to the psychoactive effect provided by the composition of the present invention.
  • the “other minor alkaloids” present in the examples in Table 1 include, but are not limited to, any combination of minor alkaloids derived from tobacco, including, for example, a combination of nicotyrine, (R,S)- anatabine, a-Nicotine (o-Nicotine), n-methyl anabasine, 2,3’-dipyridyl, N(2- carbomethoxyvinyl)methylamine, N-ethyl-3-methyl-benzenamine, methyl nicotinate, isopropyl toluidine, 2-methoxy benzenamine, N-methyl-3- pyridinecarboxamide, pentyl pyridine, 1 -methyl-3, 4-dihydro-1 H-quinolin-2- one, 1 ,2, 3, 6-tetrahydro-2, 3-bipyridine, 2-(2,2,3,4-tetramethyl-4- cyclopenten-1 -ylidene)-propanedinitrile, 1 -cyclohexyl-2,
  • each other minor alkaloid in the concentrated composition is relatively low compared to the named minor alkaloids.
  • Example 4 was fully characterised by gas chromatography-mass spectrometry (GC-MS) and found to comprise the other minor alkaloids recited in Table 2 below.
  • GC-MS gas chromatography-mass spectrometry
  • Example 4 are also presented in Table 2. However, there were also other minor alkaloids present that could not be characterised.
  • Solvent analysis was also performed on Example 4 by headspace GC-MS, and the results showed ⁇ 0.005% by weight residual solvents were present in the composition.
  • the alkaloid compositions provided in Tables 1 and 3 above are used in the preparation of nicotine replacement therapy products.
  • the alkaloid composition is used in the preparation of a vaping liquid for inhalation by the user.
  • the alkaloid composition can also be used in the manufacture of patches, inhalators, sprays, or other nicotine replacement therapy products.
  • the alkaloid composition may be used in the preparation of a powder suitable for buccal administration, such as buccal pouches.
  • the alkaloid composition can be standardised by adding a standardising agent, such as high purity, USP grade nicotine or a pharmaceutical grade minor alkaloid, to the composition.
  • a standardising agent such as high purity, USP grade nicotine or a pharmaceutical grade minor alkaloid
  • the composition may be standardised by adding USP grade nicotine or USP grade anatabine to the composition to obtain a nicotine to minor alkaloid ratio of 9:1.
  • the composition can be standardised to any suitable ratio.
  • Examples 1 and 2 were standardised to obtain a nicotine to minor alkaloid ratio of 9:1.
  • USP grade nicotine was added to the alkaloid composition of Examples 1 and 2, such that the resulting compositions comprise approximately 90% by weight nicotine and 10% by weight minor alkaloids.
  • Table 4 The results are provided in Table 4 below.
  • Table 4 The percentage by weight amounts of Examples in Table 4 are presented in Table 5 below.
  • Example alkaloid compositions 9 and 10 were extracted from uncured tobacco.
  • the percentage weights of Examples 9 and 10 were obtained by analysis using HPLC (high performance liquid chromatography) and are shown in Table 10 below.
  • HPLC high performance liquid chromatography
  • the HPLC method is has been reproduced from the United States Pharmacopeia (USP) Monograph for Nicotine.
  • HPLC analysis used the following conditions:
  • HPLC analysis used the following time programme in Table 6:
  • Mobile phase A To 900 mL of water, add 25 mL of 60 g/l solution of acetic acid, and then add 6 mL of concentrated ammonia. Adjust to pH 10.0 with dilute ammonia solution or dilute acetic acid solution and diluted to 1000 mL with water and mix. Filter through 0.45m filter paper and sonicate.
  • Mobile phase B Acetonitrile (HPLC grade)
  • Test preparation (Prepare immediately before use)
  • test sample Accurately weigh and transfer 20 mg of test sample in 25 ml_ volumetric flask containing water. Dissolve and dilute to volume with water and mix.
  • HPLC injection details were as follows in Table 7:
  • HPLC retention times (RT) were as follows in Table 8:
  • Un-known impurity Area obtained in the test solution due to un-known impurity should not be more the area obtained with principal peak in the chromatogram obtained with reference solution (b) (0.1 percent).
  • Total impurities (Known and unknown):
  • Disregard Limit Disregard any peak with an area less than 0.5 times the area obtained with principal peak in the chromatogram obtained with reference solution (b) (0.05 percent).
  • Nicotine-N-oxide is produced during analysis and is not detected at source.
  • the following examples relate to the use of the alkaloid composition in the preparation of a vaping liquid.
  • the composition may be used in the preparation of other nicotine replacement products and the dilution of the alkaloid composition may differ in the manufacturing process for these other products.
  • a diluent is added to the alkaloid composition.
  • the diluent is typically a solvent, however it should be understood that the diluent may also be water and/or a flavouring agent.
  • the solvent is typically any alcohol that, when heated, provides a vapour that the user can inhale.
  • Example 1 non-standardised diluted in different volumes of propylene glycol to provide a vaping composition with an alkaloid composition concentration of 3 mg/mL (0.3 % w/v), 20 mg/mL (2% w/v), 72 mg/mL (7.2% w/v) and 200 mg/mL (20% w/v).
  • alkaloid ratio for example, 90 % by weight nicotine to 10% by weight minor alkaloids
  • Table 9 shows Example 1 (non- standardised) diluted in different volumes of propylene glycol to provide a vaping composition with an alkaloid composition concentration of 3 mg/mL (0.3 % w/v), 20 mg/mL (2% w/v), 72 mg/mL (7.2% w/v) and 200 mg/mL (20% w/v).
  • the alkaloid ratio for example, 90 % by weight nicotine to 10% by weight minor alkaloids
  • the example at 72 mg/mL was fully characterised using gas chromatography-mass spectrometry (GC-MS) and found to comprise the following other minor alkaloids: o-nicotine ( ⁇ 1 pg/mL), n-methyl anabasine (38 pg/mL), N’-nitrosonornicotine ( ⁇ 1 pg/mL), nicotine-derived nitrosamine ketone ( ⁇ 5 pg/mL).
  • o-nicotine ⁇ 1 pg/mL
  • n-methyl anabasine 38 pg/mL
  • N’-nitrosonornicotine ⁇ 1 pg/mL
  • nicotine-derived nitrosamine ketone ⁇ 5 pg/mL
  • Example 2 (non-standardised) diluted in propylene glycol to provide a vaping composition with an alkaloid composition concentration of 3 mg/mL (0.3 % w/v), 20 mg/mL (2% w/v), 72 mg/mL (7.2% w/v) and 200 mg/mL (20% w/v).
  • the alkaloid composition is diluted in propylene glycol.
  • any suitable combination of the following solvents may be used: propylene glycol, vegetable glycerine (glycerol), polyethylene glycol 400 (PEG 400), polyethylene glycol 300 (PEG 300), ethanol, or any suitable alcohol.
  • the examples above describe vaping liquids where the alkaloids are in the free base, or “freebase”, form. That is, the alkaloids are unprotonated.
  • This free base composition can be used in both vaping liquids and nicotine replacement therapies.
  • an organic acid may be added to the composition to provide an alkaloid salt, or “nicotine salts” version of the composition.
  • nicotinic bitartrate dihydrate and nicotinic salicylate salts may be formed by the following methods.
  • Nicotinic bitartrate dihydrate is created using a 1 : 1 molar ratio of Tartaric acid to Nicotinic alkaloids.
  • tartaric acid is a di acid only one of the acid groups is used in the reaction to form the salt.
  • a calculation is performed to calculate the physical weights of nicotinic alkaloids and tartaric acid disodium dihydrate required to be left with a dry salt.
  • An appropriate solvent ethanol
  • This is performed in an inert atmospheric environment, such as nitrogen, so there is no opportunity for oxidative degradation during the formulating or mixing process. This is also performed in an environment free of UV to avoid light degradation. Once both constituents are fully dissolved and incorporated in the solvent, the resulting liquid is evaporated to leave a dry powder (in an inert temperature controlled environment). Nicotinic Salicylate Salts
  • Nicotinic salicylate is created using a 1 : 1 by molar ratio of salicylic acid to nicotinic alkaloids. A calculation is performed to calculate the physical weights of nicotinic alkaloids and salicylic acid required to be left with a dry salt. An appropriate solvent (ethanol) is then used to incorporate the acid, then the nicotinic alkaloid composition. This is performed in an inert atmospheric environment, such as nitrogen, so there is no opportunity for oxidative degradation during the formulating or mixing process. This is also performed in an environment free from UV radiation to avoid light degradation. Once both constituents are fully dissolved and incorporated, the resulting liquid is evaporated to leave a dry powder (in an inert temperature controlled environment).
  • TSNAs tobacco-specific nitrosamines
  • EC electronic cigarette
  • LC-MS Liquid chromatography-Mass spectrometry
  • variable 1 The average recovery of TSNAs in terms of variable 1 is 134 ⁇ 22.1 % for ACN and 92.6 ⁇ 8.27% for AA.
  • the average recovery in terms of variable 2 is 83.4 ⁇ 7.33% for QW and 58.5 ⁇ 12.9% for CFP.
  • NN N'-nitrosonornicotine
  • NK 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
  • Ion spray voltage and ion spray temperature are set to 4.5 kV and 700 °C, respectively.
  • Pure nitrogen gas is used as a nebulizing gas at a flow rate of 3 L/minute to make fine droplets.
  • a drying gas flow rate of 15 L/minute, which de-solvates the droplet is used.
  • Argon gas is used as a collision gas, which fragments the ions at a pressure of 230 kPa.
  • Three ion transition pairs are then detected in the multiple reaction monitoring (MRM) mode. These pairs are presented (precursor ion to product ions), the collision energy and dwell time for the two TSNA compounds are calculated.
  • MRM multiple reaction monitoring
  • HPLC high-performance liquid chromatography
  • MS/MS tandem mass spectrometry
  • MRM multiple reaction monitoring
  • TSNAs tobacco-specific nitrosamines
  • Electrospray Ionization ESI mode
  • Polarity Positive Nebulizing Gas Flow (N2): 3.0 L/minute
  • composition of the vaping liquid per ml_ 6mg Nicotinic Levulinate salts, 14mg Nicotinic Bitartrate salts, diluted in 50:50 mix of propylene glycol and glycerol. Below the limit of detection
  • vaping liquids which were prepared using the formulations of above Examples 9 and 10. These vaping liquids were compared to USP nicotine.
  • Each batch comprised the freebase at a concentration of 18 mg/mL prepared with a 50:50 volume/volume mixture of monopropylene glycol and glycerol.
  • Each participant inhaled the liquid by vaping using Uwell Caliburn Koko Pods with 1.2 ohm kanthal coils. The vaping equipment was fully charged prior to use.
  • Example 9 Users noted a pronounced “nicotine rush” combined with a “relaxing and clear cigarette like feel”.
  • Example 10 Users noted an “pronounced relaxing effect” with the feeling “akin to a cigar rather than a cigarette”.
  • no additional flavourings have been added to the composition.
  • the composition may be diluted with water and flavouring agents to improve the taste of the vaping liquid for the end user.
  • composition of the present invention has a similar alkaloid profile to that of traditional tobacco cigarettes.
  • the composition comprises an effective ratio of nicotine and minor alkaloids, which has been shown to provide an increased stimulant effect to the user. This enables the user to achieve a very similar psychoactive effect from the composition as they would from traditional tobacco cigarettes. This is of benefit to users as they can still obtain the stimulant effect provided by traditional cigarettes, but without the health risks associated with smoking tobacco.
  • composition of the present invention provides the user with an effective dose of nicotine and minor alkaloids, which aims to prevent the user from returning to the use of traditional cigarettes by reducing nicotine and minor alkaloid cravings. This aims to help the user quit smoking.

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Abstract

La présente invention concerne une composition d'alcaloïdes destinée à être utilisée dans la préparation d'une composition pour une administration à des mammifères ou à des hommes, la composition d'alcaloïdes comprenant : (i) de la nicotine, et (ii) des alcaloïdes mineurs, la composition d'alcaloïdes comprenant environ 70 % en poids à environ 98 % en poids de nicotine. L'invention concerne également des compositions pour une administration à des mammifères ou à des hommes, telles qu'une composition de vapotage, un liquide de vapotage, un e-liquide ou similaire pour une utilisation dans une cigarette électronique, ou une composition buccale en sachet, ou similaire.
PCT/GB2021/051055 2020-05-01 2021-04-30 Composition et utilisation correspondante WO2021220018A1 (fr)

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WO2023241103A1 (fr) * 2022-06-16 2023-12-21 深圳麦克韦尔科技有限公司 Sel de nicotine composite, formulation de sel de nicotine composite et son procédé de préparation et son utilisation
JP7436590B2 (ja) 2022-04-18 2024-02-21 汪冶 個体フレーク及びその製造方法
JP7436587B2 (ja) 2022-04-15 2024-02-21 汪冶 霧化電子送達製品に用いられる霧化溶液

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