WO2020176791A1

WO2020176791A1 - Nitric oxide releasing vaping formulations, compounds, use, and methods of forming

Info

Publication number: WO2020176791A1
Application number: PCT/US2020/020202
Authority: WO
Inventors: Mel EHRLICH; Mahantesh S. Navati; Jyothishree Tholalu JAYADEVA; Girish Vallerinteavide MAVELLI
Original assignee: Nano Vape Corporation
Priority date: 2019-02-28
Filing date: 2020-02-27
Publication date: 2020-09-03

Abstract

The present invention generally relates to vaping formulations that comprise a nitric oxide releasing (NO-releasing) component, for use in vaping devices, in particular formulations comprising nitric oxide (NO) in combination with nicotine, and formulations comprising NO- releasing nicotine derivatives, and methods to make and use them. Specifically, embodiments of the present invention relate to vaping formulations comprising a lower amount of nicotine having an improved effect.

Description

PATENT COOPERATION TREATY APPLICATION

NITRIC OXIDE RELEASING VAPING FORMULATIONS, COMPOUNDS, USE, AND METHODS OF FORMING

By: Mahantesh S. Navati, Mel Ehrlich, Jyothishree Tholalu Jayadeva, Girish Vallerinteavide

Mavelli

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Applications No. 62/811,581, filed on February 28, 2019, and 62/982494, filed February 27, 2020, the entire disclosures of which are herein expressly incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention generally relates to vaping formulations that comprise a nitric oxide releasing (NO-releasing) component, for use in vaping devices, in particular formulations comprising nitric oxide (NO) in combination with nicotine, and formulations comprising NO- releasing nicotine derivatives, and methods to make and use them. Specifically, embodiments of the present invention relate to vaping formulations comprising a lower amount of nicotine having an improved effect.

BACKGROUND

[0003] Nicotine is a stimulant and potent parasympathomimetic alkaloid that is naturally produced by plants of the nightshade family. Traditional delivery devices for nicotine include rolls of dried plant material such as cigarettes and cigars, however inhaling of the resulting smoke causes various associated health risks and an accumulation of tar in the lungs, and associated health issues.

[0004] Electronic nicotine delivery systems or vaping devices, also called e-cigarettes or electronic cigarettes, are devices typically operated by battery that contain an inhalation- activated mechanism that heats a cartridge containing a liquid, thus producing an aerosol or vapor that the user inhales. Use of an e-cigarette to inhale a vapor is known as vaping, and the user of a vaping device may be referred to as vaper. In addition to nicotine, the liquid in the vaping device may include one or more liquid carriers such as propylene glycol or glycerin, and excipients, e.g. flavorings and the like.

[0005] Vaping devices are easy to carry, handle and cost effective. Vaping allows easy absorption of the stimulant in to the lungs while avoiding deposits of tar, unlike cigarettes and cigars.

[0006] A problem with vaping devices is that the nicotine in the concentrations typically employed can upon improper use, e.g. if the liquid in the cartridge is accidentally swallowed rather than slowly inhaled, be detrimental to health.

[0007] Another problems with vaping devices is that the nicotine in the concentrations typically employed may not or may not be perceived by the user to create a strong enough effect in comparison to traditional nicotine delivery devices such as cigarettes and cigars, or the effect may be perceived as different or less pleasant.

[0008] Therefore, there remains a need in the art for improved formulations for vaping devices that advantageously reduce user exposure to various hazards, provide a more pleasant vaping experience, a more effective, faster or longer nicotine delivery, and/or require a lower concentration or amount of nicotine in the formulation. These and other features and advantages of the present invention will be explained and will become apparent to one of ordinary skill in the art through the summary of the invention that follows.

SUMMARY OF THE INVENTION

[0009] Accordingly, embodiments of the present invention provide a method of vaping wherein a vapor is formed from a liquid formulation comprising a nitric oxide releasing component for release of nitric oxide upon activation of a vaping device.

[0010] In embodiments, provided are methods wherein the nitric oxide releasing component of the formulation comprises a nicotine compound, wherein the nicotine is provided in unconjugated or in conjugated derivative form, wherein the nicotine or the nicotine derivative is provided in form of its base or in form of a salt thereof, and wherein the nitric oxide releasing component comprises one or more of: a) a nicotine-SNO complex, b) a mixture of nicotine with a nitric oxide releasing compound, c) a nicotine conjugate selected from the group comprising nicotine-thioether, and nicotine-imide-thiol-ether, or salts thereof.

[0011] In embodiments, provided are methods wherein the formulation comprises a nicotine salt, or a conjugate or complex thereof.

[0012] In embodiments, provided are methods wherein the formulation comprises: i. one or more of a) unconjugated nicotine free base, and b) one or more unconjugated salt of nicotine; and ii. a nitric oxide releasing component; and wherein the nitric oxide releasing component is conjugated or unconjugated to nicotine.

[0013] In embodiments, provided are methods wherein ii. is an S-nitrosothiol, wherein the S- nitrosothiol is selected from the group comprising R-SNO and R-S-N=0, and wherein R is an alkyl residue selected from the group comprising a Cl to C8 alkyl—(example 3)—

[0014] In embodiments, provided are nitric oxide-releasing nicotine conjugate compounds comprising nicotine selected from the group comprising a nicotine-thioether, a nicotine-imide- thiol-ether, or salts thereof.

[0015] In embodiments, provided are nitric oxide-releasing conjugates, wherein the conjugate is a thioether compound of formula I below, and wherein R is selected from the group comprising Ci-Cs alkyl residues including a -CH3 residue:

FI

[0016] In embodiments, provided are formulations comprising a nitric oxide releasing component, wherein the nitric oxide releasing component comprises one or more of: a) a nicotine-SNO complex, b) a mixture of nicotine with a nitric oxide releasing compound, c) a nicotine conjugate selected from the group comprising nicotine-thioether, and nicotine-imide- thiol-ether, or salts thereof.

[0017] In embodiments, provided are formulations, wherein the concentration of nicotine, or a salt therof, in conjugated or unconjugated form, is selected from the group of a concentration from about 0.5% to about 20% (w/w), about 0.5% to about 10% w/w, about 0.5% to about 5% w/w, about 0.5% to about 4% w/w, about 0.5% to about 3% w/w, about 0.5% to about 2% w/w, or about 0.5% to about 1% w/w of the formulation.

[0018] In embodiments, provided are cartridges, or refill receptacles adapted for refilling a cartridge, the cartridge or receptacle configured to securely hold a liquid, to prevent it from spilling, and to release it upon use when inserted into a vaping device, the cartridge comprising a formulation, wherein the formulation comprises a nitric oxide releasing component, and wherein the nitric oxide releasing component comprises one or more of: d) a nicotine-SNO complex, e) a mixture of nicotine with a nitric oxide releasing compound, f) a nicotine conjugate selected from the group comprising nicotine-thioether, and nicotine-imide-thiol-ether, or salts thereof.

[0019] In embodiments, provided is a process to form a nicotine-conjugated nitric oxide releasing component for release of nitric oxide during vaping by means of a vaping device, comprising the steps of: 1) providing a solution A of nicotine base, a nicotine salt, or a combination thereof, 2) providing a solution B of thioglycolic acid, 3) mixing solutions A with a sufficient amount of solution B at a sufficiently elevated temperature, and for a sufficient time to form a thiolated nicotine derivative; 4) further reacting the formed thiolated nicotine derivative by adding a suitable nitrite at a suitable temperature in the presence of oxygen or air, and allowing the reaction to proceed for a sufficient time to form the nitric oxide releasing component, e.g. without limitation, a nicotine-SNO conjugate or a nicotine-SNO complex.

[0020] In embodiments, provided is a process to form a nicotine-conjugated nitric oxide releasing component for release of nitric oxide during vaping by means of a vaping device, comprising the steps of: 1) providing nicotine selected from nicotine free base, a nicotine salt, or a combination thereof; 2) reacting the nicotine by introducing an alkyl-NH2 residue, thus forming a reactive nicotine- alky 1-NH2 intermediate, 3) reacting nicotine- alky 1-NH2 intermediate by introducing a dioxofuran residue, thus forming a reactive nicotine-imide intermediate, 4) reacting the nicotine-imide intermediate with a thiol, thus forming a NO- releasing nicotine-imide- thioether.

[0021] In embodiments, provided is a process as described herein, wherein in step 2), nicotine is reacted with a halogen-alkyl-carbamate comprising a suitable protective group, the protective group being removed during intermediate reactions, to introduce an alkyl-NH2 residue and thus forming a reactive nicotine- alky 1-NH2 intermediate.

[0022] In embodiments, provided is a process as described herein, wherein in step 3), the nicotine-alkyl-NH2 intermediate is reacted with a dioxofuran to form a nicotine-imide intermediate.

[0023] In embodiments, provided is a process as described herein wherein in step 4), the nicotine-imide intermediate is reacted with a thiol to form a nicotine-imide-thioether, the nicotine-imide moeity of the nicotine-imide-thioether comprising a S-R residue, and wherein R is a residue selected from the group of Ci-Cs alkyl.

[0024] In embodiments, provided is a process as described herein, wherein the nitric oxide releasing thioether nicotine derivative is the of formula I below, wherein R is selected from the group comprising, without limitation, an alkyl, e.g. a Ci-Cs alkyl, including without limitation CH :

FI

[0025] In embodiments, provided is a process to form a an unconjugated nitric oxide releasing component for release of nitric oxide during vaping by means of a vaping device, comprising the steps of: 1) providing a solution A of nicotine base, a nicotine salt, or a combination thereof; 2) providing a solution B comprising an S-nitrosothiol, the S-nitrosothiol comprising R-SNO and R-S-N=0, wherein optionally the S-nitrosothiol is provided by nitrosylation of a thiol R-SH by mixing the thiol R-SH with reduced nitrites or nitrates in a suitable liquid carrier, and wherein R optionally is an alkyl residue selected from a Cl to C8 alkyl; and 3) mixing solution A with solution B at a suitable amount and molar ratio of nicotine to S-nitrosothiol, the molar ration being optionally selected from about 1:1 to about 10:1 (nicotine: S-nitrosothiol), thereby providing a nicotine formulation having the same effect of nicotine at a lower nicotine concentration.

[0026] In embodiments, provided is a process as decribed herein, wherein the thiol R-SH is an organic thiol selected from the group comprising one or more of: methanethiol, dimercaptosuccinic acid, a dimercaptoalkylsulfonic acid, 2,3-Dimercapto-l-propanesulfonic acid, a dimercapto-alcohol, 2,3-Dimercapto-l -propanol.

DETAILED SPECIFICATION [0027] The present invention generally relates to vaping formulations that comprise a nitric oxide releasing (NO-releasing) component, for use in vaping devices, in particular formulations comprising nitric oxide (NO) in combination with nicotine, and formulations comprising NO- releasing nicotine derivatives, and methods to make and use them. Specifically, embodiments of the present invention relate to vaping formulations comprising a lower amount of nicotine having an improved effect when compared to formulations that are not able to release NO, or do so to a lesser extent.

[0028] NO is an endogenous signaling molecule with vasodilatory properties, i.e. it can dilate airways and pulmonary vessels, both of which are important for pulmonary function.

[0029] Without wishing to be bound by theory, it is believed that formulations that contain components that comprise nicotine and NO or an NO-releasing component, or NO-releasing nicotine derivates, alone or in combination, may provide one or more of an increase of inhalation volume, pulmonary perfusion, and/or air exchange, and/or a reduced resistance in the lung of the vaper, thus facilitating enhanced nicotine inhalation and/or absorption, e.g. an increased amount or a faster absorption of nicotine.

[0030] Further, without wishing to be bound by theory, it is believed that use of the NO- providing formulations described herein for vaping thus may contribute to the use of less nicotine and/or a lower concentration of nicotine while providing the same stimulatory effects.

[0031] Without wishing to be bound by theory, it is believed that less than 5% of the inhaled nicotine reaches the respiratory tract. For example, of 10 mg of nicotine in a cartridge, 4 mg can be inhaled and 2 mg (i.e. 50%) will be absorbed into the body.

[0032] Without wishing to be bound by theory, it is believed that on average, a smoker may absorb about 1 mg of nicotine per cigarette into the body, with nicotine absorption through the skin and the mucosal linings in the nose, mouth and lungs taking about 10 seconds after inhalation until nicotine is delivered through the bloodstream to the brain. [0033] Nicotine for use in embodiments of the invention may generally be either in form of its free base, or in form of a salt. Nicotine base is readily absorbed through mucosal membranes but generally less stable than nicotine salts. In contrast, nicotine salts may not be readily absorbed through mucosal membranes. Without wishing to be bound by theory, in some embodiments, nicotine absorption may be enhanced, stability may be increased, oxidation may be reduced, and/or volatility may be reduced. Nicotine salts should be selected for sufficient solubility to provide a solution in the formulations described herein. Also, depending on the temperature that the formulation is heated to in a vaping device, all compounds selected should be resistant to decomposition at the temperatures occurring in the vaping device selected. A person of ordinary skill in the art can easily select suitable nicotine salts possessing the relevant properties to the desired degree.

[0034] Illustrative examples of nicotine salts suitable for use in formulations as described herein may include one or more of nicotine benzoate, nicotine hydrochloride, nicotine dihydrochloride, nicotine malate, nicotine monotartrate, nicotine bitartrate, nicotine bitartrate dihydrate, nicotine sulphate, nicotine zinc chloride monohydrate and nicotine salicylate.

[0035] In embodiments, a formulation comprising nicotine may further comprise contain a biologically acceptable liquid carrier and excipients, including one or more of solubilizing agents, stabilizers, pH stabilizers, acids, buffers, flavoring agents, and other excipients to stabilize or enhance the ingredients or to provide a particular optional functionality. Nicotine may also be combined with additional actives, e.g. medications, if desired.

[0036] In embodiments suitable biologically acceptable liquid carriers may include propylene glycol, glycerin, and vegetable glycerin, or mixtures thereof.

[0037] In embodiments, the formulation may contain one or more pH adjusting agent, to provide a suitable pH, e.g. by addition of a base or an acid, or a combination thereof (e.g. a buffer) so that nicotine is present in unprotonated form for effective absorption.

[0038] Suitable acids may include one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, succinic acid, tartaric acid, and citric acid. [0039] In embodiments, the concentration of nicotine base, nicotine salts, or a combination thereof in a formulation for vaping may be from about 0.5% to about 20% (w/w) in the formulation, e.g. about 0.5% to about 10% w/w, about 0.5% to about 5% w/w, about 0.5% to about 4% w/w, about 0.5% to about 3% w/w, about 0.5% to about 2% w/w, or about 0.5% to about 1% w/w.

[0040] The nitric oxide releasing component for release of nitric oxide in a vaping device may be a covalently bound conjugate comprising nicotine and an NO-moiety that releasably comprises nitric oxide, e.g. a nicotine-SNO complex (S=thiol, NO=nitric oxide), a s alt-nicotine- S NO complex, or combinations thereof; alternatively the nitric oxide releasing component may be formed by combining nicotine base, nicotine salt, or combinations thereof with a S-nitrosothiol (e.g. R-SNO or R-S-N=0); illustrative examples how to form these nitric oxide releasing components are described in the exemplary embodiments herein-below.

[0041] In embodiments, the concentration of the nitric oxide releasing components described herein in the formulations for use in a vaping device may be about 0.1 to about 10 nanomol/ml, e.g. about 0.5 to about 5 nanomol/ml, about 1 to about 2 nanomol/ml, or about 1 to about 1.5 nanomol/ml, for example about 1.1 nanomol/ml.

[0042] In embodiments, a formulation may comprise nicotine in a concentration from about 0.5% (w/w) to about 5% (w/w) or more, and an acid at a molar ratio of said acid to said nicotine from about 1:1 to about 4:1; and a biologically acceptable liquid carrier.

[0043] In embodiments, a formulation as described herein may be used in a vaping device many types of which are commonly known and commercially available, as will be apparent to a person of ordinary skill. Generally liquid formulations for such devices are made available in suitable cartridges that can be inserted into the relevant device, or alternatively, the vaping device may be available pre-filled, e.g. for one time use. Any vaping device suitable for generating an inhalable vapor may be used, as will be apparent to a person of ordinary skill.

[0044] In embodiments, some vaping devices may provide an automatic inhalable vapor generation, as shortly described herein below, which may improve a user’s access to inhalable vapor. For example, a user in such a scenario desiring to relieve disease symptoms may experience symptom relief sooner.

[0045] For example, in embodiments, formulations described herein may be used in a vaping device having a compressible fluid storage reservoir with magnets configured to compress fluid retained within the reservoir, and a transducer to vaporize fluid in a fluid vaporization chamber fluidly coupled with the fluid storage reservoir, thus automatically generating a vapor by powering the transducer and transferring fluid from the fluid storage reservoir into the fluid vaporization chamber when a vacuum is applied to a mouthpiece fluidly coupled with the fluid vaporization chamber. Suitable vaping devices include, without limitation, those wherein the transducer may be ultrasonic, thus permitting safe fluid vaporization based on ultrasonic agitation. Alternatively or additionally, the transducer may be powered by a charged capacitor. In some vaping device designs, the fluid storage reservoir may be a replaceable pod with a needle- puncturable leak proof seal to permit fluid transfer to the vaporization chamber.

[0046] In an illustrative example, a vaping device may also be used with any aqueous solution or liquid formulation containing medicines or other water soluble or colloidal suspended material, or materials or compounds soluble or suspending in propylene glycol (PG) or glycerin, which a user desires to inhale, including cannabis solutions, asthma or other respiratory medications, flavored substances, and the like.

[0047] For example, in embodiments, formulations described herein may be used in a vaping device wherein the inhalable vapor may be automatically generated for a user on demand, when the user inhales through the vapor generating device’s mouthpiece. Such automatic inhalable vapor generation may improve a user’s access to inhalable vapor. Some embodiments may reduce a user’s exposure to toxic chemicals related to the use of inhalable vapor, in particular when used with a particular vaping device, e.g. one able to generate vapor on demand, e.g. only upon inhalation, e.g. by using a vaping device that generates inhalable vapor based on ultrasonic fluid vaporization. Such use may allow vaporization at or near ambient temperature, e.g. about 20-40 DEG C, and may advantageously avoid heating compounds to an unnecessarily high temperature and reduce health risk and/or risk of injury. [0048] Suitable vaping devices for use with the formulations described herein may include devices having a compressible fluid storage reservoir to compress fluid retained within the reservoir and configured with a transducer to vaporize fluid in a fluid vaporization chamber fluidly coupled with the fluid storage reservoir and automatically generating a vapor by powering the transducer and transferring fluid from the fluid storage reservoir into the fluid vaporization chamber when a vacuum is applied to a mouthpiece fluidly coupled with the fluid vaporization chamber. Suitable transducers include ultrasonic transducers. The compressible fluid storage reservoir of the vaping device may optionally be adapted with at least one movable magnet configured to pressurize the fluid with a compressing action applied to the reservoir. The compressible fluid storage reservoir may further comprise two magnets configured to attract each other, thereby to pressurize the fluid with a compressing action applied to the reservoir by the magnets. Alternatively or additionally, the transducer may be configured to be powered by an energy storage device, for example, without limitation, a capacitor. Optionally, the device may further be configured with a switch to power the transducer when the vacuum applied to the mouthpiece acts on the switch. Optionally, the device or any of its components including its transducer, energy storage device, capacitor and or switch may be configured with a valve to govern the fluid transfer controlled as a function of the vacuum applied to the mouthpiece. Optionally the vaping device may be configured to automatically generate a vapor by powering the transducer and discharging fluid from the fluid storage reservoir into the fluid vaporization chamber when a vacuum is applied to the mouthpiece.

[0049] In embodiments, the compounds and their combinations as described herein may be used in aqueous solution or in a liquid carrier (PG, glycerin and others) further containing medicine, or other water soluble or colloidal suspended material which a user desires to inhale, and excipients as described herein. In an illustrative example, various embodiment implementations may be employed to generate inhalable vapor from aqueous fluids including cannabis solutions, asthma or other respiratory medications, flavored substances, and the like.

[0050] Alternatively, in embodiments, a formulation as described herein may be used and applied to a mucosal membrane of a subject, e.g. a mammal, in particular a human mammal, as a liquid. For example, the formulation, or the nicotine compounds and derivatives therein, may be formulated for oral or transdermal application, using commonly known excipients for such formulations, as will be apparent to a person of ordinary skill.

[0051] Exemplary illustrative embodiments follow.

[0052] Example 1, nicotine base formulation

[0053] Solution A of nicotine base in a suitable solvent and concentration, for example, nicotine in propylene glycol at a concentration of 100 mg/ml is prepared (MW 162.23 g/mol, mass of solute 100 mg, total volume of solution 1 ml, i.e. nicotine concentration = 616.4 mM).

[0054] Solution B of thioglycolic acid (TGA, HSCH₂C0₂H) is prepared in a suitable solvent as above for solution A to give the same mM (MW 92.11 g/mol, mass of solute = 56.777 mg for same concentration 616.4 mM in 1 ml).

[0055] Equal volumes of solutions A and B above (and thus equimolar amounts), e.g. 5 ml each, are mixed at elevated temperature, for example about 30°C to about 70°C, e.g. about 40°C to about 60°C, about 50°C to about 60°C e.g. about 55°C in an incubator overnight, e.g. for about 8 to 12 hours or longer, with constant mixing under dark condition/exclusion of natural or artificial light, to form thiolated nicotine.

[0056] Optionally a suitable catalyst may be added during all or part of the incubation of solution A and B above, to descrease the reaction time and/or increase the amount of thiolated nicotine formed. Suitable catalysts are those that promote reaction to a thiolate of nicotine; such catalysts may include metal and non-metal catalysts, including, e.g., Pd, Ni, Rh, complexes of lanthanides (Sm, La, Lu), actinides (U, Th), zirconium, Pd(OAc)2, Ni(PPli2Me)4 and Ni(acac)2. Alternative catalysts may be used, as will be apparent to a person of ordinary skill in the art.

[0057] The resulting solution of the formed thiolated nicotine is further reacted to form nicotine - SNO, e.g. by adding an equal molar concentration of a suitable nitrite, e.g. sodium nitrite, or potassium nitrite, which may be added at room temperature, e.g. about 20°C, in the presence of oxygen or air, to form a nitric oxide releasing component, e.g. a nicotine-SNO or nicotine-R- SNO complex or conjugate (e.g. S=thiol, NO=nitric oxide, or nitric oxide releasing moiety), for example a S-Nitrosothiol. R, without limitation, may be an alkyl, for example, without limitation, a Ci-Cs alkyl residue. The formation of the complex may require one or more of incubation for a suitable duration of 1 second to 24 hours, and/or mixing.

[0058] The resulting nitric oxide releasing component includes e.g. a nicotine-SNO complex also referred to herein as“NO-releasing nicotine” and may be used as a vaping liquid, optionally with addition of excipients as described herein. The concentration of the nitric oxide releasing component, e.g. nicotine-SNO complex, may be adjusted as desired, as will be apparent to a person of ordinary skill.

[0059] Example 2, nicotine salt formulation

[0060] A salt-nicotine-SNO complex, also referred to herein as nitric oxide releasing component or“NO-releasing nicotine” may be formed generally as described herein under example 1, with the following changes:

[0061] As solution A, a solution of nicotine salts in a suitable solvent and concentration are used at the same nicotine concentration, for example, nicotine salt 100 mg/ml in PPG (616.4 mM) may be prepared generally as described above, except using one or more nicotine salt instead of nicotine base. Nicotine salts may be created by combining the nicotine base with an acid or multiple acids. Nicotine salts are commercially available in synthesized form or may be extracted from natural sources such as plant sources (for example, without limitation, tobacco plants).

[0062] The resulting nicotine salt solution is reacted as described in example above for the base, forming a thiolated nicotine salt. This thiolated reaction product is further reacted as described in example 1 for the base to form a nitric oxide releasing component, here a salt-nicotine-SNO complex, which may be used in vaping formulations as described as described in example 1.

[0063] Example 3, Combination of nicotine base or nicotine salt(s), or a mixture thereof, with a solution comprising an S-Nitrosothiol or R-SNO or R-S-N=0 [0064] R may be the residue of any thiol R-SH, e.g. R may be, without limitation, an Ci to Cs alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc..

[0065] In a first step, a solution of nicotine ± salts in propylene glycol (100 mg/ml or 616.4 mM, MW 162.23 g/mol, mass of solute 100 mg in total vol. of solution 1 ml) is prepared. Nicotine base, one or more nicotine salt, or a mixture of free base and salts of nicotine may be used.

[0066] In a second step, the thiol (R-SH), e.g., without limitation, methanethiol, may be nitrosylated, e.g. by treatment with reduced nitrites or nitrates, to form a solution comprising R- SNO (e.g. R-S-N=0) in a suitable liquid carrier, for example in propylene glycol. Suitable thiols include, without limitation, e.g. methanethiol (also known as methyl mercaptan or CH3SH), and dimercaptosuccinic acid (also known as DMSA or succimer, e.g. C4H6O4S2, (2R,3S)-2,3- dimercaptosuccinic acid or meso-2,3-dimercaptosuccinic acid succimer and its (2R,3R) and (2S,3S) stereoisomers). Other thiol alternatives may include, without limitation, dimercaptoalkylsulfonic acids, e.g. 2,3-Dimercapto-l-propanesulfonic acid (DMPS), and dimercapto-alcohols, e.g. 2,3 -Dimercapto-1 -propanol (BAL or dimercaprol), and others, as will be apparent to a person of ordinary skill.

[0067] In a third step, the R-SNO solution of step 2 is mixed in an equal or lesser concentration with the nicotine ± salts solution of step 1.

[0068] The mixture of step 3 may be used as a vaping liquid, with optional excipients as commonly known by a person of ordinary skill (e.g. water, fragrance, propylene glycol, secondary actives, etc.).

[0069] Without wishing to be bound by theory, it is believed that the resulting mixture provides a stronger effect of nicotine, or to reach the same effect, less nicotine can be used than when using nicotine without R-SNO.

[0070] Example 4, Synthesis of NO-releasing thioether nicotine derivatives from nicotine. [0071] Suitable R-thiol-derivatives of nicotine may be synthesized in various ways by reacting nicotine in one or more steps, as will be apparent to a person of ordinary skill. Typically these may be achieved in a multi-step process. These options may include the four-step process described herein-below, for example as illustrated in the reaction scheme 1 shown in FIG. 1.

[0072] In a first step, educts 1 and 2 may be reacted to form product 1; educt 1 is nicotine (also known as 3-(l-methyl-2-pyrrolidinyl)pyridine) and educt 2 may be selected from suitably reactive functional groups, e.g., without limitation, an amine, protected by a protective group, e.g., without limitation, a Boc (i.e. Butoxycarbonyl) reagent, to introduce the desired functional group, for example, without limitation, an amino group (-Nth). For example, without limitation, Boc may be a tert-butyloxycarbonyl protecting group or tert-butoxy carbonyl protecting group which may be used to introduce a NH moiety, to be reacted into an amino group in the second step. Boc (-NFICC C CFh ) may be covalently bound to a suitable alkyl residue, such as a halogen-alkyl residue, in particular a halogen-alkyl-carbamate, of suitable chain length, e.g. Ci- Ci5, e.g. Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, C12, C13, C14, C15, or longer.

[0073] For example, in this first step, Boc may be, without limitation, N-Boc-2-bromoethyl- amine (also known as 2-(Boc-amino)ethyl bromide, tert-Butyl N-(2-bromoethyl)carbamate or BrCFhCFhNFICC CiCFh , also referenced herein as Boc-NH-C2H4-Br), which may thus be used to introduce an amino group (-NFh). As will be apparent to a person of ordinary skill, educt 2 may be replaced by a suitable alternative to form a suitable product 1 carrying the desired functional group, with or without linking group linking the functional group to nicotine. The Boc-protected reactive nicotine formed in step 1 can then undergo further reaction in step 2; alternatively, a different linker, protective group, halogen or functional group may be used.

[0074] In a second step, Boc is removed as will be apparent to a person of ordinary skill to form product 2, a reactive nicotine intermediate, here Nicotine-C2H4-NH2. Alternatively, other reagents may be used to result in a different linker than -C2H4- for the functional group, or a different functional group than -NFh may be used, as will be a apparent to a person of ordinary skill. [0075] In a third step, the reactive Nicotine-C₂H₄-NH₂ intermediate may then be further reacted to introduce a group that upon reaction with a thiol can form an NO-releasing group in the fourth and final step. For example, without limitation, the group introduced in step 3 may be an imide functional group. This may be achieved e.g. with a furan compound such as a dioxofuran, for example, without limitation, a 2,5-dioxofuran such as, without limitation, maleic anhydride (C4H2O3), to form maleimide nicotine (i.e. H2C2(CO)2N-nicotine); other reactions may be used as will be apparent to a person of ordinary skill to generate a reactive nicotine derivative comprising an imide functional group (i.e. a -C(0)NHC(0)- functional group).

[0076] In a fourth and final step, the resulting maleimide nicotine may be reacted with a suitably reactive thiol (R-SH) to form the NO-releasing thioether nicotine derivative, e.g. the corresponding R-thiol maleimide nicotine derivative (depending on educts used in steps 1-3). The pH of the reaction mixture may be adjusted to favor the reaction, for example, for reacting the maleimide it may be between about 6.5 and about 7.5. As will be apparent to a person of ordinary skill, for use as reactive thiol, many organosulfo compounds with one, two or more thiol groups will be suitable, depending on the desired size and characteristics of the R residue. Suitable R residues for the thiol include, without limitation, e.g. methanethiol (also known as methyl mercaptan or CH3SH), or dimercaptosuccinic acid (also known as DMSA or succimer, e.g. C4H6O4S2, (2R,3S)-2,3-dimercaptosuccinic acid or meso-2,3-dimercaptosuccinic acid succimer and its (2R,3R) and (2S,3S) stereoisomers).

[0077] Other thiol alternatives may include, without limitation, dimercaptoalkylsulfonic acids, e.g. 2,3-Dimercapto-l-propanesulfonic acid (DMPS), and dimercapto-alcohols, e.g. 2,3- Dimercapto-1 -propanol (BAL or dimercaprol), and others.

[0078] The resulting NO-releasing thioether nicotine derivative may be tested enzymatically or non-enzymatically for release of NO (nitric oxide), as will be apparent to a person of ordinary skill, including e.g. addition of a mammalian NO releasing enzyme, e.g., without limitation, of the family of nitric oxide synthases (NOS).

[0079] Many suitable methods and corresponding materials to make NO-releasing nicotine derivatives are known in the art. Suitable excipients for the formulation of such compounds, free base nicotine, nicotine salts or combinations thereof will be apparent to the skilled person, and as exemplified herein-above. According to an embodiment, the nicotine derivatives and formulations as described herein may be used in any vaping device suitable for nicotine delivery of liquid formulations, as will be apparent to a person of ordinary skill in the art.

[0080] It should be noted that the features of the reaction scheme illustrated in the drawings are illustrative only, and one or more feature of one embodiment may be modified and/or employed with other embodiments as a person of ordinary skill would recognize, even if not explicitly stated herein. Descriptions of well-known components, compounds, ingredients, excipients, reactions, and processing techniques may be omitted so as to not unnecessarily obscure the embodiments.

[0081] While multiple embodiments are disclosed, still other embodiments of the present invention will become apparent to those of ordinary skill in the art from this detailed description. The invention is capable of myriad modifications in various obvious aspects, all without departing from the spirit and scope of the present invention. Accordingly, the drawings and descriptions are to be regarded as illustrative in nature rather than restrictive.

Claims

1. A method of vaping wherein a vapor is formed from a liquid formulation comprising a nitric oxide releasing component for release of nitric oxide upon activation of a vaping device.

2. The method of claim 1, wherein the nitric oxide releasing component of the formulation comprises a nicotine compound, wherein the nicotine is provided in unconjugated or in conjugated derivative form, wherein the nicotine or the nicotine derivative is provided in form of its base or in form of a salt thereof, and wherein the nitric oxide releasing component comprises one or more of: a) a nicotine-SNO complex,

b) a mixture of nicotine with a nitric oxide releasing compound,

c) a nicotine conjugate selected from the group comprising nicotine-thioether, and nicotine-imide-thiol-ether, or salts thereof.

3. The method of claim 2 wherein the formulation comprises a nicotine salt, or a conjugate or complex thereof.

4. The method of claim 2 wherein the formulation comprises: i. one or more of a) unconjugated nicotine free base, and b) one or more unconjugated salt of nicotine; and

ii. a nitric oxide releasing component; and wherein the nitric oxide releasing component is conjugated or unconjugated to nicotine.

5. The method of claim 4, wherein ii. is an S-nitrosothiol, wherein the S-nitrosothiol is selected from the group comprising R-SNO and R-S-N=0, and wherein R is an alkyl residue selected from the group comprising a Ci to Cs alkyl.

6. A nitric oxide-releasing nicotine conjugate compound comprising nicotine selected from the group comprising a nicotine-thioether, a nicotine-imide-thiol-ether, or salts thereof.

7. The nitric oxide-releasing nicotine conjugate of claim 6, wherein the conjugate is a thioether compound of formula I below, and wherein R is selected from the group comprising CH3:

8. A formulation comprising a nitric oxide releasing component, wherein the nitric oxide releasing component comprises one or more of: a) a nicotine-SNO complex,

b) a mixture of nicotine with a nitric oxide releasing compound,

The formulation of claim 8, wherein the concentration of nicotine, or a salt therof, in conjugated or unconjugated form, is selected from the group of a concentration from about 0.5% to about 20% (w/w), about 0.5% to about 10% w/w, about 0.5% to about 5% w/w, about 0.5% to about 4% w/w, about 0.5% to about 3% w/w, about 0.5% to about 2% w/w, or about 0.5% to about 1% w/w of the formulation.

10. A cartridge, or a refill receptacle adapted for refilling a cartridge, the cartridge or receptacle configured to securely hold a liquid, to prevent it from spilling, and to release it upon use when inserted into a vaping device, the cartridge comprising a formulation, wherein the formulation comprises a nitric oxide releasing component, and wherein the nitric oxide releasing component comprises one or more of: d) a nicotine-SNO complex,

e) a mixture of nicotine with a nitric oxide releasing compound,

f) a nicotine conjugate selected from the group comprising nicotine-thioether, and nicotine-imide-thiol-ether, or salts thereof.

11. A process to form a nicotine-conjugated nitric oxide releasing component for release of nitric oxide during vaping by means of a vaping device, comprising the steps of:

1) providing a solution A of nicotine base, a nicotine salt, or a combination thereof,

2) providing a solution B of thioglycolic acid,

3) mixing solutions A with a sufficient amount of B at a sufficiently elevated temperature and for a sufficient time to form a thiolated nicotine derivative;

4) further reacting the formed thiolated nicotine derivative by adding a suitable nitrite at a suitable temperature in the presence of oxygen or air, and allowing the reaction to proceed for a sufficient time to form the nitric oxide releasing component.

12. A process to form a nicotine-conjugated nitric oxide releasing component for release of nitric oxide during vaping by means of a vaping device, comprising the steps of:

1) providing nicotine selected from nicotine free base, a nicotine salt, or a combination thereof;

2) reacting the nicotine by introducing an alkyl-Nth residue, thus forming a reactive nicotine-alkyl-Nth intermediate, 3) reacting nicotine-alkyl-NFh intermediate by introducing a dioxofuran residue, thus forming a reactive nicotine-imide intermediate,

4) reacting the nicotine-imide intermediate with a thiol, thus forming a NO-releasing nicotine-imide- thioether.

13. The process of claim 12, wherein in step 2), nicotine is reacted with a halogen- alkyl- carbamate comprising a suitable protective group, the protective group being removed during intermediate reactions, to introduce an alkyl-NFh residue and thus forming a reactive nicotine-alkyl-Nth intermediate.

14. The process of claim 12, wherein in step 3), the nicotine-alkyl-Nth intermediate is reacted with a dioxofuran to form a nicotine-imide intermediate.

15. The process of claim 12, wherein in step 4), the nicotine-imide intermediate is reacted with a thiol to form a nicotine-imide-thioether, the nicotine-imide moeity of the nicotine-imide- thioether comprising a S-R residue, and wherein R is a residue selected from the group of Ci- C₈ alkyl.

16. The process of claim 12, wherein the nitric oxide-releasing thioether nicotine derivative is the of formula I below, wherein R is selected from the group comprising Ci-Cs alkyl residues including a -CFh residue:

FI

17. A process to form a an unconjugated nitric oxide releasing component for release of nitric oxide during vaping by means of a vaping device, comprising the steps of:

1) providing a solution A of nicotine base, a nicotine salt, or a combination thereof; 2) providing a solution B comprising an S-nitrosothiol, the S-nitrosothiol comprising R- SNO and R-S-N=0, wherein optionally the S-nitrosothiol is provided by nitrosylation of a thiol R-SH by mixing the thiol R-SH with reduced nitrites or nitrates in a suitable liquid carrier, and wherein R optionally is an alkyl residue selected from a Ci to Cs alkyl; and

3) mixing solution A with solution B at a suitable amount and molar ratio of nicotine to S- nitrosothiol, the molar ration being optionally from about 1:1 to about 10:1 (nicotine:S- nitrosothiol), thereby providing a nicotine formulation having the same effect of nicotine at a lower nicotine concentration.

18. The process of claim 17 wherein the thiol R-SH is an organic thiol selected from the group comprising one or more of: methanethiol, dimercaptosuccinic acid, a dimercaptoalkylsulfonic acid, 2,3-Dimercapto-l-propanesulfonic acid, a dimercapto- alcohol, 2, 3-Dimercapto- 1-propanol.

19. The invention substantially as described herein.