[go: up one dir, main page]

WO2024243290A1 - Formulation d'analogue de nicotine synthétique pour le remplacement et l'amplification de nicotine - Google Patents

Formulation d'analogue de nicotine synthétique pour le remplacement et l'amplification de nicotine Download PDF

Info

Publication number
WO2024243290A1
WO2024243290A1 PCT/US2024/030538 US2024030538W WO2024243290A1 WO 2024243290 A1 WO2024243290 A1 WO 2024243290A1 US 2024030538 W US2024030538 W US 2024030538W WO 2024243290 A1 WO2024243290 A1 WO 2024243290A1
Authority
WO
WIPO (PCT)
Prior art keywords
nicotine
methylnicotine
synthetic
analogue
delivery systems
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
PCT/US2024/030538
Other languages
English (en)
Inventor
Michael KRIZNIC
Samuel BENAIM
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.)
Purple Sky LLC
Original Assignee
Purple Sky LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Purple Sky LLC filed Critical Purple Sky LLC
Publication of WO2024243290A1 publication Critical patent/WO2024243290A1/fr
Anticipated expiration legal-status Critical
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
    • 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
    • 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
    • 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
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
    • A24D1/00—Cigars; Cigarettes
    • A24D1/20—Cigarettes specially adapted for simulated smoking devices

Definitions

  • Certain aspects of the present disclosure generally relate to a synthetic nicotine replacement for electronic delivery systems, particularly for use in vaporizers and heat-not-burn delivery systems.
  • Nicotine is a highly addictive substance that is commonly used as a stimulant and is found in various forms, including tobacco products, nicotine replacement therapy products, and electronic nicotine delivery systems. Despite its widespread use, nicotine is associated with negative health effects, including increased risk of heart disease, stroke, and various types of cancer.
  • Atomized electronic cigarettes in current markets are typically synthesized from a concoction of propylene glycol, glycerol, flavorings, and nicotine salts.
  • the heat-not-burn products utilize tobacco or non-tobacco herbal particulates as carriers. These carriers incorporate typical additives such as nicotine, flavorings, sweetening agents, and cooling agents, dissolved in prevalent solvents like propylene glycol, glycerol, or water. This solution is homogenously combined with the carrier and encapsulated into heat-not-burn cartridges, effectively omitting tar derivatives produced through traditional cigarette combustion.
  • Nicotine is absorbed into the bloodstream through the mucous membranes in the mouth and lungs.
  • the speed and efficiency of nicotine absorption can vary depending on the method of delivery, such as smoking, chewing, or using nicotine replacement therapy products such as patches, gum, or lozenges.
  • the rate of nicotine absorption is typically slower and more controlled, as the nicotine is absorbed gradually through the mucous membranes in the mouth or skin. This can help to reduce the risk of nicotine overdose and decrease the likelihood of developing dependence on nicotine.
  • Nicotine acts on specific receptors in the body known as nicotinic acetylcholine receptors (nAChRs). These receptors are found in various parts of the body, including the central and peripheral nervous systems, and they play a role in various physiological processes such as autonomic ganglionic transmission, muscle contraction, and synaptic transmission in the brain.
  • nAChRs nicotinic acetylcholine receptors
  • Nicotine primarily binds to alpha4beta2 nAChRs, which are found in high concentrations in the brain and are involved in the regulation of dopamine release, which is the key neurotransmitter responsible for the reinforcing effects of nicotine.
  • Patent application CN114437025A discloses a method for making a racemic 6- Methylnicotine, which results in the production of a chiral compound which is a racemic mixture.
  • Nicotine replacement therapy products involve the controlled delivery of nicotine in order to satisfy cravings and gradually reduce dependence in nicotine cessation.
  • the amount and rate of nicotine delivered through these systems are often insufficient to satisfy nicotine cravings, thereby reducing the effectiveness of the nicotine replacement therapy. It is thus desired to provide a nicotine amplifying formulation to satisfy nicotine cravings with less nicotine.
  • One form of nicotine replacement therapy involves the use of electronic nicotine delivery systems, such as vaporizers or e-cigarettes. These products have attracted considerable attention in view of certain public health events in recent years. However, due to regulatory limitations and costs, the amount and rate of nicotine delivered through these systems are often insufficient to satisfy nicotine cravings, thereby reducing the effectiveness of the nicotine replacement therapy. It is thus desired to provide a synthetic nicotine analogue formulation for electronic delivery systems which offers a more effective alternative for managing nicotine cravings.
  • Another form of nicotine replacement therapy involves the use of oral nicotine delivery systems, such as pouches or gums.
  • Another form of nicotine replacement therapy involves the use of nasal sprays or powders.
  • One aspect of the present disclosure provides a use of a synthetic nicotine analogue compound, (S)-6-Methylnicotine as a nicotine replacement in electronic nicotine delivery systems, for example, vaporizers, e-cigarettes or heat-not-burn products to provide improved effectiveness, safety and cost reductions over existing devices.
  • One aspect of the present disclosure provides a use of a synthetic nicotine analogue compound, S-(6)-Methylnicotine as a nicotine replacement in oral or nasal nicotine delivery systems for example, nicotine pouches or gums to provide improved effectiveness, safety and cost reductions over existing devices.
  • One aspect of the present disclosure provides a use of a synthetic nicotine analogue compound, S-(6)-Methylnicotine as a nicotine amplifying agent to provide improved effectiveness, safety and cost reductions over existing devices.
  • One aspect of the present disclosure provides a use of a synthetic nicotine analogue as a nicotine replacement, wherein the synthetic nicotine analogue is at least one of (S)-6- methylnicotine or a (S)-6-methylnicotine carboxylate salt.
  • the (S)-6-methylnicotine carboxylate salt may be an acetate, ascorbate, benzoate, butyrate, citrate, lactate, levulinate, malate, pyruvate, succinate, tartrate, or salicylate salt, or any other commercially and organoleptically viable carboxylate salt.
  • the synthetic nicotine analogue can be used as a nicotine replacement for electronic delivery systems.
  • the synthetic nicotine analogue can be used as a nicotine replacement in combustion applications.
  • the synthetic nicotine analogue can be used as a nicotine replacement in heat-not-burn applications.
  • the synthetic nicotine analogue can be used as a nicotine replacement in oral delivery applications.
  • the synthetic nicotine analogue can be used as a nicotine replacement in nasal delivery applications.
  • the synthetic nicotine analogue can be used as a nicotine replacement in heat-not-burn applications.
  • the synthetic nicotine analogue can also be used for nicotine replacement therapy.
  • Another aspect of the present disclosure provides a use of a synthetic nicotine analogue as a nicotine amplification agent, wherein the synthetic nicotine analogue is at least one of (S)- 6-methylnicotine or a (S)-6-methylnicotine carboxylate salt.
  • the (S)-6-methylnicotine carboxylate salt may be an acetate, ascorbate, benzoate, butyrate, citrate, lactate, levulinate, malate, pyruvate, succinate, tartrate, or salicylate salt.
  • a synthetic nicotine analogue comprising a (S)-6-methylnicotine or a (S)-6-methylnicotine carboxylate salt.
  • the (S)-6- methylnicotine carboxylate salt may be an acetate, ascorbate, benzoate, butyrate, citrate, lactate, levulinate, malate, pyruvate, succinate, tartrate, or salicylate salt.
  • FIG. 1 is the chemical structure of (S)-6-Methylnicotine also known as (S)-2-methyl-5-(l- methy 1 py rroli din-2 -yl )py ri di ne .
  • FIG. 2 is a table showing study results comparing the biological effect of the formulation compared to nicotine according to one aspect of the present disclosure.
  • FIG. 3 is a table showing preliminary acute oral toxicity test results in mice for (S)-6- Methylnicotine according to one aspect of the present disclosure.
  • FIG. 4 is a table showing preliminary acute oral toxicity test results for (S)-6-Methylnicotine benzoate according to one aspect of the present disclosure.
  • FIG. 5 is a reaction scheme showing synthesis of (S)-6-Methylnicotine acetate.
  • FIG. 6 is a reaction scheme showing synthesis of (S)-6-Methylnicotine ascorbate.
  • FIG. 7 is a reaction scheme showing synthesis of (S)-6-Methylnicotine benzoate.
  • FIG. 8 is a reaction scheme showing synthesis of (S)-6-Methylnicotine butyrate.
  • FIG. 9 is a reaction scheme showing synthesis of (S)-6-Methylnicotine citrate.
  • FIG. 10 is a reaction scheme showing synthesis of (S)-6-Methylnicotine lactate.
  • FIG. 11 is a reaction scheme showing synthesis of (S)-6-Methylnicotine levulinate.
  • FIG. 12 is a reaction scheme showing synthesis of (S)-6-Methylnicotine malate.
  • FIG. 13 is a reaction scheme showing synthesis of (S)-6-Methylnicotine pyruvate.
  • FIG. 14 is a reaction scheme showing synthesis of (S)-6-Methylnicotine succinate.
  • FIG. 15 is a reaction scheme showing synthesis of (S)-6-Methylnicotine tartrate.
  • FIG. 16 is a reaction scheme showing synthesis of (S)-6-Methylnicotine salicylate.
  • the present invention provides a use of a synthetic nicotine analogue formulation in electronic delivery systems for nicotine replacement therapy.
  • the present invention provides a use of a synthetic nicotine analogue formulation in electronic delivery systems.
  • the present invention provides a use of a synthetic nicotine analogue formulation in heat-not-bum delivery systems for nicotine replacement therapy.
  • the present invention provides a use of a synthetic nicotine analogue formulation in heat-not-burn delivery systems.
  • the present invention provides a use of a synthetic nicotine analogue formulation in oral delivery systems for nicotine replacement therapy.
  • the present invention provides a use of a synthetic nicotine analogue formulation in nasal delivery systems for nicotine replacement therapy.
  • the present invention provides a use of a synthetic nicotine analogue formulation in oral delivery systems to provide a delivery method that provides enjoyment and satisfaction to a user that is similar to the effects provided by nicotine.
  • the present invention provides a use of a synthetic nicotine analogue formulation in nasal delivery systems to provide a delivery method that provides enjoyment and satisfaction to a user that is similar to the effects provided by nicotine.
  • the present invention provides a use of a synthetic nicotine analogue formulation for use as a nicotine amplifier for nicotine replacement therapy.
  • FIG. 1 is an illustration of the chemical structure of a preferred embodiment of a synthetic nicotine analogue, (S)-6-Methylni cotine, also known as (S)-2-methyl-5-(l- methylpyrrolidin-2-yl)pyridine.
  • 6-Methylnicotine is a derivative of nicotine with a methyl substitution at the 6-position of the pyridine ring. 6-Methylnicotine has been used as a precursor in the preparation of other 6-subtituted nicotine derivatives.
  • 6-Methylnicotine is a chiral compound and is typically produced in a racemic mixture. In the racemate, the efficacy of 6-Methylnicotine is reduced, as the R-enantiomer, (R)-6- Methyl nicotine is not effective as a nicotine analogue, and contributes to unpleasant flavors, and is an undesirable waste product which dilutes the effectiveness and potentially increases the hazardous side effects.
  • the synthetic nicotine analogue formulation comprises between 99% and 100%, preferably between 99.5% and 100%, and ideally between 99.8% and 100% enantiomerically pure (S)-6-Methylnicotine.
  • a synthetic nicotine analogue formulation may be adapted for use for electronic nicotine delivery systems, such as vaporizers or e-cigarettes.
  • the formulation is designed to be used in existing electronic nicotine delivery systems without need for modification.
  • the formulation contains between 0.01% and 99.5% (S)-6-Methylnicotine, preferably between 0.20% and 10.00% and optimally between 0.50% and 2.00%.
  • the formulation may additionally comprise methyl cellulose or other similar thickeners, humectants, flavors, and other active ingredients such as caffeine, nicotine, taurine, or guaranine, for example.
  • the formulation has a pH between 5 and 10.5, preferably between 7 and 10, and optimally between 8.0 and 9.5.
  • the formulation comprises PG/VG (propylene glycol and vegetable glycerin).
  • the formulation further comprises flavoring in liquid form.
  • (S)-6-Methylnicotine is used instead of nicotine in an e- liquid for use in nicotine replacement therapy.
  • (S)-6-Methylnicotine is used instead of nicotine in an e- liquid for use in electronic nicotine delivery systems.
  • (S)-6-Methylnicotine is used instead of nicotine in a heat-not-burn carrier materials for use in nicotine replacement therapy.
  • (S)-6-Methylnicotine is used instead of nicotine in a heat-not-burn carrier materials for use in heat-not-burn delivery systems.
  • a synthetic nicotine analogue formulation it may be adapted for use for oral nicotine delivery systems, such as nicotine pouches, chewing gum, strips, lozenges, tablets, gummies, gels, thin films, or other forms designed to be placed inside a user’ s mouth.
  • the formulation is designed to be used in existing oral nicotine delivery systems without need for extensive modification.
  • the formulation contains between 0.01% and 99.5% (S)- 6-Methylnicotine, preferably between 0.01% and 30.0% and optimally between 1.00% and 18.00%.
  • the formulation may additionally comprise methyl cellulose or other similar thickeners, humectants, flavors, and other active ingredients such as caffeine, nicotine, taurine, or guaranine, for example.
  • the formulation has a pH between 5 and 10.5, preferably between 7 and 10, and optimally between 8.0 and 9.5.
  • the moisture level of the formulation is below 50%, and preferably between 15% and 35%.
  • (S)-6- Methylnicotine is bound with a salt, polymer, or other ingredient including but not limited to: tartaric acid, benzoic acid, lactic acid, malic acid, polacrilex resin, or betacylcodextrin.
  • the formulation is processed using a high sheer mixer to increase potential uptake.
  • (S)-6-Methylnicotine may be combined with a lipid or a combination of lipids, such as monoglyceride or a triglyceride, to reduce bitterness, improve texture, facilitate absorption, provide stability or increased shelf-life, or to modify the release profiles of the (S)-6-Methylnicotine and/or flavourant(s) and/or sweetener(s), thereby increasing the user experience.
  • the formulation further comprises one of more flavorings in liquid or solid form.
  • a synthetic nicotine analogue formulation it may be adapted for use for nasal nicotine delivery systems, such sprays, powders, liquids, gels or other forms designed to be delivered inside a user’ s nasal cavity.
  • the formulation is designed to be used in existing nasal nicotine delivery systems without need for extensive modification.
  • the formulation contains between 0.01% and 99.5% (S)-6-Methylnicotine, preferably between 0.01% and 30.0% and optimally between 1.00% and 18.00%.
  • the formulation may additionally comprise moisturizers or other similar oils, humectants, flavors, and other active ingredients such as caffeine, nicotine, taurine, or guaranine, for example.
  • the formulation has a pH between 5 and 10.5, preferably between 7 and 10, and optimally between 8.0 and 9.5.
  • (S)-6-Methylnicotine is bound with a salt, polymer, or other ingredient including but not limited to: tartaric acid, benzoic acid, lactic acid, malic acid, polacrilex resin, or betacylcodextrin.
  • the formulation is processed using a high sheer mixer to increase potential uptake.
  • (S)-6- Methylnicotine may be combined with a lipid or a combination of lipids, such as monoglyceride or a triglyceride, to reduce bitterness, improve texture, facilitate absorption, provide stability or increased shelf-life, or to modify the release profiles of the (S)-6- Methyl nicotine and/or flavourant(s) and/or sweetener(s), thereby increasing the user experience.
  • the formulation further comprises one of more flavorings in liquid or solid form.
  • the formulation further comprises one of more additional active ingredients in liquid or solid form.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine pouch for use in nicotine replacement therapy.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine gum for use in nicotine replacement therapy.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine spray for use in nicotine replacement therapy.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine powder for use in nicotine replacement therapy.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine pouch for use in nicotine replacement products.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine gum for use in nicotine replacement products.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine spray for use in nicotine replacement products.
  • (S)-6-Methylnicotine is used instead of nicotine in a nicotine powder for use in nicotine replacement products.
  • (S)-6-Methylnicotine is approximately 4 to 5 times more potent than nicotine per unit mass, and may be faster acting, providing a more effective solution for managing nicotine cravings.
  • preliminary results indicate that the potency may be even higher, between 6 to 8 times more potent, or even 10 to 12 times more potent.
  • This increased strength allows individuals to experience relief from nicotine cravings more quickly and effectively, using much lower dosages, and induces a subjective “hit” sensation which satisfies cravings.
  • This increased pharmacological potency allows for the use of a reduced amount of active ingredient when compared to synthetic nicotine formulations. As less active ingredient is required, additional inert stabilizing agents can be included in the formulation, increasing stability.
  • (S)-6-Methylnicotine has been observed to be more chemically stable than nicotine, and resists degradation and discoloration.
  • (S)-6-Methylnicotine may potentially last up to five times (5x) longer in the air compared to nicotine which may result in an increased shelf life, and it may be able to resist higher temperatures which may also contribute to a longer shelf life and increased product stability.
  • a test was conducted whereby (S)-6-Methylnicotine and nicotine were allowed to be exposed to atmosphere for 24 hours and nicotine yellowing was observed sooner than (S)-6-Methylnicotine, indicating that nicotine experiences more rapid decomposition that (S)-6-Methylnicotine.
  • Test results have shown that (S)-6-Methylnicotine is more stable than nicotine when blended with other compounds, enabling combinations of active ingredients.
  • the formulation may comprise additional secondary active ingredients in addition to (S)-6-Methylnicotine, such as Caffeine, Ethanol, Tobacco additives, and various medications, herbs and supplements.
  • Ethanol a central nervous system depressant that can increase the absorption and potency of (S)-6-Methylnicotine leading to a stronger effect, is used to further reduce the amount of primary active ingredient required to achieve craving reduction.
  • Suitable substrates include natural biomaterials, such as ground herbal or botanical blends, of tobacco or non-tobacco origin, artificial or synthetic fibrous or ground materials, or any other type of natural or artificial porous material capable of adsorbing liquid or particulates, for example.
  • a liquid solution containing (S)-6- Methylnicotine is atomized or aerosolized using an air-powered sprayer, such as an airbrush, and applied to an appropriate substrate.
  • the substrate may be immersed or coated with liquid solution. The concentration and amount of liquid solution applied can be finely controlled to control the amount of (S)-6-Methylnicotine present to ensure consistent dosage.
  • the substrate is tobacco, or another combustible or heat- activated active plant substrate such as cannabis
  • (S)-6-Methylnicotine may be used as the main active compound, as or co-active compound, or as an enhancer or amplifier.
  • (S)-6-Methylnicotine may be replaced with or used in combination with one or more (S)-6-Methylnicotine carboxylate salts.
  • (S)-6-Methylnicotine carboxylate salts can be synthesized by reaction of (S)-6-Methylnicotine with the corresponding carboxylic acid in appropriate solvent.
  • Appropriate solvents include common solvents such as glycerol, propylene glycol, and water, which are generally considered safe for human consumption.
  • novel (S)-6-Methylnicotine carboxylates were synthesized and tested.
  • (S)-6-Methylnicotine carboxylates synthesized include (S)-6-Methylnicotine acetate, (S)-6-Methylnicotine ascorbate, (S)-6-Methylnicotine benzoate, (S)-6-Methylnicotine butyrate, (S)-6-Methylnicotine citrate, (S)-6-Methylnicotine lactate, (S)-6-Methylnicotine levulinate, (S)-6-Methylnicotine malate, (S)-6-Methylnicotine pyruvate, (S)-6- Methylnicotine succinate, (S)-6-Methylnicotine tartrate, and (S)-6-Methylnicotine salicylate.
  • (S)-6-Methylnicotine carboxylate salts have been found to have reduced perceived ‘harshness’ or ‘burning’ sensation, and improves the perceived texture of (S)-6- Methylnicotine formulations for some delivery methods, such as vaporizer, combustion, or heat-not-burn.
  • the formulations may further comprise further active ingredients, such as a mild local anesthetic, which modulates the sensory experience of the surfaces of the human body, such as the nostril and nasal cavity, in order to further enhance the user experience.
  • the molar ratio of carboxylic acid and free base (S)-6-Methylnicotine can be adjusted to attain a more effective pH level for the respective delivery methods. Further, preliminary studies indicate that carboxylate salts of (S)-6-Methylnicotine appear to be more stable, and further improve the stability of, (S)-6-Methylnicotine, allowing for further product stability over time.
  • the optimal ratio of carboxylic acid to free base (S)-6-Methylnicotine is between 1: 1 to 1.6: 1, with an equivalent amount or excess of carboxylic acid. Adjustment of the molar ratio of carboxylate salt to free base (S)- 6-Methylnicotine also allows for tuning of the perceived user experience. Increasing carboxylate salt content reduces the instantaneous “throat hit” sensation, and smooths the sensation. Furthermore, the carboxylic acid additional imparts flavor, and can be used to compliment the flavoring of the e-liquid.
  • Preferred carboxylates for the vaporizer application include (S)-6-Methylnicotine benzoate, (S)-6-Methylnicotine lactate, (S)-6- Methylnicotine levulinate, and (S)-6-Methylnicotine salicylate.
  • (S)-6-Methylnicotine levulinate is noted for having a particularly desirable flavor in mixture.
  • Other carboxylates may offer superior texture and sensation, but may have corresponding tradeoffs in terms of flavor.
  • the preferred pH is basic, and accordingly, the preferred ratio of carboxylic acid to free base (S)-6-Methylnicotine is less than or equal to 1 : 1, with an excess or equivalent amount of free base (S)-6-Methylnicotine. While it is possible to have excess carboxylic acid, the resulting pH-lowering due to the present of acid requires additional buffering agents.
  • the carboxylate salt form has superior organoleptic properties, with the sensation being described as less harsh and peppery, and smoother than the free base (S)-6-Methylnicotine. Similar user experiences have been reported for both oral and nasal application of the (S)-6-Methylnicotine carboxylate salt compared to the free base. In such applications, the texture effect of the carboxylate is the dominant consideration over flavor, as the combustion or partial -combustion process releases a degree of smoke, which masks the flavor of the carboxylates.
  • (S)-6-Methylnicotine carboxylate salts offer superior solubility, in the appropriate solvents, compared to free base (S)-6-Methylnicotine, though the solubility of free base (S)-6-Methylnicotine has been found to be acceptable for all of the aforementioned applications.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un remplacement de nicotine synthétique pour divers systèmes de distribution, en particulier pour une utilisation dans des systèmes de distribution de nicotine électroniques, par exemple, des vaporisateurs, des cigarettes électroniques, une combustion, des produits à base de tabac chauffé, des systèmes d'administration orale ou nasale de nicotine. La (S)-6-Méthylnicotine, également connue sous le nom de (S)-2-méthyl-5-(1-méthylpyrrolidin-2-yl)pyridine, est un dérivé de nicotine avec une substitution méthyle en position 6 du cycle pyridine. Des données empiriques préliminaires indiquent que (S)-6-Méthylnicotine est d'environ 4 à 5 fois plus puissante que la nicotine par unité de masse, et peut être à action plus rapide, fournissant une solution plus efficace pour gérer ou satisfaire les envies de nicotine. Des sels de carboxylate de celle-ci sont également appropriés. Cette résistance accrue permet à des individus de ressentir un soulagement des envies de nicotine de manière plus rapide et efficace, à l'aide de dosages beaucoup plus faibles, et induit une sensation de satisfaction subjective qui satisfait les envies. En plus d'autres avantages potentiels, cette puissance pharmacologique accrue permet l'utilisation d'une quantité réduite de principe actif par comparaison avec des formulations de nicotine synthétiques.
PCT/US2024/030538 2023-05-23 2024-05-22 Formulation d'analogue de nicotine synthétique pour le remplacement et l'amplification de nicotine Pending WO2024243290A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202363468349P 2023-05-23 2023-05-23
US202363468351P 2023-05-23 2023-05-23
US202363468343P 2023-05-23 2023-05-23
US63/468,343 2023-05-23
US63/468,351 2023-05-23
US63/468,349 2023-05-23

Publications (1)

Publication Number Publication Date
WO2024243290A1 true WO2024243290A1 (fr) 2024-11-28

Family

ID=91580771

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/030538 Pending WO2024243290A1 (fr) 2023-05-23 2024-05-22 Formulation d'analogue de nicotine synthétique pour le remplacement et l'amplification de nicotine

Country Status (1)

Country Link
WO (1) WO2024243290A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025153974A1 (fr) * 2024-01-17 2025-07-24 Rai Strategic Holdings, Inc. Produits oraux

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012031220A2 (fr) * 2010-09-03 2012-03-08 University Of Florida Research Foundation, Inc. Composés de nicotine et leurs analogues, procédés de synthèse pour fabriquer les composés et procédés d'utilisation
WO2017117575A1 (fr) * 2015-12-30 2017-07-06 Next Generation Labs, LLC Produits de substitution de la nicotine comprenant une nicotine de synthèse
US20210061783A1 (en) * 2019-09-03 2021-03-04 Yunnan Xike Science & Technology Co., Ltd. Synthetic Nicotine Composition
CN114437031A (zh) * 2022-02-16 2022-05-06 深圳市真味生物科技有限公司 一种6-甲基尼古丁的合成方法
CN114437025A (zh) 2020-11-05 2022-05-06 上海零诺生物科技有限公司 消旋6-甲基烟碱及其制备方法、以及应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012031220A2 (fr) * 2010-09-03 2012-03-08 University Of Florida Research Foundation, Inc. Composés de nicotine et leurs analogues, procédés de synthèse pour fabriquer les composés et procédés d'utilisation
WO2017117575A1 (fr) * 2015-12-30 2017-07-06 Next Generation Labs, LLC Produits de substitution de la nicotine comprenant une nicotine de synthèse
US20210061783A1 (en) * 2019-09-03 2021-03-04 Yunnan Xike Science & Technology Co., Ltd. Synthetic Nicotine Composition
CN114437025A (zh) 2020-11-05 2022-05-06 上海零诺生物科技有限公司 消旋6-甲基烟碱及其制备方法、以及应用
CN114437031A (zh) * 2022-02-16 2022-05-06 深圳市真味生物科技有限公司 一种6-甲基尼古丁的合成方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025153974A1 (fr) * 2024-01-17 2025-07-24 Rai Strategic Holdings, Inc. Produits oraux

Similar Documents

Publication Publication Date Title
US12167744B2 (en) Nicotine liquid formulations for aerosol devices and methods thereof
AU2021204112B2 (en) Nicotine salt formulations for aerosol devices and methods thereof
US10610526B2 (en) Nicotine replacement therapy products comprising synthetic nicotine
RU2283111C2 (ru) Забуференная жидкая никотиновая композиция для легочного введения
US20040034068A1 (en) New formulation and use thereof
US20150024012A1 (en) Article and methods for oral self-administration of nicotine
WO2024243290A1 (fr) Formulation d'analogue de nicotine synthétique pour le remplacement et l'amplification de nicotine
CN101583354A (zh) 用于终止烟草使用的系统
WO2023008063A1 (fr) Liquide pour cigarettes électroniques, procédé de fabrication de liquide pour cigarettes électroniques, cartouche pour cigarette électronique et cigarette électronique
AU2009328589B2 (en) Nicotine-containing product
US20130287704A1 (en) Article and methods for oral self-administration of nicotine
CN115191639A (zh) 气溶胶形成基质以及气溶胶生成系统
US20220175755A1 (en) Methods of treating tobacco smoking addiction, and treating nicotine and tobacco smoking addiction
Wang et al. Lung Delivery of Nicotine for Smoking Cessation
WO2025017181A1 (fr) Composition de nicotine présentant une stabilité et une toxicologie améliorées
CN120167676A (zh) 一种雾化液、雾化器及电子雾化装置
ROSE Smoking-Cessation Treatments
HK1229644A (en) Nicotine liquid formulations for aerosol devices and methods thereof
HK1229644B (en) Nicotine liquid formulations for aerosol devices and methods thereof
HK1229644A1 (en) Nicotine liquid formulations for aerosol devices and methods thereof

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24733434

Country of ref document: EP

Kind code of ref document: A1

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112025025560

Country of ref document: BR