GB2595967A - Composition and use thereof - Google Patents

Composition and use thereof Download PDF

Info

Publication number
GB2595967A
GB2595967A GB2106282.3A GB202106282A GB2595967A GB 2595967 A GB2595967 A GB 2595967A GB 202106282 A GB202106282 A GB 202106282A GB 2595967 A GB2595967 A GB 2595967A
Authority
GB
United Kingdom
Prior art keywords
approximately
weight
composition
alkaloid
acid
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.)
Pending
Application number
GB2106282.3A
Other versions
GB202106282D0 (en
Inventor
Richard Lovedale Michael
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.)
Exhale Tech Ltd
Original Assignee
Exhale Tech Ltd
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 Exhale Tech Ltd filed Critical Exhale Tech Ltd
Publication of GB202106282D0 publication Critical patent/GB202106282D0/en
Publication of GB2595967A publication Critical patent/GB2595967A/en
Pending legal-status Critical Current

Links

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

Abstract

An alkaloid composition for use in the preparation of a composition for human/mammalian administration comprises: nicotine at approximately 70% to 98% by weight; and minor alkaloids. The alkaloid composition may be a non-tobacco alkaloid composition, and the minor alkaloids may be a mixture of one or more of myosmine, anabasine, β-nicotyrine, anatabine, nornicotine and cotinine. A composition for human/mammalian administration may comprise the alkaloid composition at approximately 0.2% to 20% weight by volume, and a diluent or an excipient. The diluent may be water, a flavouring agent, or a solvent such as propylene glycol, glycerol, polyethylene glycol or ethanol, and the excipient may be a bulking agent. The composition may further comprise an acid such as salicylic acid, tartaric acid, pyruvic acid, levulinic acid, and the alkaloids may be in the free base form and/or alkaloid salts such as levulinate, bitartrate and/or pyruvate salts. The composition may be a liquid solution, vaping composition, e-liquid or vaping liquid for use in an e-cigarette, or in solid or powder form as a buccal pouch composition.

Description

COMPOSITION AND USE THEREOF
Field of Invention
The present invention relates to a composition and use thereof In particular, the present invention relates to an alkaloid composition for use in the preparation of a composition for mammalian or human administration. In particular examples, the composition for mammalian or human administration is a vaping composition, vaping liquid, e-liquid, or the like.
Background
Traditional tobacco cigarette smoking is one of the biggest causes of death and illness in the UK, and worldwide. In particular, 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. For example, 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. In particular, Clemens et al. (International Journal of Neuropsychopharmacology, Volume 12, Issue 10, November 2009, pages 1355-1366, https://doi.org/10.1017/S1461145709000273) reported that five minor alkaloids found in tobacco smoke (namely anabasine, nornicotine, anatabine, cotinine and myosmine) exhibit properties pharmacologically relevant to the addictive profile of tobacco. Specifically, it was found that tobacco extracts comprising both nicotine and minor alkaloids exhibited an increased locomotor response, or greater psychoactive effect on the user, compared to tobacco extracts comprising nicotine alone. Therefore, these minor alkaloids are understood to increase the motivation, or craving, for cigarette smoking.
Furthermore, tobacco extracts comprising nicotine and all minor alkaloids present in tobacco provide the user with a complete tobacco-analogous psychoactive effect. In particular, Harris et al. (Drug Alcohol Depend., 2015, Volume 153, pages 330-334, doi:10.1016/j.drugalcdep.2015.06.005) reported that 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).
Due to the health risks associated with tobacco smoke, there is a need for an adequate substitute for traditional cigarette smoking that will satisfy the cravings of the user without providing the health risks associated with tobacco smoke.
Electronic cigarettes, or vaping devices, are a known, safer alternative to traditional cigarettes. Electronic cigarettes contain a liquid nicotine solution, which is inhaled by the user. Vaping is becoming an increasingly popular alternative to smoking because it provides the user with a dose of nicotine, without the harmful toxins associated with tobacco smoke.
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. However, many 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. Therefore, users of current vaping products do not experience the same psychoactive effect provided by the alkaloid profile in traditional cigarettes.
Consequently, 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.
As such, it is an object of the present invention to obviate or mitigate at least some of the disadvantages of the prior art.
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.
Disclosure of Invention
According to a first aspect of the invention, there is provided an alkaloid composition for use in the preparation of a composition for mammalian or human administration, the alkaloid composition comprising: (i) nicotine, and (ii) minor alkaloids, wherein the 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. In this respect, 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. In this respect, 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. The National Institute for Occupational Safety and Health (NIOSH) recommends that recommended exposure level (REL) for n-hexane has a time-weighted average concentration for up to a 10-hour workday during a 40-hour workweek (TWA) of 50 ppm. NIOSH considers chloroform to be a potential occupational carcinogen with a short-term exposure limit (ST) of 2 ppm over 60 minutes. It is desirable therefore to reduce or eliminate the inhalation exposure risk to residual solvents present in tobacco substitutes. 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.
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. In contrast to traditional cigarettes, the alkaloid composition of the present invention may comprise no or substantially no TSNA. By "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- (methylnitrosam ino)-1-(3-pyridy1)-1-butanone (NN K), and a mixture thereof.
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. In contrast to traditional tobacco, the alkaloid composition of the present invention does not comprise PAHs.
By the term "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, p-nicotyrine, anatabine, nornicotine and cotinine.
The alkaloids may be nicotinic alkaloids.
By the term "nicotinic alkaloid" is meant an alkaloid that: binds to nicotinic receptors in human, insect and other metabolisms; is structurally related to nicotine; and/or Hi. 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. However, it should be understood that 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.
By the term "administration" is meant the path by which a substance enters the human body. This includes, for example, inhalation of a substance into the lungs.
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.
By the term "minor alkaloid" is meant any alkaloid derived from tobacco, except 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, p-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, p-nicotyrine, anatabine, nornicotine and cotinine. The minor alkaloids may be a mixture of minor alkaloids comprising at least one or more (e.g. 2, 3, 4, or 5) of the group consisting of: myosmine, anabasine, anatabine, nornicotine and cotinine. 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.
In certain embodiments, it is desirable to maximise the anabasine content within the ranges given above in view of its anti-depressant-like effect.
The alkaloid composition may comprise from approximately 0% by weight to approximately 0.4% by weight P-nicotyrine, optionally from approximately 0.01% by weight to approximately 0.2% by weight I-nicotyrine, optionally from approximately 0.05% by weight to approximately 0.1% by weight p-nicotyrine. The alkaloid composition may comprise approximately 0.1% by weight p-nicotyrine.
The alkaloid composition may comprise from approximately 0% by weight to approximately 0.15% by weight p-nicotyrine, optionally from approximately 0.01% by weight to approximately 0.1% by weight 13-nicotyrine, optionally from approximately 0.02% by weight to approximately 0.09% by weight p-nicotyrine. The alkaloid composition may comprise approximately 0.033% by weight p-nicotyrine. The alkaloid composition may comprise approximately 0.04% by weight P-nicotyrine.
The alkaloid composition may comprise approximately 0.05% by weight pnicotyrine.
The alkaloid composition may comprise from approximately 0.05% by weight to approximately 0.07% by weight p-nicotyrine. The alkaloid composition may comprise approximately 0.06% by weight p-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.
In certain embodiments, it is desirable to minimise the nornicotine content within the ranges given above as it is may be metabolised in vivo.
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.
By the term "other minor alkaloids" is meant any alkaloid derived from tobacco, except nicotine, myosmine, anabasine, p-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-methy1-3-pyridinecarboxamide, pentyl pyridine, 1-methy1-3,4-dihydro-1H-quinolin-2-one, 1,2,3,6-tetrahydro-2,3-bipyridine, 2-(2,2,3,4-tetramethy1-4- cyclopenten-1-ylidene)-propanedinitrile, 1-cyclohexy1-2,5- dimethylpiperidin-4-one, 5,7-dimethy1-1,8-naphthyridin-2-amine, 3'-hydroxybenzo[1',2'-b]-1,4-diazicyclo[2.2.2]octene, 1-nitro anabasine, Nacetyl-DL-nornicotine, N-acetyl-(R,S)-norcotinine, piperidine diyl bispyridine and 5-amino-1-benzy1-4-(1-methyl)-2-benzimidazoly1)-pyerol- 3(2H)-one, and 2-acetylpyridine.
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 Cio_12 and C18_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 Of 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: (i) an alkaloid composition comprising: (a) nicotine, and (b) minor alkaloids, wherein the alkaloid composition comprises from approximately 70% by weight to approximately 98%, such as approximately 70% by weight to approximately 95% by weight nicotine; and (ii) a diluent, wherein the 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. Optionally, 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.
By the term "flavouring agent" is meant 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. However, it should be appreciated that 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. Alternatively, the ratio of propylene glycol to vegetable glycerine may be 4:1. The ratio of propylene glycol to vegetable glycerine may be 6:4. Alternatively, the ratio of propylene glycol to vegetable glycerine may be 4:6. However, it should be appreciated that any suitable ratio may be used.
The alkaloids in the alkaloid composition may be in the free base form.
By the term "free base" is meant that the alkaloids are unprotonated.
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 salicylic acid. The organic acid may be tartaric acid. The organic acid may be pyruvic acid. The organic acid may be levulinic acid.
When an organic acid is added to the composition, the alkaloids in the alkaloid composition may be alkaloid salts. Optionally, the nicotine may be nicotine salt. The salt may be a bitartrate or ditartrate salt, such as the bitartrate dihydrate.
By the term "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. For example, the composition may contain alkaloid salts in which approximately 30% are levulinate salts, approximately 60% are bitartrate hem ihydrate salts, and approximately 10% are pyruvate salts. Alternatively, the composition may contain alkaloid salts in which approximately 30% are levulinate salts, and approximately 70% are bitartrate hem ihydrate salts.
The acid utilised in the salt of the alkaloid composition may be an active acid, inactive acid or a combination of both. By "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. For example, the active acid may be ferulic acid, which has a nootropic effect. Ferulic acid may be used to form ferulate alkaloid salts.
By "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. When 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. For example, the liquid solution may be inhaled as a vapour, or applied as a spray, patch, cream, lotion, or the like. However, it should be appreciated that the composition may exist in any suitable form, and for any suitable route of administration. In certain embodiments, 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.
By the term "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.
By the term "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. Examples of 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. On completion, a proportion of the solvent may be evaporated if desired prior to recovery of the alkaloid salts. Furthermore, if desired 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.
Howsoever the alkaloid salts are recovered, 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.
According to a third aspect of the invention there is provided a vaping composition, said vaping composition comprising: (i) an alkaloid composition comprising: (a) nicotine, and (b) minor alkaloids, wherein the alkaloid composition comprises from approximately 70% by weight to approximately 98%, such as approximately 70% by weight to approximately 95% by weight nicotine; and (ii) a diluent, wherein the vaping composition comprises from approximately 0.3% weight by volume to approximately 20% weight by volume of the alkaloid composition.
According to a fourth aspect of the invention, there is provided a vaping composition, said vaping composition comprising: (i) an alkaloid composition comprising: (a) nicotine, and (b) minor alkaloids, wherein the alkaloid composition comprises from approximately 90% by weight nicotine, and approximately 10% by weight minor alkaloids; and (ii) a diluent, wherein the vaping composition comprises from approximately 0.3% weight by volume to approximately 20% weight by volume of the alkaloid composition.
According to a fifth aspect of the invention, there is provided a vaping composition, said vaping composition comprising: (i) an alkaloid composition comprising: (a) nicotine, and (b) minor alkaloids, wherein the alkaloid composition comprises from approximately 95% by weight nicotine, and approximately 5% by weight minor alkaloids; and (H) a diluent, wherein the vaping composition comprises from approximately 0.3% weight by volume to approximately 20% weight by volume of the alkaloid composition.
According to a sixth aspect of the invention there is provided a composition for mammalian or human administration, the composition comprising: (i) an alkaloid composition comprising: (a) nicotine, and (b) minor alkaloids, wherein the alkaloid composition comprises from approximately 70% by weight to approximately 98%, such as approximately 70% by weight to approximately 95% by weight nicotine; and (H) an excipient, wherein the 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. Optionally, the administration may be by buccal administration.
By the term "buccal 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. For example, the solid may be administered as a gum, powder, lozenge, capsule, film, or the like.
However, it should be appreciated that 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. However, it should be appreciated that the composition may be suitable for use in any nicotine replacement therapy products.
By the term "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.
By the term "bulking agent" is meant 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.
By the term "humectant" is meant any compound that retains or preserves moisture in the composition.
By the term "flavouring agent" is meant 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. When 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.
By the term "acidity regulator" is meant any compound that controls the pH of the composition.
According to a seventh aspect of the invention, there is provided a buccal pouch composition, said buccal pouch composition comprising: (i) an alkaloid composition comprising: (a) nicotine, and (b) minor alkaloids, wherein the alkaloid composition comprises from approximately 70% by weight to approximately 98%, such as approximately 70% by weight to approximately 95% by weight nicotine; and (H) an excipient, wherein the buccal pouch composition comprises from approximately 0.2% by weight to approximately 20% by weight of the alkaloid composition.
According to an eighth aspect of the invention, there is provided 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. The respiratory disease may be caused by a coronavirus, optionally wherein the coronavirus is SARS-CoV-2 and the respiratory disease that is caused is COVID-19.
The alternative features and different embodiments as described apply each and every aspect and each and every embodiment thereof mutatis mutandis.
Embodiments of the invention will now be described, by way of example only.
Detailed Description
The % 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.
However, the alkaloid composition of the present invention comprises a combination of nicotine and minor alkaloids.
Examples
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. Alternatively, 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.
In the above extraction process, 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.
Alkaloid Example No.
(pg/g) 1 2 3 4 5 6 7 8 Nicotine 833250 779922 700000 780000 949000 949000 820000 820000 Myosmine 1250 6799 9273 6800 1576 395 1420 5564 Anabasine 3055 18998 25909 19000 23252 964 3472 25909 p-Nicotyrine 167 1300 1773 1300 1591 53 189 1773 Anatabine 4444 6699 9136 6700 8199 1403 5050 9136 Nornicotine 264 2600 3545 2600 3182 83 300 3545 Cotinine 1667 4300 5864 4300 5262 526 1894 5864 Other Minor Alkaloids 155804 179282 244400 179200 7838 47476 167575 128109 Total Alkaloid Content 999900 999900 999900 999900 999900 999900 999900 999900 Nicotine 83.3% 78.0% 70.0% 78.0% 94.9% 94.9% 82.0% 82.0% Content (% w/w) Minor Alkaloid Content (% w/w) 16.7% 22.0% 30.0% 22.0% 5.1% 5.1% 18.0% 18.0%
Table 1
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 (0-Nicotine), n-methyl anabasine, 2,3'-dipyridyl, N(2-carbomethoxyvinyl)methylamine, N-ethyl-3-methyl-benzenamine, methyl nicotinate, isopropyl toluidine, 2-methoxy benzenamine, N-methy1-3- pyridinecarboxamide, pentyl pyridine, 1-methy1-3,4-dihydro-1H-quinolin-2-one, 1,2,3,6-tetrahydro-2,3-bipyridine, 2-(2,2,3,4-tetramethy1-4-cyclopenten-1-ylidene)-propanedinitrile, 1-cyclohexy1-2,5-dimethylpiperidin-4-one, 5,7-dimethy1-1,8-naphthyridin-2-amine, 3'- hydroxybenzo[1',2'-b]-1,4-diazicyclo[2.2.2]octene, 1-nitro anabasine, N- acetyl-DL-nornicotine, N-acetyl-(R,S)-norcotinine, piperidine diyl bis-pyridine and 5-am ino-1-benzy1-4-(1-methyl)-2-benzim idazolyI)-pyerol3(2H)-one, and 2-acetylpyridine.
However, the content of each other minor alkaloid in the concentrated composition is relatively low compared to the named minor alkaloids.
Therefore, most other minor alkaloids present cannot be characterised by standard analysis. For example, Example 4 above was fully characterised by gas chromatography-mass spectrometry (GC-MS) and found to comprise the other minor alkaloids recited in Table 2 below. The percentage by weight amounts of each other minor alkaloid identified in Example 4 are also presented in Table 2. However, there were also other minor alkaloids present that could not be characterised.
Other Minor Alkaloid Concentration Other Minor Alkaloid Content (% w/w) (pg/g) o-Nicotine <1 0.00 n-methyl anabasine 1400 0.14 Ncnitrosonornicotine (NNN) <1 0.00 nicotine-derived nitrosamine ketone (NNK) <5 0.00 N(2-Carbomethoxyvinyl)methylami ne 25 0.00 N-ethyl-3-methyl-benzenamine 79 0.01 Methyl nicotinate 180 0.02 Isopropyl toluidine 70 0.01 2-Methoxy benzenamine 31 0.00 N-methyl-3-pyridinecarboxamide 740 0.07 Pentyl pyridine 2000 0.20 2,3'-Dipyridyl 1600 0.16 1-Methy1-3,4-dihydro-1H-quinolin-2-one 250 0.03 1,2,3,6-Tetrahydro-2,3-bipyridine 370 0.04 2-(2,2,3,4-tetramethy1-4-cyclopenten-1-ylidene)-propaned in itri le 530 0.05 1-Cyclohexy1-2,6-dimethylpiperidin-4-one 260 0.03 5,7-Dimethy1-1,8-naphthyridin-2-amine 64 0.01 Series of unidentified aromatic compounds containing N circa C12 2800 0.28 Series of unidentified aromatic compounds containing N & 0 circa C16-C18 2100 0.21 3'-Hydroxybenzo[11,21-1,]-1,4-diazicyclo[2.2.2]octene 3100 0.31 1-Nitro anabasine 340 0.03 N-Acetyl-DL-nornicotine 110 0.01 N-AcetylR,S)-norcotinine 490 0.05 Series of unidentified aromatic compounds containing N & 0 circa C20-C22 4600 0.46 Piperidine diyl bis-pyridine 510 0.05 5-amino-1-benzy1-4-(1-methyl)-2-benzimidazolyI)-pyerol-3(2H)-one 2400 0.24 Series of unidentified alkoloid type compounds 20000 2.00
Table 2
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 percentage by weight amounts of the alkaloids in the Examples in Table 1 are presented in Table 3 below.
Alkaloid Example No.
(% w/w) 1 2 3 4 5 6 7 8 Nicotine 83.33 78.00 70.01 78.01 94.91 94.91 82.01 82.01 Myosmine 0.13 0.68 0.93 0.68 0.16 0.04 0.14 0.56 Anabasine 0.31 1.90 2.59 1.90 2.33 0.10 0.35 2.59 p-Nicotyrine 0.02 0.13 0.18 0.13 0.16 0.01 0.02 0.18 Anatabine 0.44 0.67 0.91 0.67 0.82 0.14 0.51 0.91 Nornicotine 0.03 0.26 0.35 0.26 0.32 0.01 0.03 0.35 Cotinine 0.17 0.43 0.59 0.43 0.53 0.05 0.19 0.59 Other Minor Alkaloids 15.58 17.93 24.44 17.92 0.78 4.75 16.76 12.81 Total Alkaloid Content 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Nicotine 83.3% 78.0% 70.0% 78.0% 94.9% 94.9% 82.0% 82.0% Content (% w/w) Minor Alkaloid Content (% w/w) 16.7% 22.0% 30.0% 22.0% 5.1% 5.1% 18.0% 18.0%
Table 3
The alkaloid compositions provided in Tables 1 and 3 above are used in the preparation of nicotine replacement therapy products. Typically, the alkaloid composition is used in the preparation of a vaping liquid for inhalation by the user. However, it should be appreciated that the alkaloid composition can also be used in the manufacture of patches, inhalators, sprays, or other nicotine replacement therapy products. For example, the alkaloid composition may be used in the preparation of a powder suitable for buccal administration, such as buccal pouches.
Due to the large variation in the ratio of nicotine to minor alkaloids within the alkaloid composition, 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. In particular, the composition may be standardised by adding USP grade nicotine or lisp grade anatabine to the composition to obtain a nicotine to minor alkaloid ratio of 9:1. However, it should be appreciated that 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. In particular, 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.
The results are provided in Table 4 below.
Alkaloid (pg/g) Example No. 1 2 Nicotine 899554 899682 Myosmine 751 3093 Anabasine 1837 8643 p-Nicotyrine 100 591 Anatabine 2672 3048 Nornicotine 159 1183 Cotinine 1002 1956 Other Minor Alkaloids 93668 81565 Total Alkaloid Content 999900 999900 Nicotine Content (% w/w) 90.0% 90.0% Minor Alkaloid Content (% w/w) 10.0% 10.0%
Table 4
The percentage by weight amounts of Examples in Table 4 are presented
in Table 5 below.
Alkaloid (% w/w) Example No. 1 2 Nicotine 89.96 89.98 Myosmine 0.08 0.31 Anabasi ne 0.18 0.86 p-Nicotyrine 0.01 0.06 Anatabine 0.27 0.30 Nornicotine 0.02 0.12 Cotinine 0.10 0.20 Other Minor Alkaloids 9.37 8.16 Total Alkaloid Content 99.98 99.99 Nicotine Content (% w/w) 90.0% 90.0% Minor Alkaloid Content (% w/w) 10.0% 10.0%
Table 5
Example alkaloid compositions 9 and 10 (below) 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. The HPLC method is has been reproduced from the United States Pharmacopeia (USP) Monograph for Nicotine.
The HPLC analysis used the following conditions: Column 150 mm x 4.6 mm end capped polar embedded octadecylsilyl amorphous organosilica polymer (5 pm) Temperature Ambient Detector UV Detector Wavelength 254 nm Flow rate 1.0 m L/minute Injection Volume 20 pL Runtime 50 minutes Rinsing Solvent Acetonitrile:H20 (80:20) The HPLC analysis used the following time programme in Table 6: Time (min) Mobile Phase A Mobile Phase B (% volume/volume) (% volume/volume) 0 -3 100 0 3 -3.01 100 -95 0 -5 3.01 -28 95 -74 5-26 28 -32 74 -60 26 -40 32 -38 60 -100 40-0 38 -50 100 0
Table 6
The relevant solutions and mobile phases for the HPLC analysis were prepared as follows: Acetic acid solution (60 g/lit): Weigh exactly about 60 g (or 57 mL) of glacial acetic acid and transfer into 1000 mL volumetric flask. Dissolve and dilute to volume with water and mix.
Dilute Ammonia Solution: Weigh exactly about 14 g (or 15.4 mL) of concentrated ammonia into 100 mL volumetric flask. Dissolve and dilute to volume with water and mix.
Dilute acetic acid Solution: Weigh exactly about 12 g (or 11.4 mL) of glacial acetic acid into 100 mL volumetric flask. Dissolve and dilute to volume with water and mix.
Mobile Phase Preparation: Mobile phase A: To 900 mL of water, add 25 mL of 60 g/I 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 0.45p filter paper and sonicate.
Mobile phase B: Acetonitrile (HPLC grade) Test preparation: (Prepare immediately before use) 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.
Reference solution (a): Dissolve the contents of vial of Nicotine for system suitability CRS (Containing impurities A, B, C, D, E, F and G) in 1.0 mL of water and mix.
Reference solution (b): (Prepare immediately before use) Dilute 1.0 mL of the test solution to 10 mL with water and mix. Further dilute 1.0 mL of this solution to 100 mL with water and mix.
Sensitivity solution as per USP: Transfer 5 mL reference solution b in 10 mL volumetric flask and dilute to volume with water and mix.
Blank Preparation: Use water as such The HPLC injection details were as follows in Table 7: Replicate Injection Detail 1 Blank preparation 1 Reference Solution (a) Resolution between the peaks due to impurity G and Nicotine is not less than 2.5.
Tailing Factor: NMT 2.0 for Nicotine 1 Sensitivity solution Signal-to-Noise ratio * NLT 10 6 Reference Solution (b) Relative standard Deviation for the replicate injection should be less than 5.0%.
1 Test preparation set I 1 Test preparation set E Calculate the mean area and report the result 1 Blank preparation 1 Reference Solution (a) Resolution between the peaks due to impurity G and Nicotine is not less than 2.5.
Tailing Factor: NMT 2.0 for Nicotine 1 Sensitivity solution, Signal-to-Noise ratio: NLT 10 1 Reference Solution (b) Cumulative Relative standard Deviation for the replicate injection should be less than 5.0% The HPLC retention times (RT) used were as follows in Table 8: Name of Impurity Retention Time (minutes) Relative Retention Time Nicotine Impurity E (Nicotine 11-N-oxide) 5.34 0.30 Nicotine Impurity C (cotinine) 9.79 0.55 Nicotine Impurity F (nornicotine) 12.46 0.70 Nicotine Impurity A (anatabine) 14.24 0.80 Nicotine Impurity D (myosmine) 15.30 0.86 Nicotine Impurity G (anabasine) 16.02 0.90 Nicotine 17.80 1.00 Nicotine Impurity B (13-nicotyrine) 28.48 1.60
Table 7
The impurities were identified as below: Known impurity: Area obtained in the test solution due to each known impurities A, B, C, D, E, F and G, should not be more 3 times the area obtained with principal peak in the chromatogram obtained with reference solution (b) (0.3 percent).
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): Not more than 8 times the area obtained with principal peak in the chromatogram obtained with reference solution (b) (0.8 percent).
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).
Analysis of Examples 9 and 10 using the above process gave results as
shown in Table 9.
Substances Identified Example No. (% w/w) 9 10 Specified Impurities* Nicotine 92.60% 91.20% Myosmine 0.45% 0.61% Anabasine 1.62% 1.68% g-Nicotyrine 0.04% 0.05% Anatabine 2.46% 2.53% Nornicotine 2.20% 2.71% Cotinine 0.08% 0.14% Nicotine-N-oxide not detected 0.03%4 Unspecified Impurities** Unspecified Impurity (Single Greatest) 0.19% 0.26% Unspecified Impurities 0.36% 0.79% Nicotine Content (4/0 w/w) 92.60% 91.20% Sum of Impurities 7.40% 8.80% (Identified and Unidentified) (% w/w) Sum (% w/w) 100.00% 100.00% The USP monograph for Nicotine identifies the minor alkaloids as "specified impurities".
The term unspecified impurities originates from the USP monograph for Nicotine. Without wishing to be bound by theory, the applicant believes these include other minor alkaloids and other alkaloid compounds.
Nicotine-N-oxide is produced during analysis and is not detected at source.
Table 9
The following examples relate to the use of the alkaloid composition in the preparation of a vaping liquid. However, it should be understood that 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.
To provide a vaping liquid, 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. **
The examples provided in Table 10 below 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). It should be noted that the alkaloid ratio (for example, 90 % by weight nicotine to 10% by weight minor alkaloids) in the alkaloid composition of the vaping liquid remains the same irrespective of the overall concentration of the vaping liquid. This is illustrated in the final two rows of Table 9 below.
Alkaloid Examp e No. 1 (pg/mL) 3 mg/mL 20 mg/mL 72 mg/mL 200 mg/mL Nicotine 2500 16667 60000 166667 Myosmine 4 25 90 250 Anabasine 9 61 220 611 p-Nicotyrine 1 3 12 33 Anatabine 13 89 320 889 Nornicotine 1 5 19 53 Cotinine 5 33 120 333 Other Minor Alkaloids 467 3116 11219 31164 Total Alkaloid Content 3000 20000 72000 200000 Nicotine Content (% w/w) 83.3% 83.3% 83.3% 83.3% Minor Alkaloid Content (% w/w) 16.7% 16.7% 16.7% 16.7%
Table 10
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). However, there were also other minor alkaloids present that could not be characterised.
Table 11 below shows 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).
Alkaloid Examp e No. 2 (pg/m L) 3 mg/mL 20 mg/mL 72 mg/mL 200 mg/mL Nicotine 2340 15600 56160 156000 Mysomine 20 136 490 1360 Anabasine 57 380 1368 3800 p-Nicotyrine 4 26 94 260 Anatabine 20 134 482 1340 Nornicotine 8 52 187 520 Cotinine 13 86 310 860 Other Minor Alkaloids 538 3586 12910 35860 Total Alkaloid Content 3000 20000 72000 200000 Nicotine Content (% w/w) 78.0% 78.0% 78.0% 78.0% Minor Alkaloid Content (% w/w) 22.0% 22.0% 22.0% 22.0%
Table 11
In the examples described above, the alkaloid composition is diluted in propylene glycol. However, it should be appreciated that 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. For use in vaping liquids, an organic acid may be added to the composition to provide an alkaloid salt, or "nicotine salts" version of the composition.
Specific nicotinic bitartrate dihydrate and nicotinic salicylate salts may be formed by the following methods.
N icoti n ic Bitartrate Dihydrate Salts Nicotinic bitartrate dihydrate is created using a 1:1 molar ratio of Tartaric acid to Nicotinic alkaloids. As 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) 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 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).
Analysis of TSNA:NNK and TSNA:NNN An experimental method was developed and validated for the collection and analysis of tobacco-specific nitrosamines (TSNAs) that are present in electronic cigarette (EC) liquid or are released from aerosol samples using a Liquid chromatography-Mass spectrometry (LC-MS) system. As part of this study, the relative recovery of two target TSNAs was assessed by spiking standards in a mixture of Propylene glycol and vegetable Glycerin. Recovery was assessed against two major variables: (1) The chemical media (solution) selected for sample dilution (Acetonitrile [ACN] vs. Ammonium acetate [AA]) (2) The type of sampling filter used (Cambridge filter pad [CFP] vs. quartz wool [OW] tube). 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.
(3) Based on these conditions, the detection limits of N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyI)-1-butanone (NNK) are calculated as 0.002 mg/minute.
Spiked samples were analyzed by HPLC-MS. After the automatic injection of 1 pL of sample into the HPLC system, the two target compounds are separated using a ZORBAX Eclipse Plus C18 column (film thickness: 0.35 pm, diameter: 3 mm, length: 150 mm) with the column temperature of 55 C. Two mobile phases with a flow rate of 0.4 mL/minute are used to elute the analyte: Solvent A (0.1% acetic acid in deionized water) and Solvent B (0.1% acetic acid in methanol). The HPLC-MS system is operated with Electrospray ionization in the positive ion mode (ESI+). Ion spray voltage and ion spray temperature are set to 4.5 kV and 700 cC, 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.
Operational condition of high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) system and multiple reaction monitoring (MRM) conditions for the analysis of tobacco-specific nitrosamines (TSNAs) are given below.
The parameters of the HPLC system are given below: Instrument: Column: Oven Temperature: Injection Volume: Flow Rate: Pump Mode. Mobile Phase A: Mobile Phase B: Gradient: Agilent High Performance Liquid Chromatograph 1260 Infinity II ZOPRBAX Eclipse Plus C18, 3 x 150 mm, particle size 3.5 pm 55°C 1pL 0.4 mL/minute Binary Gradient 0.1% Acetic acid in HPLC grade water 0.1% Acetic acid in HPLC grade methanol Time 0 4 7 8 20 25 (min) Solvent 55 98 98 2 2 55
B
Total Analysis Time: 25 minutes The parameters of the mass spectrometer are given below: Acquisition Mode: MRM Electrospray Ionization: ESI mode Polarity: Positive Nebulizing Gas Flow (N2): 3.0 L/minute Drying Gas (N2): CID Gas (Ar): Interface Voltage: Loop Time: Dwell Time: 15.0 L/minute 230 kPa 4.5 kV 0.348 seconds 26 milliseconds The results of the analysis are shown in Table 12.
Sample Subject of determination Result of analysis Vaping liquid of Example 9* NNK <0.002 pg/g# Vaping liquid of Example 9* NNN <0.002 pg/g # The 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
Table 12
Vaping Test A panel of 5 people performed testing of 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 UweII Caliburn Koko Pods with 1.2 ohm kanthal coils. The vaping equipment was fully charged prior to use.
Results USP nicotine -Users noted stimulant effects and reported "harshness" of flavour.
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".
In the examples described above, no additional flavourings have been added to the composition. However, it should be understood that the composition may be diluted with water and flavouring agents to improve the taste of the vaping liquid for the end user.
The composition of the present invention has a similar alkaloid profile to that of traditional tobacco cigarettes. In particular, 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.
Furthermore, the 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.
Various modifications and variations to the described embodiments of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention as a whole. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the art are intended to be covered by the present invention.

Claims (32)

  1. CLAIMS1. An alkaloid composition for use in the preparation of a composition for mammalian or human administration, the alkaloid composition comprising: (i) nicotine, and (ii) minor alkaloids, wherein the alkaloid composition comprises from approximately 70% by weight to approximately 98% by weight nicotine.
  2. The alkaloid composition of claim 1, wherein the alkaloid composition comprises from approximately 70% by weight to approximately 95% by weight nicotine.
  3. 3. The alkaloid composition of claim 1 or claim 2, wherein the alkaloid composition is a non-tobacco alkaloid composition.
  4. 4. The alkaloid composition of any one of claims 1 to 3, wherein the alkaloid composition comprises 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, optionally approximately 90% by weight nicotine.
  5. 5. The alkaloid composition of any one of claims 1 to 4, wherein the alkaloid composition comprises from approximately 2% to approximately 30% by weight minor alkaloids, optionally from approximately 5% to approximately 30% by weight minor alkaloids, 6. 7. 8. 9.optionally from approximately 6% by weight to approximately 22% by weight minor alkaloids, optionally from approximately 6% by weight to approximately 18% by weight minor alkaloids, optionally approximately 10% by weight minor alkaloids.
  6. The alkaloid composition of any preceding claim, wherein the minor alkaloids are a mixture of minor alkaloids comprising at least one or more of the group consisting of: myosmine, anabasine, p-nicotyrine, anatabine, nornicotine and cotinine.
  7. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises 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, preferably approximately 0.3% by weight myosmine.
  8. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises 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, preferably approximately 0.9% anabasine.
  9. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises from approximately 0% by weight to approximately 0.4% by weight p-nicotyrine, optionally from approximately 0.01% by weight to approximately 0.2% by weight 6-nicotyrine, optionally from approximately 0.05% by weight to approximately 0.1% by weight p-nicotyrine, preferably approximately 0.1% by weight p-nicotyrine.
  10. 10. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises 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.for example, the alkaloid composition comprises 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, preferably approximately 0.3% by weight anatabine.11. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises 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, preferably approximately 2.2% by weight nornicotine, approximately 2.71% by weight nornicotine; for example, the alkaloid composition comprises from approximately 0% by weight to approximately 0.7% by weight nornicotine, optionally from approximately 0.01% by weight to approximately 12. 13. 14. 15. 16.0.4% by weight nornicotine, optionally from approximately 0.05% by weight to approximately 0.2% by weight nornicotine, preferably approximately 0.1% by weight nornicotine.
  11. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises 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, preferably approximately 0.2% by weight cotinine.
  12. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises no or substantially no extraction solvent, such as hexane and/or chloroform.
  13. The alkaloid composition of any preceding claim, wherein the alkaloid composition comprises no or substantially no tobacco-specific nitrosamine, such as N'-nitrosonornicotine (NNN), 4(methylnitrosamino)-1-(3-pyridy1)-1-butanone (NN K), or a mixture thereof.
  14. The alkaloid composition of any preceding claim, wherein the alkaloid composition does not comprise polycyclic aromatic hydrocarbons.
  15. A composition for mammalian or human administration, the composition comprising: 17. 18. 19. 20. 21.
  16. (i) approximately 0.3% weight by volume to approximately 20% weight by volume of the alkaloid composition of any one of claims 1 to 15, and (ii) a diluent.
  17. The composition of claim 16, wherein the diluent is selected from one or more of the group consisting of: water, a flavouring agent and a solvent.
  18. The composition of claim 17, wherein the solvent is an alcohol, optionally wherein the alcohol is selected from one or more of the group consisting of: propylene glycol, vegetable glycerine (glycerol), polyethylene glycol, polyethylene glycol 400 (PEG 400), polyethylene glycol 300 (PEG 300) and ethanol.
  19. The composition of any one of claims 16 to 18, wherein the alkaloids in the alkaloid composition are in the free base form.
  20. The composition of any one of claims 16 to 18, wherein the composition further comprises an active acid, an inactive acid, or a mixture thereof.
  21. The composition of claim 20, wherein the composition further comprises at least one organic acid, optionally wherein the organic acid is 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, optionally wherein the organic acid is salicylic acid, optionally wherein the organic acid is tartaric acid, optionally wherein the organic acid is pyruvic acid, optionally wherein the organic acid is levulinic acid.
  22. 22. The composition of claim 21, wherein the alkaloids in the alkaloid composition are alkaloid salts, optionally wherein the nicotine is nicotine salt.
  23. 23. The composition of claim 22, wherein the mixture of salts is selected from the group consisting of levulinate salts, bitartrate salts, and pyruvate salts.
  24. 24. The composition of any one of claims 16 to 18, wherein the alkaloid composition may be a mixture of alkaloids in free base form and one or more alkaloid salts as defined in any one of claims 20 to 24.
  25. 25. The composition of any one of claims 16 to 24, wherein the composition is a liquid solution, optionally wherein the liquid solution is in a form suitable for inhalation as a vapour.
  26. 26. The composition of any one of claims 16 to 25, wherein the composition is a vaping composition, an e-liquid, a vaping liquid, or the like for use in an e-cigarette.
  27. 27. A composition for mammalian or human administration, the composition comprising: (i) approximately 0.2% by weight to approximately 20% by weight of the alkaloid composition of any one of claims 1 to 15, and (ii) an excipient.
  28. 28. The composition of claim 27, wherein the excipient is a bulking agent.
  29. 29. The composition of any one of claims 27 to 28, wherein the composition is in the form of a solid, optionally wherein the solid is a powder suitable for buccal administration.
  30. 30. The composition of claim 29, wherein the composition is a buccal pouch composition, or the like.
  31. 31. A vaping composition, vaping liquid, e-liquid, or the like, comprising the alkaloid composition as described in any one of claims 1 to 15.
  32. 32. A buccal pouch composition, or the like, comprising the alkaloid composition as described in any one of claims 1 to 15.
GB2106282.3A 2020-05-01 2021-04-30 Composition and use thereof Pending GB2595967A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GBGB2006481.2A GB202006481D0 (en) 2020-05-01 2020-05-01 Composition and use thereof

Publications (2)

Publication Number Publication Date
GB202106282D0 GB202106282D0 (en) 2021-06-16
GB2595967A true GB2595967A (en) 2021-12-15

Family

ID=71080450

Family Applications (2)

Application Number Title Priority Date Filing Date
GBGB2006481.2A Ceased GB202006481D0 (en) 2020-05-01 2020-05-01 Composition and use thereof
GB2106282.3A Pending GB2595967A (en) 2020-05-01 2021-04-30 Composition and use thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
GBGB2006481.2A Ceased GB202006481D0 (en) 2020-05-01 2020-05-01 Composition and use thereof

Country Status (2)

Country Link
GB (2) GB202006481D0 (en)
WO (1) WO2021220018A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113406231B (en) * 2021-06-18 2023-06-09 云南民族大学 Nicotine with low secondary alkaloid content and application thereof
CN114831335A (en) 2022-04-15 2022-08-02 汪冶 Application of anabasine in atomized electronic delivery product
CN114732148A (en) 2022-04-18 2022-07-12 汪冶 Application of anabasine in heating non-combustion electron delivery product, solid-state slice and preparation method thereof
CN117281286A (en) * 2022-06-16 2023-12-26 深圳麦克韦尔科技有限公司 Composite nicotine salt, composite nicotine salt formulation, preparation method and application thereof
CN115226729B (en) * 2022-08-29 2023-04-07 湖北省烟草科学研究院 Tobacco leaf surface spraying material and method for reducing harmful ingredients of cigar and tobacco shreds

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120325228A1 (en) * 2011-06-23 2012-12-27 Williams Jonnie R Alkaloid composition for e-cigarette
US20130298921A1 (en) * 2011-06-23 2013-11-14 Rock Creek Pharmaceuticals, Inc. Inhaler for smoking cessation
US20140261479A1 (en) * 2013-03-15 2014-09-18 Altria Client Services Inc. Nicotine-containing products and methods of making
CN108968165A (en) * 2018-10-10 2018-12-11 湖北中烟工业有限责任公司 A method of improving electronic cigarette and aspirates strength
US20190380378A1 (en) * 2018-06-15 2019-12-19 R.J. Reynolds Tobacco Company Purification of nicotine
US20200035118A1 (en) * 2018-07-27 2020-01-30 Joseph Pandolfino Methods and products to facilitate smokers switching to a tobacco heating product or e-cigarettes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107660812B (en) * 2016-07-27 2021-02-23 湖南中烟工业有限责任公司 Cured tobacco nicotine extract and extraction process
CN107660811B (en) * 2016-07-27 2021-02-23 湖南中烟工业有限责任公司 Burley tobacco nicotine extract and extraction process
US11871778B2 (en) * 2018-06-28 2024-01-16 Philip Morris Products S.A. Cartridge for an aerosol-generating system comprising an alkaloid source comprising a liquid alkaloid formulation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120325228A1 (en) * 2011-06-23 2012-12-27 Williams Jonnie R Alkaloid composition for e-cigarette
US20130298921A1 (en) * 2011-06-23 2013-11-14 Rock Creek Pharmaceuticals, Inc. Inhaler for smoking cessation
US20140261479A1 (en) * 2013-03-15 2014-09-18 Altria Client Services Inc. Nicotine-containing products and methods of making
US20190380378A1 (en) * 2018-06-15 2019-12-19 R.J. Reynolds Tobacco Company Purification of nicotine
US20200035118A1 (en) * 2018-07-27 2020-01-30 Joseph Pandolfino Methods and products to facilitate smokers switching to a tobacco heating product or e-cigarettes
CN108968165A (en) * 2018-10-10 2018-12-11 湖北中烟工业有限责任公司 A method of improving electronic cigarette and aspirates strength

Also Published As

Publication number Publication date
GB202006481D0 (en) 2020-06-17
GB202106282D0 (en) 2021-06-16
WO2021220018A1 (en) 2021-11-04

Similar Documents

Publication Publication Date Title
GB2595967A (en) Composition and use thereof
AU2021204112B2 (en) Nicotine salt formulations for aerosol devices and methods thereof
JP7224375B2 (en) nicotine preparation
AU2016381372B2 (en) Nicotine replacement therapy products comprising synthetic nicotine
EP3214956B1 (en) Solution comprising nicotine in unprotonated form and protonated form
US20170112182A1 (en) Nicotine composition for vaping devices and vaping devices employing the same
US8241680B2 (en) Nutraceutical product containing anatabine and yerba maté
CN113142679A (en) Nicotine liquid formulations for aerosol devices and methods thereof
US9526270B2 (en) Synthetic or imitation nicotine compositions, processes and methods of manufacture
CA2883379A1 (en) Nicotine composition
RU2736854C1 (en) Aerosol-forming composition
WO2006070288A2 (en) Aerosol generator
CN113015444A (en) Aerosol formulation
CN113163842A (en) Aerosol formulation
UA127837C2 (en) Aerosolisable formulation
CN113226067A (en) Aerosol formulation
RU2770248C1 (en) Aerosol-forming composition
CN113163840A (en) Aerosol formulation
KR20120083648A (en) Composition of antismoking aid containing damascone
WO2022218310A1 (en) Aerosol-forming substrate and aerosol-generating system
JP7102590B1 (en) Liquids for e-cigarettes and liquids for e-cigarettes, as well as cartridges for e-cigarettes, e-cigarettes
EP4138585A1 (en) Aerosolisable formulation
CN114947174A (en) Aerosol-forming substrate and aerosol-generating system

Legal Events

Date Code Title Description
732E Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977)

Free format text: REGISTERED BETWEEN 20220106 AND 20220112