Patent Grant
11744277
In some aspects, provided herein is a method of generating an inhalable aerosol comprising nicotine for delivery to a user comprising using low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises said nicotine, an acid, and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some embodiments, said amount comprises about 4 μL of said nicotine liquid formulation. In some embodiments, said amount comprises about 4.5 mg of said nicotine liquid formulation. In some embodiments, a concentration of said nicotine is from about 0.5% (w/w) to about 20% (w/w). In some embodiments, a molar ratio of said acid to said nicotine is from about 0.25:1 to about 4:1. In some embodiments, said acid comprises one or more acidic functional groups, and wherein a molar ratio of said acidic functional groups to said nicotine is from about 0.25:1 to about 4:1. In some embodiments, said acid and said nicotine form a nicotine salt. In some embodiments, said nicotine is stabilized in said nicotine salt in said inhalable aerosol. In some embodiments of the methods described herein, said inhalable aerosol comprises one or more of said nicotine, said acid, said carrier, and said nicotine salt. In some embodiments of the methods described herein, one or more particles of said inhalable aerosol are sized for delivery to alveoli in a lung of said user. In some embodiments of the methods described herein, said acid is selected from the group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, succinic acid, and citric acid. In some embodiments of the methods described herein, said acid is selected from the group consisting of: benzoic acid, pyruvic acid, and salicylic acid. In some embodiments of the methods described herein, said acid is benzoic acid. In some embodiments of the methods described herein, said concentration is from about 2% (w/w) to about 6% (w/w). In some embodiments of the methods described herein, said concentration is about 5% (w/w). In some embodiments of the methods described herein, said biologically acceptable liquid carrier comprises from about 20% to about 50% of propylene glycol and from about 80% to about 50% of vegetable glycerin. In some embodiments of the methods described herein, said biologically acceptable liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin. In some embodiments of the methods described herein, said heater heats said amount of said nicotine liquid formulation from about 150° C. to about 250° C. In some embodiments of the methods described herein, said heater heats said amount of said nicotine liquid formulation from about 180° C. to about 220° C. In some embodiments of the methods described herein, said heater heats said amount of said nicotine liquid formulation to about 200° C. In some embodiments of the methods described herein, said nicotine liquid formulation further comprises an additional acid selected from said group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid. In some embodiments of the methods described herein, said additional acid forms an additional nicotine salt. In some embodiments of the methods described herein, at least about 60% a to about 90% of said acid in said amount is in said aerosol. In some embodiments of the methods described herein, at least about 70% to about 90% of said acid in said amount is in said aerosol. In some embodiments of the methods described herein, at least about 80% to about 90% of said acid in said amount is in said aerosol. In some embodiments of the methods described herein, more than about 90% of said acid in said amount is in said aerosol.
In some aspects, provided herein is a method of generating an inhalable aerosol comprising nicotine for delivery to a user comprising using low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises: said nicotine at a concentration from about 0.5% (w/w) to about 20% (w/w); an acid at a molar ratio of said acid to said nicotine from about 0.25:1 to about 4:1; and a biologically acceptable liquid carrier; wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided herein is a method of generating an inhalable aerosol comprising nicotine for delivery to a user comprising using low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises: nicotine at a concentration from about 2% (w/w) to about 6% (w/w); 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; wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to a heater, the heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided herein is a method of generating an inhalable aerosol comprising nicotine for delivery to a user comprising using low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises: nicotine at a concentration from about 2% (w/w) to about 6% (w/w); 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; wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to a heater; the heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 90% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided herein is a method of generating an inhalable aerosol comprising nicotine for delivery to a user comprising using low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises: nicotine at a concentration from about 2% (w/w) to about 6% (w/w); benzoic acid at a molar ratio of said benzoic acid to said nicotine of about 1:1; and a biologically acceptable liquid carrier; wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to a heater; the heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 90% of said benzoic acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided herein is a cartridge for use with low temperature electronic vaporization device, i.e. an electronic cigarette, said cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, said fluid compartment comprising a nicotine formulation comprising said nicotine, an acid, and a biologically acceptable liquid carrier, wherein using said electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some embodiments of the cartridges described herein, said amount comprises about 4 μL of said nicotine liquid formulation. In some embodiments of the cartridges described herein, said amount comprises about 4.5 mg of said nicotine liquid formulation. In some embodiments of the cartridges described herein, a concentration of said nicotine is from about 0.5% (w/w) to about 20% (w/w). In some embodiments of the cartridges described herein, a molar ratio of said acid to said nicotine is from about 0.25:1 to about 4:1. In some embodiments of the cartridges described herein, said acid comprises one or more acidic functional groups, and wherein a molar ratio of said acidic functional groups to said nicotine is from about 0.25:1 to about 4:1. In some embodiments of the cartridges described herein, said acid and said nicotine form a nicotine salt. In some embodiments of the cartridges described herein, said nicotine is stabilized in said nicotine salt in said inhalable aerosol. In some embodiments of the cartridges described herein, said inhalable aerosol comprises one or more of said nicotine, said acid, said carrier, and said nicotine salt. In some embodiments of the cartridges described herein, one or more particles of said inhalable aerosol are sized for delivery to alveoli in a lung of said user. In some embodiments of the cartridges described herein, said acid is selected from the group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, succinic acid, and citric acid. In some embodiments of the cartridges described herein, said acid is selected from the group consisting of: benzoic acid, pyruvic acid, and salicylic acid. In some embodiments of the cartridges described herein, said acid is benzoic acid. In some embodiments of the cartridges described herein, said concentration is from about 2% (w/w) to about 6% (w/w). In some embodiments of the cartridges described herein, said concentration is about 5% (w/w). In some embodiments of the cartridges described herein, said biologically acceptable liquid carrier comprises from about 20% to about 50% of propylene glycol and from about 80% to about 50% of vegetable glycerin. In some embodiments of the cartridges described herein, said biologically acceptable liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin. In some embodiments of the cartridges described herein, said heater heats said amount of said nicotine liquid formulation from about 150° C. to about 250° C. In some embodiments of the cartridges described herein, said heater heats said amount of said nicotine liquid formulation from about 180° C. to about 220° C. In some embodiments of the cartridges described herein, said heater heats said amount of said nicotine liquid formulation to about 200° C. In some embodiments of the cartridges described herein, said nicotine liquid formulation further comprises an additional acid selected from said group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid. In some embodiments of the cartridges described herein, said additional acid forms an additional nicotine salt. In some embodiments of the cartridges described herein, at least about 60% to about 90% of said acid in said amount is in said aerosol. In some embodiments of the cartridges described herein, at least about 70% to about 90% of said acid in said amount is in said aerosol. In some embodiments of the cartridges described herein, at least about 80% to about 90% of said acid in said amount is in said aerosol. In some embodiments of the cartridges described herein, more than about 90% of said acid in said amount is in said aerosol.
In some aspects, provided here is a cartridge for use with low temperature electronic vaporization device, i.e. an electronic cigarette, said cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, said fluid compartment comprising a nicotine formulation comprising: said nicotine at a concentration from about 0.5% (w/w) to about 20% (w/w); an acid at a molar ratio of said acid to said nicotine from about 0.25:1 to about 4:1; and a biologically acceptable liquid carrier; wherein using said electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided here is a cartridge for use with low temperature electronic vaporization device, i.e. an electronic cigarette, said cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, said fluid compartment comprising a nicotine formulation comprising: said nicotine at a concentration from about 2% (w/w) to about 6% (w/w); 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 wherein using said electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided here is a cartridge for use with low temperature electronic vaporization device, i.e. an electronic cigarette, said cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, said fluid compartment comprising a nicotine formulation comprising: said nicotine at a concentration from about 2% (w/w) to about 6% (w/w); 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; wherein using said electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 90% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided here is a cartridge for use with low temperature electronic vaporization device, i.e. an electronic cigarette, said cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, said fluid compartment comprising a nicotine formulation comprising: said nicotine at a concentration from about 2% (w/w) to about 6% (w/w); benzoic acid at a molar ratio of said benzoic acid to said nicotine of about 1:1; and a biologically acceptable liquid carrier; wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to a heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 90% of said benzoic acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided here is a formulation for use in low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a heater, the formulation comprising nicotine, an acid, and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some embodiments of the formulations described herein, said amount comprises about 4 μL of said nicotine liquid formulation. In some embodiments of the formulations described herein, wherein said amount comprises about 4.5 mg of said nicotine liquid formulation. In some embodiments of the formulations described herein, a concentration of said nicotine is from about 0.5% (w/w) to about 20% (w/w). In some embodiments of the formulations described herein, a molar ratio of said acid to said nicotine is from about 0.25:1 to about 4:1. In some embodiments of the formulations described herein, said acid comprises one or more acidic functional groups, and wherein a molar ratio of said acidic functional groups to said nicotine is from about 0.25:1 to about 4:1. In some embodiments of the formulations described herein, said acid and said nicotine form a nicotine salt. In some embodiments of the formulations described herein, wherein said nicotine is stabilized in said nicotine salt in said inhalable aerosol. In some embodiments of the formulations described herein, said inhalable aerosol comprises one or more of said nicotine, said acid, said carrier, and said nicotine salt. In some embodiments of the formulations described herein, one or more particles of said inhalable aerosol are sized for delivery to alveoli in a lung of said user. In some embodiments of the formulations described herein, said acid is selected from the group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, succinic acid, and citric acid. In some embodiments of the formulations described herein, said acid is selected from the group consisting of: benzoic acid, pyruvic acid, and salicylic acid. In some embodiments of the formulations described herein, said acid is benzoic acid. In some embodiments of the formulations described herein, said concentration is from about 2% (w/w) to about 6% (w/w). In some embodiments of the formulations described herein, said concentration is about 5% (w/w). In some embodiments of the formulations described herein, said biologically acceptable liquid carrier comprises from about 20% to about 50% of propylene glycol and from about 80% to about 50% of vegetable glycerin. In some embodiments of the formulations described herein, said biologically acceptable liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin. In some embodiments of the formulations described herein, said heater heats said amount of said nicotine liquid formulation from about 150° C. to about 250° C. In some embodiments of the formulations described herein, said heater heats said amount of said nicotine liquid formulation from about 180° C. to about 220° C. In some embodiments of the formulations described herein, said heater heats said amount of said nicotine liquid formulation to about 200° C. In some embodiments of the formulations described herein, said nicotine liquid formulation further comprises an additional acid selected from said group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid. In some embodiments of the formulations described herein, said additional acid forms an additional nicotine salt. In some embodiments of the formulations described herein, at least about 60% to about 90% of said acid in said amount is in said aerosol. In some embodiments of the formulations described herein, at least about 70% to about 90% of said acid in said amount is in said aerosol. In some embodiments of the formulations described herein, at least about 80% to about 90% of said acid in said amount is in said aerosol. In some embodiments, wherein more than about 90% of said acid in said amount is in said aerosol.
In some aspects, provided herein is a formulation for use in low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a heater, the formulation comprising: said nicotine at a concentration from about 0.5% (w/w) to about 20% (w/w); an acid at a molar ratio of said acid to said nicotine from about 0.25:1 to about 4:1; and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater, and said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided herein is a formulation for use in low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a heater, the formulation comprising: nicotine at a concentration from about 2% (w/w) to about 6% (w/w); 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; wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; and said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided herein is a formulation for use in low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a heater, the formulation comprising: nicotine at a concentration from about 2% (w/w) to about 6% (w/w); 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 wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; and said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 90% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
In some aspects, provided herein is a formulation for use in low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a heater, the formulation comprising: nicotine at a concentration from about 2% (w/w) to about 6% (w/w); benzoic acid at a molar ratio of said benzoic acid to said nicotine of about 1:1; and a biologically acceptable liquid carrier; wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; and said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 90% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol.
All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.
A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are used, and the accompanying drawings of which:
Nicotine is a chemical stimulant and increases heart rate and blood pressure when provided to an individual or animal. Nicotine transfer to an individual is associated with a feeling of physical and/or emotional satisfaction. Conflicting reports have been published regarding the transfer efficiency of free base nicotine in comparison to mono- or di-protonated nicotine salts. Studies on the transfer efficiency of free base nicotine and nicotine salts are complex and have yielded unpredictable results. Further, such transfer efficiency studies have been performed wider extremely high temperature conditions, comparable to smoking; therefore, they offer scant guidance on the transfer efficiency of free base nicotine and nicotine salts under low-temperature vaporization conditions, for example low temperature vaporization device, i.e. an electronic cigarette, conditions. Some reports have posited that nicotine free base should give rise to a greater satisfaction in a user than any corresponding nicotine salt.
It has been unexpectedly discovered herein that certain nicotine liquid formulations provide satisfaction in an individual superior to that of free base nicotine, and more comparable to the satisfaction in an individual smoking a traditional cigarette. The satisfaction effect is consistent with an efficient transfer of nicotine to the lungs, for example the alveoli of the lungs, of an individual and a rapid rise of nicotine absorption in the plasma as shown, in a non-limiting example, in Examples 8, 13 and 14, at least. It has also been unexpectedly discovered herein that certain nicotine liquid formulations provide greater satisfaction than other nicotine liquid formulations. Such effect has been shown in blood plasma levels of example nicotine liquid formulations herein, as a non-limiting example, in Examples 3 and 8, at least. These results demonstrate a rate of nicotine uptake in the blood is higher for nicotine liquid formulations, for example nicotine salt liquid formulations, than nicotine freebase formulations. Moreover, the studies depicted herein, demonstrate that the transfer efficiency of a nicotine liquid formulation, for example a nicotine salt, is dependent on the acid used in the formulation. As demonstrated in, at least, the non-limiting Example 13, certain acids used in the nicotine liquid formulation result in better transfer from the liquid formulation to the vapor and/or the aerosol. Therefore, described herein are nicotine liquid formulations, for example a nicotine salt liquid formulation, for use in low temperature electronic vaporization device, i.e. an electronic cigarette, or the like, that provide a general satisfaction effect consistent with an efficient transfer of nicotine to the lungs of an individual and a rapid rise of nicotine absorption in the plasma. Provided herein, therefore, are devices, nicotine liquid formulations comprising one or more nicotine salts, systems, cartomizers, kits and methods that are used to inhale an aerosol generated from a nicotine salt liquid formulation in a low temperature vaporization device, i.e. low temperature electronic vaporization device, i.e. an electronic cigarette, through the mouth or nose as described herein or as would be obvious to one of skill in the art upon reading the disclosure herein.
Consistent with these satisfaction effects, it has unexpectedly been found herein that there is a difference between the Cmax (maximum concentration) and Tmax (time at which the maximum concentration is measured) when measuring blood plasma nicotine levels of freebase nicotine liquid formulations inhaled using a low temperature vaporization device, i.e. electronic cigarette, as compared to the Cmax and Tmax (similarly measuring blood plasma nicotine levels) of a traditional cigarette. Also consistent with these satisfaction effects, it has unexpectedly been found herein that there is a difference between the Cmax and Tmax when measuring blood plasma nicotine levels of freebase nicotine liquid formulations inhaled using a low temperature vaporization device, i.e. electronic cigarette, as compared to the Cmax and Tmax (similarly measuring blood plasma nicotine levels) of nicotine liquid formulations, for example nicotine salt liquid formulations, inhaled using a low temperature vaporization device, i.e. electronic cigarette. Additionally, it has unexpectedly been found that there is a difference between the rate of nicotine uptake in the plasma of users inhaling freebase nicotine liquid formulations using a low temperature vaporization device, i.e. electronic cigarette, as compared to the rate of nicotine uptake in the plasma of users inhaling smoke of a traditional cigarette. Furthermore, it has unexpectedly been found that there is a difference between the rate of nicotine uptake in the plasma of users inhaling freebase nicotine liquid formulations using a low temperature vaporization device, i.e. electronic cigarette, as compared to the rate of nicotine uptake in the plasma of users inhaling nicotine liquid formulations, for example a nicotine salt liquid formulations, using a low temperature vaporization device, i.e. electronic cigarette.
In some embodiments, inhalation of a vapor and/or an aerosol generated using a freebase nicotine composition in a low temperature vaporization device, i.e. an electronic cigarette, is not necessarily comparable in blood plasma levels (Cmax and Tmax) to a traditional cigarette's nicotine delivery to blood when inhaled. Further, inhalation of a vapor and/or an aerosol generated using a freebase nicotine composition in a low temperature vaporization device, i.e. an electronic cigarette, is not necessarily comparable in blood plasma levels (Cmax and Tmax) to inhalation of a vapor and/or an aerosol comprising nicotine generated from a nicotine liquid formulation, for example a nicotine salt liquid formulation. Further, inhalation of a vapor and/or an aerosol generated using a freebase nicotine composition in a low temperature vaporization device, i.e. an electronic cigarette, is not necessarily comparable in blood plasma levels when measuring the rate of nicotine uptake in the blood within the first 0-8 minutes to a traditional cigarette's nicotine delivery to blood when inhaled. Further, inhalation of a vapor and/or an aerosol generated using a freebase nicotine composition in a low temperature vaporization device, i.e. an electronic cigarette, is not necessarily comparable in blood plasma levels when measuring the rate of nicotine uptake in the blood within the first 0-8 minutes to inhalation of a vapor and/or an aerosol comprising nicotine generated from a nicotine liquid formulation, for example a nicotine salt liquid formulation.
Consistent with the observed differences in nicotine blood plasma levels when using freebase nicotine as a source of nicotine in a low temperature vaporization device, i.e. an electronic cigarette, in comparison to a nicotine liquid formulation, for example a nicotine salt liquid formulation, the transfer efficiency of the nicotine liquid formulation delivers more nicotine from the liquid formulation to the vapor and/or to the aerosol. As demonstrated, in a non-limiting Example 13 freebase nicotine as a source of nicotine in low temperature electronic vaporization device, i.e. an electronic cigarette, results in less nicotine present in an aerosol as compared to using a nicotine liquid formulation, for example a nicotine salt liquid formulation, as a source of nicotine in low temperature electronic vaporization device, i.e. an electronic cigarette. Further, this is consistent with the observed differences in nicotine blood plasma levels when using freebase nicotine as a source of nicotine in a low temperature vaporization device, i.e. an electronic cigarette, compared to using a nicotine liquid formulation, for example a nicotine salt liquid formulation, wherein the higher transfer efficiency of the nicotine liquid formulation from the liquid to the vapor and/or the aerosol results in a higher rate of nicotine uptake in the blood. One explanation for this observation is that the aerosol comprising nicotine, for example liquid droplets of the aerosol, is more readily delivered to the user's lungs and/or alveoli therein resulting in more efficient uptake into the user's bloodstream. Moreover, the aerosol is delivered in particles sized to be delivered through the oral or nasal cavity and to a user's lungs, for example the alveoli of a user's lungs.
Compared to vaporized nicotine, aerosolized nicotine is more likely to travel to a user's lungs and be absorbed in alveoli. One reason that aerosolized nicotine has a greater chance of being absorbed in the lungs compared to vaporized nicotine is, for example, vaporized nicotine has a greater chance of being absorbed in mouth tissues and upper respiratory tract tissues of the user. Moreover, it is likely nicotine will absorb at a slower rate in the mouth and upper respiratory tract compared to nicotine absorbed in the lung tissue thus resulting in a less satisfying effect for a user. As shown in non-limiting Examples 8 and 13, at least, using a low temperature electronic vaporization device, i.e. an electronic cigarette, to deliver nicotine to a user, there is a direct correlation between the time to max concentration of nicotine in blood (Tmax) to the amount of aerosolized nicotine delivered to aerosol. For example, using a freebase nicotine liquid formulation results in a significant decrease in the amount of aerosolized nicotine compared to nicotine benzoate (1:1 nicotine:benzoic acid molar ratio) and nicotine malate (1:2 nicotine:malate molar ratio). Further, as shown in a non-limiting Example 8, the Tmax is longer for freebase compared to nicotine benzoic acid and nicotine malate resulting from less aerosolized nicotine and thus less rapid uptake in the user's lungs.
In comparison to acids that do not degrade at room temperature and/or an operating temperature(s) of the device, acids that degrade at room temperature and/or an operating temperature of the device require a higher molar ratio of acid to nicotine to transfer the same molar amount of the acid from the liquid to the aerosol. As such, in some embodiments, twice the molar amount of acids that degrade at room temperature and/or an operating temperature(s) of the device compared to acids that do not degrade is required to generate an aerosol comprising the same molar amount of nicotine in the aerosol, in some embodiments in a non-gas phase (e.g. liquid droplets) of the aerosol. As shown in a non-limiting Example 13, the correlation between the benzoic acid to nicotine molar ratio and the percent of acid captured demonstrates that more acid is the aerosol, in some embodiments in a non-gas phase of the aerosol, and as such, more nicotine is likely present the aerosol, in some embodiments in a non-gas phase of the aerosol. Further, malic acid is known to decompose at about 150° C., which is below the temperature at which low temperature electronic vaporization device, i.e. an electronic cigarette, operates, and as shown in a non-limiting Example 13, less than 50% of the malic acid in the liquid formulation is recovered when using malic acid in the nicotine liquid formulation. This is significantly different than 90% of benzoic acid in the liquid formulation being recovered when using benzoic acid in the nicotine liquid formulation. The lower percent recovery of malic acid is likely due to degradation of malic acid. Therefore, as shown in Example 13, about twice the amount of malic acid compared to benzoic acid is needed to generate an aerosol comprising the same molar amount of acid in the aerosol, in some embodiments in a non-gas phase of the aerosol, and as such, twice the amount of malic acid is more nicotine is likely required to generate an aerosol comprising the same amount of nicotine the aerosol, in some embodiments in a non-gas phase of the aerosol. Moreover, the degradation products of malic acid are likely present in the aerosol, which may be result in a user having an unfavorable experience when using the device and a malic acid nicotine liquid formulation. In some embodiments, an unfavorable experience comprises a flavor, a nervous response, and/or an irritation of one or more of an oral cavity, an upper respiratory tract, and/or the lungs.
The presence of acid in the aerosol stabilizes and/or carries nicotine to a user's lungs. In some embodiments, the formulation comprises a 1:1 ratio of moles of acid functional groups to moles of nicotine such that nicotine is stabilized in the aerosol produced by low temperature electronic vaporization device. i.e. an electronic cigarette. In some embodiments, the formulation comprises a 1:1 ratio of moles of carboxylic acid functional group hydrogens to moles of nicotine such that nicotine is stabilized in the aerosol produced by low temperature electronic vaporization device, i.e. an electronic cigarette. As shown in Example 14, nicotine is aerosolized at a 1:1 ratio of moles of benzoic acid to moles of nicotine, and since benzoic acid comprises one carboxylic acid functional group, nicotine is aerosolized at a 1:1 ratio of moles of carboxylic acid functional groups to moles of nicotine. Further, as shown in Example 14, nicotine is aerosolized at a 0.5:1 ratio of moles of succinic acid to moles of nicotine, and since succinic acid comprises two carboxylic acid functional groups, nicotine is aerosolized at a 1:1 ratio of moles of carboxylic acid functional groups to moles of nicotine. As shown in Example 14, each nicotine molecule is associated with one carboxylic acid functional group and thus is likely protonated by the acid. Moreover, this demonstrates nicotine is likely delivered to the lungs of the user in a protonated form in the aerosol.
Some reasons for not using acids in a nicotine liquid formulation are listed below. Other reasons for using certain acids in a nicotine liquid formulation are unrelated to the rate of nicotine uptake. In some embodiments, an acid that is corrosive or otherwise incompatible with the electronic vaporization device materials is not used in the nicotine liquid formulation. As a non-limiting example, sulfuric acid would corrode and/or react with device components making it inappropriate to be included in the nicotine liquid formulation. In some embodiments, an acid that is toxic to a user of the electronic vaporization device is not useful in the nicotine liquid formulation because it is not compatible for human consumption, ingestion, or inhalation. As a non-limiting example, sulfuric acid is an example of such an acid, which may be inappropriate for a user of low temperature electronic vaporization device, i.e. an electronic cigarette, device, depending on the embodiment of the composition. In some embodiments, an acid in the nicotine liquid formulation is that is bitter or otherwise bad-tasting to a user is not useful in the nicotine liquid formulation. A non-limiting example of such an acid is acetic acid or citric acid at a high concentration. In some embodiments, acids that oxidize at room temperature and/or at the operating temperature of the device are not included in the nicotine liquid formulation. A non-limiting example of such acids comprises sorbic acid and malic, which are unstable at the room temperature and/or the operating temperature of the device. Decomposition of acids at room or operating temperatures may indicate that the acid is inappropriate for use in the embodiment formulations. As a non-limiting example, citric acid decomposes at 175° C., and malic acid decomposes at 140° C., thus for a device operating at 200° C., these acids may not be appropriate. In some embodiments, acids that have poor solubility in the composition constituents are inappropriate for use in certain embodiments of the compositions herein. As a non-limiting example, nicotine bitartrate with a composition of nicotine and tartaric acid at a 1:2 molar ratio will not produce a solution at a concentration of 0.5% (w/w) nicotine or higher and 0.9% (w/w) tartaric acid or higher in propylene glycol (PG) or vegetable glycerin (VG) or any mixture of PG and VG at ambient conditions. As used herein, weight percentage (w/w) refers to the weight of the individual component over the weight of the total formulation.
In some embodiments, a nicotine liquid formulation, for example a nicotine salt liquid formulation, made using an acid having a Vapor Pressure between 20-300 mmHg @200° C., or Vapor Pressure >20 mmHg @200° C., or a Vapor Pressure from 20 to 300 mmHg @200° C., or a Vapor Pressure from 20 to 200 mmHg @200° C., a Vapor Pressure between 20 and 300 mmHg @200° C. provide satisfaction comparable to a traditional cigarette or closer to a traditional cigarette (as compared to other nicotine salt formulations or as compared to nicotine freebase formulations). For non-limiting example, acids that meet one or more criteria of the prior sentence comprise salicylic acid, sorbic acid, benzoic acid, lauric acid, and levulinic acid. In some embodiments, a nicotine liquid formulation, for example a nicotine salt liquid formulation, made using an acid that has a difference between boiling point and melting point of at least 50° C., and a boiling point greater than 160° C., and a melting point less than 160° C. provide satisfaction comparable to a traditional cigarette or closer to a traditional cigarette (as compared to other nicotine salt formulations or as compared to nicotine freebase formulations). For non-limiting example, acids that meet the criteria of the prior sentence comprise salicylic acid, sorbic acid, benzoic acid, pyruvic acid, lauric acid, and levulinic acid. In some embodiments, a nicotine liquid formulation, for example a nicotine salt liquid formulation, made using an acid that has a difference between boiling point and melting point of at least 50° C., and a boiling point at most 40° C. less than operating temperature, and a melting point at least 40° C. lower than operating temperature provide satisfaction comparable to a traditional cigarette or closer to a traditional cigarette (as compared to other nicotine salt formulations or as compared to nicotine freebase formulations). In some embodiments, an operating temperature can be 100° C. to 300° C., or about 200° C., about 150° C. to about 250° C., 180 C to 220° C., about 180° C. to about 220° C., 185° C. to 215° C., about 185° C. to about 215° C., about 190° C. to about 210° C., 190° C. to 210° C., 195° C. to 205° C., or about 195° C. to about 205° C. For non-limiting example, acids that meet the aforementioned criteria comprise salicylic acid, sorbic acid, benzoic acid, pyruvic acid, lauric acid, and levulinic acid. In some embodiments, a combination of these criteria for preference of certain nicotine salt formulations are contemplated herein.
As used in this specification and the claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
As used in this specification and the claims, the term “vapor” refers to a gas or a gas phase of a material. As used in the specification and the claims, the term “aerosol” refers to a colloidal suspension of particles, for example liquid droplets, dispersed in air or gas.
The term “organic acid” as used herein, refers to an organic compound with acidic properties (e.g., by Brønsted-Lowry definition, or Lewis definition). A common organic acid is the carboxylic acids, whose acidity is associated with their carboxyl group —COOH. A dicarboxylic acid possesses two carboxylic acid groups. The relative acidity of an organic is measured by its pKa value and one of skill in the art knows how to determine the acidity of an organic acid based on its given pKa value. The term “keto acid” as used herein, refers to organic compounds that contain a carboxylic acid group and a ketone group. Common types of keto acids include alpha-keto acids, or 2-oxoacids, such as pyruvic acid or oxaloacetic acid, having the keto group adjacent to the carboxylic acid; beta-keto acids, or 3-oxoacids, such as acetoacetic acid, having the ketone group at the second carbon from the carboxylic acid; gamma-keto acids, or 4-oxoacids, such as levulinic acid, having the ketone group at the third carbon from the carboxylic acid.
The term “electronic cigarette” or “low temperature vaporization device” as used herein, refers to an electronic inhaler that vaporizes a liquid solution into an aerosol mist, simulating the act of tobacco smoking. The liquid solution comprises a formulation comprising nicotine. There are many a low temperature vaporization device, i.e. an electronic cigarette, which do not resemble conventional cigarettes at all. The amount of nicotine contained can be chosen by the user via the inhalation. In general, low temperature electronic vaporization device, i.e. an electronic cigarette, contains three essential components: a plastic cartridge that serves as a mouthpiece and a reservoir for liquid, an “atomizer” that vaporizes the liquid, and a battery. Other embodiment a low temperature vaporization device, i.e. an electronic cigarette, include a combined atomizer and reservoir, called a “cartomizer” that may or may not be disposable, a mouthpiece that may be integrated with the cartomizer or not, and a battery.
As used in this specification and the claims, unless otherwise stated, the term “about” refers to variations of 1%, 2%, 3%, 4%, 5%, 10%, 15%, or 25%, depending on the embodiment.
Suitable carriers (e.g., a liquid solvent) for the nicotine salts described herein include a medium in which a nicotine salt is soluble at ambient conditions, such that the nicotine salt does not form a solid precipitate. Examples include, but are not limited to, glycerol, propylene glycol, trimethylene glycol, water, ethanol and the like, as well as combinations thereof. In some embodiments, the liquid carrier comprises from about 0% to about 100% of propylene glycol and from about 100% to about 0% of vegetable glycerin. In some embodiments, the liquid carrier comprises from about 10% to about 70% of propylene glycol and from about 90% to about 30% of vegetable glycerin. In some embodiments, the liquid carrier comprises from about 20% to about 50% of propylene glycol and from about 80% to about 50% of vegetable glycerin. In some embodiments, the liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin.
The formulations described herein vary in nicotine concentration. In some formulations, the concentration of nicotine in the formulation is dilute. In some formulations, the nicotine concentration in the formulation is less dilute. In some formulations the concentration of nicotine in the nicotine liquid formulation is from about 1% (w/w) to about 25% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is from about 1% (w/w) to about 20% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is from about 1% (w/w) to about 18% (w/w). In some embodiments the concentration of nicotine in the nicotine liquid formulation is from about 1% (w/w) to about 15% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is from about 4% (w/w) to about 12% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is from about 2% (w/w) to about 6% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is about 5% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is about 4% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is about 3% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is about 2% (w/w). In some embodiments the concentration of nicotine in the nicotine liquid formulation is about 1% (w/w). In some formulations the concentration of nicotine in the nicotine liquid formulation is form about 1% (w/w) to about 25% (w/w).
The formulations described herein vary in nicotine salt concentration. In some formulations, the concentration of nicotine salt in the nicotine liquid formulation is dilute. In some formulations, the nicotine concentration in the formulation is less dilute. In some formulations the concentration of nicotine salt in the nicotine liquid formulation is from about 1% (w/w) to about 25% (w/w). In some formulations the concentration of nicotine salt in the nicotine liquid formulation is from about 1% (w/w) to about 20% (w/w). In some formulations the concentration of nicotine salt in the nicotine liquid formulation is from about 1% (w/w) to about 18% (w/w). In some embodiments the concentration of nicotine salt in the nicotine liquid formulation is from about 1% (w/w) to about 15% (w/w). In some formulations the concentration of nicotine salt in the nicotine liquid formulation is from about 4% (w/w) to about 12% (w/w). In some formulations the concentration of nicotine salt in the nicotine liquid formulation is from about 2% (w/w) to about 6% (w/w). In some Formulations the concentration of nicotine salt in the nicotine liquid formulation is about 5% (w/w). In some formulations the concentration of nicotine salt in the nicotine liquid formulation is about 4% (w/w). In some formulations the concentration of nicotine salt in the nicotine liquid formulation is about 3% (w/w). In some formulations the concentration of nicotine salt in the nicotine liquid formulation is about 2% (w/w).
In some embodiments the concentration of nicotine salt in the nicotine liquid formulation is about 1% (w/w). In some formulations, a less dilute concentration of one nicotine salt is used in conjunction with a more dilute concentration of a second nicotine salt. In some formulations, the concentration of nicotine in the first nicotine liquid formulation is from about 1% to about 20%, and is combined with a second nicotine liquid formulation having a concentration of nicotine from about 1% to about 20% or any range or concentration therein. In some formulations, the concentration of nicotine salt in the first nicotine liquid formulation is from about 1% to about 20%, and is combined with a second nicotine liquid formulation having a concentration of nicotine from 1% to 20% or any range or concentration therein. In some formulations, the concentration of nicotine salt in the first nicotine liquid formulation is from about 1% to about 20%, and is combined with a second nicotine liquid formulation having a concentration of nicotine salt from 1% to 20% or any range or concentration therein. As used with respect to concentrations of nicotine in the nicotine liquid formulations, the term “about” refers to ranges of 0.05% (i.e. if the concentration is from about 2%, the range is 1.95%-2.05%), 0.1 (i.e. if the concentration is from about 2%, the range is 1.9%-2.1%), 0.25 (i.e. if the concentration is from about 2%, the range is 1.75%-2.25%), 0.5 (i.e. if the concentration is from about 2%, the range is 1.5%-2.5%), or 1 (i.e. if the concentration is from about 4%, the range is 3%-5%), depending on the embodiment.
In some embodiments, the formulation comprises an organic acid and/or inorganic acid. In some embodiments, suitable organic acids comprise carboxylic acids. In some embodiments, organic carboxylic acids disclosed herein are monocarboxylic acids, dicarboxylic acids (organic acid containing two carboxylic acid groups), and carboxylic acids containing an aromatic group such as benzoic acids, hydroxycarboxylic acids, heterocyclic carboxylic acids, terpenoid acids, and sugar acids; such as the pectic acids, amino acids, cycloaliphatic acids, aliphatic carboxylic acids, keto carboxylic acids, and the like. In some embodiments, suitable acids comprise 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, gluconic acid, saccharic acid, salicyclic acid, sorbic acid, malonic acid, malic acid, or a combination thereof. In some embodiments, a suitable acid comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid. In some embodiments, a suitable acid comprises one or more of benzoic acid, pyruvic acid, and salicylic acid. In some embodiments, a suitable acid comprises benzoic acid.
Nicotine salts are formed by the addition of a suitable acid, including organic or inorganic acids. In some embodiments, suitable organic acids comprise carboxylic acids. In some embodiments, organic carboxylic acids disclosed herein are monocarboxylic acids, dicarboxylic acids (organic acid containing two carboxylic acid groups), carboxylic acids containing an aromatic group such as benzoic acids, hydroxycarboxylic acids, heterocyclic carboxylic acids, terpenoid acids, sugar acids; such as the pectic acids, amino acids, cycloaliphatic acids, aliphatic carboxylic acids, keto carboxylic acids, and the like. In some embodiments, organic acids used herein are monocarboxylic acids. Nicotine salts are formed from the addition of a suitable acid to nicotine. In some embodiments, suitable acid, comprise 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, gluconic acid, saccharic acid, salicyclic acid, sorbic acid, masonic acid, malic acid, or a combination thereof. In some embodiments, a suitable acid comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid. In some embodiments, a suitable acid comprises one or more of benzoic acid, pyruvic acid, and salicylic acid. In some embodiments, a suitable acid comprises benzoic acid.
In some embodiments, the formulation comprises various stoichiometric ratios and/or molar ratios of acid to nicotine, acidic functional groups to nicotine, and acidic functional group hydrogens to nicotine. In some embodiments, the stoichiometric ratios of the nicotine to acid (nicotine:acid) are 1:1, 1:2, 1:3, 1:4, 2:3, 2:5, 2:7, 3:4, 3:5, 3:7, 3:8, 3:10, 3:11, 4:5, 4:7, 4:9, 4:10, 4:11, 4:13, 4:14, 4:15, 5:6, 5:7, 5:8, 5:9, 5:11, 5:12, 5:13, 5:14, 5:16, 5:17, 5:18, or 5:19. In some formulations provided herein, the stoichiometric ratios of the nicotine to acid are 1:1, 1:2, 1:3, or 1:4. In some embodiments, the molar ratio of acid to nicotine in the formulation is about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, about 2.2:1, about 2.4:1, about 2.6:1, about 2.8:1, about 3:1, about 3.2:1, about 3.4:1, about 3.6:1, about 3.8:1, or about 4:1. In some embodiments, the molar ratio of acidic functional groups to nicotine in the formulation is about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, about 2.2:1, about 2.4:1, about 2.6:1, about 2.8:1, about 3:1, about 3.2:1, about 3.4:1, about 3.6:1, about 3.8:1, or about 4:1. In some embodiments, the molar ratio of acidic functional group hydrogens to nicotine in the formulation is about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, about 2.2:1, about 2.4:1, about 2.6:1, about 2.8:1, about 3:1, about 3.2:1, about 3.4:1, about 3.6:1, about 3.8:1, or about 4:1. In some embodiments, the molar ratio of acid to nicotine in the aerosol is about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, about 2.2:1, about 2.4:1, about 2.6:1, about 2.8:1, about 3:1, about 3.2:1, about 3.4:1, about 3.6:1, about 3.8:1, or about 4:1. In some embodiments, the molar ratio of acidic functional groups to nicotine in the aerosol is about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, about 2.2:1, about 2.4:1, about 2.6:1, about 2.8:1, about 3:1, about 3.2:1, about 3.4:1, about 3.6:1, about 3.8:1, or about 4:1. In some embodiments, the molar ratio of acidic functional group hydrogens to nicotine in the aerosol is about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, about 2.2:1, about 2.4:1, about 2.6:1, about 2.8:1, about 3:1, about 3.2:1, about 3.4:1, about 3.6:1, about 3.8:1, or about 4:1.
Nicotine is an alkaloid molecule that comprises two basic nitrogens. It may occur in different states of protonation. For example, if no protonation exists, nicotine is referred to as the “free base.” If one nitrogen is protonated, then the nicotine is “mono-protonated.”
In some embodiments, nicotine liquid formulations are formed by adding a suitable acid to nicotine, stirring the neat mixture at ambient temperature or at elevated temperature, and then diluting the neat mixture with a carrier mixture, such as a mixture of propylene glycol and glycerin. In some embodiments, the suitable acid is completely dissolved by the nicotine prior to dilution. The suitable acid may not completely dissolved by the nicotine prior to dilution. The addition of the suitable acid to the nicotine to form a neat mixture may cause an exothermic reaction. The addition of the suitable acid to the nicotine to form a neat mixture may be conducted at 55° C. The addition of the suitable acid to the nicotine to form a neat mixture may be conducted at 90° C. The neat mixture may be cooled to ambient temperature prior to dilution. The dilution may be carried out at elevated temperature.
In some embodiments, nicotine liquid formulations are prepared by combining nicotine and a suitable acid in a carrier mixture, such as a mixture of propylene glycol and glycerin. The mixture of nicotine and a first carrier mixture is combined with a mixture of a suitable acid in a second carrier mixture. In some embodiments, the first and second carrier mixtures are identical in composition. In some embodiments, the first and second carrier mixtures are not identical in composition. In some embodiments, heating of nicotine/acid/carrier mixture is required to facilitate complete dissolution. In some embodiments, stirring of nicotine/acid/carrier mixture is sufficient to facilitate complete dissolution.
In some embodiments, nicotine liquid formulations are prepared and added to a solution of 3:7 ratio by weight of propylene glycol (PG)/vegetable glycerin (VG), and mixed thoroughly. While described herein as producing 10 g of each of the formulations, all procedures noted infra are scalable. Other manners of formulation may also be employed form the formulations noted infra, without departing from the disclosure herein, and as would be known to one of skill in the art upon reading the disclosure herein.
In some embodiments, the acid included in the nicotine liquid formulation is determined by the vapor pressure of the acid. In some embodiments, the nicotine liquid formulation comprises an acid with a vapor pressure that is similar to the vapor pressure of free base nicotine. In some embodiments, the nicotine liquid formulations am formed from an acid with a vapor pressure that is similar to the vapor pressure of free base nicotine at the heating temperature of the device. As a non-limiting example,
Unexpectedly, different nicotine liquid formulations produced varying degrees of satisfaction in an individual. In some embodiments, the extent of protonation of the nicotine salt effects satisfaction, such that more protonation was less satisfying as compared to less protonation. In some embodiments, nicotine, for example a nicotine salt, in the formulation, vapor, and/or aerosol is monoprotonated. In some embodiments, nicotine, for example a nicotine salt, in the formulation, vapor and/or aerosol is diprotonated. In some embodiments, nicotine, for example a nicotine salt, in the formulation, vapor and/or aerosol exists in more than one protonation state, e.g., an equilibrium of mono-protonated and di-protonated nicotine salts. In some embodiments, the extent of protonation of nicotine is dependent upon the stoichiometric ratio of nicotine:acid used in the salt formation reaction. In some embodiments, the extent of protonation of nicotine is dependent upon the solvent. In some embodiments, the extent of protonation of nicotine is unknown.
In some embodiments, monoprotonated nicotine salts produced a high degree of satisfaction in the user. For example, nicotine benzoate and nicotine salicylate are mono-protonated nicotine salts and produce a high degree of satisfaction in the user. The reason for this trend may be explained by a mechanism of action wherein the nicotine is first deprotonated prior to transfer to the vapor with the constituent acid, then stabilized by the acid in the aerosol after re-protonation, and carried by the acid going down stream to the lungs of the user. In addition, the lack of satisfaction of free base nicotine indicates that a second factor may be important. A nicotine salt may be best performing when it is at its optimal extent of protonation, depending on the salt. For example, as depicted in a non-limiting Example 13, nicotine benzoate transfers the maximum amount of nicotine to the aerosol at a 1:1 ratio of benzoic acid to nicotine. A lower molar ratio results in less nicotine being transferred to the aerosol, and a higher than 1:1 molar ratio of benzoic acid to nicotine does results in the transfer of any additional nicotine to the aerosol. This may be explained as 1 mole of nicotine associates or interacts with 1 mole of benzoic acid to form a salt. When there is not enough benzoic acid to associate with all nicotine molecules, the free base nicotine left unprotonated in the formulation is vaporized thus reducing the satisfaction for the user.
In some embodiments, acids that degrade at room temperature or an operating temperature of a low temperature electronic vaporization device, i.e. a low temperature electronic cigarette, do not afford the same degree of satisfaction to a user. For example, twice the amount of malic acid, which degrades at the operating temperature of the low temperature electronic cigarette, compared to benzoic acid is required to transfer the same molar amount of the acid from the liquid to the aerosol. As such, in some embodiments, twice the molar amount of malic acid compared to benzoic acid is required to generate an aerosol comprising the same molar amount of nicotine in the aerosol, in some embodiments in a non-gas phase of the aerosol. Moreover, because malic acid comprises two carboxylic acid groups and benzoic acid comprises one, four times the amount of acidic functional groups are required when using malic acid compared to benzoic acid in the nicotine liquid formulation. Moreover, because malic acid comprises two carboxylic acid groups and benzoic acid comprises one, four times the amount of acidic functional group hydrogens are required when using malic acid compared to benzoic acid in the nicotine liquid formulation. In some embodiments, the one or more chemicals produced on degradation of the acid results in an unfavorable experience to the user. In some embodiments, an unfavorable experience comprises a flavor, a nervous response, and/or an irritation of one or more of an oral cavity, an upper respiratory tract, and/or the lungs.
In some embodiments, provided here are method, systems, devices, formulations, and kits for generating an inhalable aerosol comprising nicotine for delivery to a user comprising using low temperature electronic vaporization device, i.e. an electronic cigarette, comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises said nicotine, an acid, and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing an amount of said nicotine liquid formulation to said heater; said heater forming an aerosol by heating said amount of said nicotine liquid formulation, wherein at least about 50% of said acid in said amount is in said aerosol, and wherein at least about 90% of said nicotine in said amount is in said aerosol. In some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, or at least about 99% of said acid in said amount is in said aerosol. In some embodiments, at least about 50% to about 99% of said acid in said amount is in said aerosol. In some embodiments, at least about 50% to about 95% of said acid in said amount is in said aerosol. In some embodiments, at least about 50% to about 90% of said acid in said amount is in said aerosol. In some embodiments, at least about 50% to about 80% of said acid in said amount is in said aerosol. In some embodiments, at least about 50% to about 70% of said acid in said amount is in said aerosol. In some embodiments, at least about 50% to about 60% of said acid in said amount is in said aerosol. In some embodiments, at least about 60% to about 99% of said acid in said amount is in said aerosol. In some embodiments, at least about 60% to about 95% of said acid in said amount is in said aerosol. In some embodiments, at least about 60% to about 90% of said acid in said amount is in said aerosol. In some embodiments, at least about 60% to about 80% of said acid in said amount is in said aerosol. In some embodiments, at least about 60% to about 70% of said acid in said amount is in said aerosol. In some embodiments, at least about 70% to about 99% of said acid in said amount is in said aerosol. In some embodiments, at least about 70% to about 95% of said acid in said amount is in said aerosol. In some embodiments, at least about 70% to about 90% of said acid in said amount is in said aerosol. In some embodiments, at least about 70% to about 80% of said acid in said amount is in said aerosol.
In some embodiments, the aerosol is delivered in particles sized to be delivered through the oral or nasal cavity and to a user's lungs, for example the alveoli of a user's lungs. In some embodiments, the aerosol generated using a nicotine liquid formulation, for example a nicotine salt liquid formulation, generated using a low temperature vaporization device, for example a low temperature electronic cigarette, is delivered in particles sized to be delivered through the oral or nasal cavity and to a user's lungs, for example the alveoli of a user's lung. In some embodiments, the rate of uptake in the user's lungs, for example alveoli in the user's lungs, is affected by aerosol particle size. In some embodiments the aerosol particles are sized from about 0.1 microns to about 5 microns, from about 0.1 microns to about 4.5 microns, from about 0.1 microns to about 4 microns, from about 0.1 microns to about 3.5 microns, from about 0.1 microns to about 3 microns, from about 0.1 microns to about 2.5 microns, from about 0.1 microns to about 2 microns, from about 0.1 microns to about 1.5 microns, from about 0.1 microns to about 1 microns, from about 0.1 microns to about 0.9 microns, from about 0.1 microns to about 0.8 microns, from about 0.1 microns to about 0.7 microns, from about 0.1 microns to about 0.6 microns, from about 0.1 microns to about 0.5 microns, from about 0.1 microns to about 0.4 microns, from about 0.1 microns to about 0.3 microns, from about 0.1 microns to about 0.2 microns, from about 0.2 microns to about 5 microns, from about 0.2 microns to about 4.5 microns, from about 0.2 microns to about 4 microns, from about 0.2 microns to about 3.5 microns, from about 0.2 microns to about 3 microns, from about 0.2 microns to about 2.5 microns, from about 0.2 microns to about 2 microns, from about 0.2 microns to about 1.5 microns, from about 0.2 microns to about 1 microns, from about 0.2 microns to about 0.9 microns, from about 0.2 microns to about 0.8 microns, from about 0.2 microns to about 0.7 microns, from about 0.2 microns to about 0.6 microns, from about 0.2 microns to about 0.5 microns, from about 0.2 microns to about 0.4 microns, from about 0.2 microns to about 0.3 microns, from about 0.3 microns to about 5 microns, from about 0.3 microns to about 4.5 microns, from about 0.3 microns to about 4 microns, from about 0.3 microns to about 3.5 microns, from about 0.3 microns to about 3 microns, from about 0.3 microns to about 2.5 microns, from about 0.3 microns to about 2 microns, from about 0.3 microns to about 1.5 microns, from about 0.3 microns to about 1 microns, from about 0.3 microns to about 0.9 microns, from about 0.3 microns to about 0.8 microns, from about 0.3 microns to about 0.7 microns, from about 0.3 microns to about 0.6 microns, from about 0.3 microns to about 0.5 microns, from about 0.3 microns to about 0.4, from about 0.4 microns to about 5 microns, from about 0.4 microns to about 4.5 microns, from about 0.4 microns to about 4 microns, from about 0.4 microns to about 3.5 microns, from about 0.4 microns to about 3 microns, from about 0.4 microns to about 2.5 microns, from about 0.4 microns to about 2 microns, from about 0.4 microns to about 1.5 microns, from about 0.4 microns to about 1 microns, from about 0.4 microns to about 0.9 microns, from about 0.4 microns to about 0.8 microns, from about 0.4 microns to about 0.7 microns, from about 0.4 microns to about 0.6 microns, from about 0.4 microns to about 0.5 microns, from about 0.5 microns to about 5 microns, from about 0.5 microns to about 4.5 microns, from about 0.5 microns to about 4 microns, from about 0.5 microns to about 3.5 microns, from about 0.5 microns to about 3 microns, from about 0.5 microns to about 2.5 microns, from about 0.5 microns to about 2 microns, from about 0.5 microns to about 1.5 microns, from about 0.5 microns to about 1 microns, from about 0.5 microns to about 0.9 microns, from about 0.5 microns to about 0.8 microns, from about 0.5 microns to about 0.7 microns, from about 0.5 microns to about 0.6 microns, from about 0.6 microns to about 5 microns, from about 0.6 microns to about 4.5 microns, from about 0.6 microns to about 4 microns, from about 0.6 microns to about 3.5 microns, from about 0.6 microns to about 3 microns, from about 0.6 microns to about 2.5 microns, from about 0.6 microns to about 2 microns, from about 0.6 microns to about 1.5 microns, from about 0.6 microns to about 1 microns, from about 0.6 microns to about 0.9 microns, from about 0.6 microns to about 0.8 microns, from about 0.6 microns to about 0.7 microns, from about 0.8 microns to about 5 microns, from about 0.8 microns to about 4.5 microns, from about 0.8 microns to about 4 microns, from about 0.8 microns to about 3.5 microns, from about 0.8 microns to about 3 microns, from about 0.8 microns to about 2.5 microns, from about 0.8 microns to about 2 microns, from about 0.8 microns to about 1.5 microns, from about 0.8 microns to about 1 microns, from about 0.8 microns to about 0.9 microns, from about 0.9 microns to about 5 microns, from about 0.9 microns to about 4.5 microns, from about 0.9 microns to about 4 microns, from about 0.9 microns to about 3.5 microns, from about 0.9 microns to about 3 microns, from about 0.9 microns to about 2.5 microns, from about 0.9 microns to about 2 microns, from about 0.9 microns to about 1.5 microns, from about 0.9 microns to about 1 microns, from about 1 microns to about 5 microns, from about 1 microns to about 4.5 microns, from about 1 microns to about 4 microns, from about 1 microns to about 3.5 microns, from about 1 microns to about 3 microns, from about 1 microns to about 2.5 microns, from about 1 microns to about 2 microns, from about 1 microns to about 1.5 microns
In some embodiments, an amount of nicotine liquid formulation provided to said heater comprises a volume or a mass. In some embodiments the amount is quantified “per puff.” In some embodiments the amount comprises a volume of about 1 μL, about 2 μL, about 3 μL, about 4 μL, about 5 μL, about 6 μL, about 7 μL, about 8 μL, about 9 μL, about 10 μL, about 15 μL, about 20 μL, about 25 μL, about 30 μL, about 35 μL, about 40 μL, about 45 μL, about 50 μL, about 60 μL, about 70 μL, about 80 μL, about 90 μL, about 100 μL, or greater than about 100 μL. In some embodiments the amount comprises a mass of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or greater than about 100 mg.
The flavor of the constituent acid used in the salt formation may be a consideration in choosing the acid. A suitable acid may have minimal or no toxicity to humans in the concentrations used. A suitable acid may be compatible with the electronic cigarette components it contacts or could contact at the concentrations used. That is, such acid does not degrade or otherwise react with the electronic cigarette components it contacts or could contact. The odor of the constituent acid used in the salt formation may be a consideration in choosing a suitable acid. The concentration of the nicotine salt in the carrier may affect the satisfaction in the individual user. In some embodiments, the flavor of the formulation is adjusted by changing the acid. In some embodiments, the flavor of the formulation is adjusted by adding exogenous flavorants. In some embodiments, an unpleasant tasting or smelling acid is used in minimal quantities to mitigate such characteristics. In some embodiments, exogenous pleasant smelling or tasting acid is added to the formulation. Examples of salts which can provide flavor and aroma to the mainstream aerosol at certain levels include nicotine acetate, nicotine oxalate, nicotine malate, nicotine isovalerate, nicotine lactate, nicotine citrate, nicotine phenylacetate and nicotine myristate.
Nicotine liquid formulations may generate an inhalable aerosol upon heating in low temperature electronic vaporization device, i.e. an electronic cigarette. The amount of nicotine or nicotine salt aerosol inhaled may be user-determined. The user may, for example, modify the amount of nicotine or nicotine salt inhaled by adjusting his inhalation strength.
Formulations are described herein comprising two or more nicotine salts. In some embodiments, wherein a formulation comprises two or more nicotine salts, each individual nicotine salt is formed as described herein.
Nicotine liquid formulations, as used herein, refer to a single or mixture of nicotine salts with other suitable chemical components used for electronic cigarette, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the nicotine liquid formulation is stirred at ambient conditions for 20 minutes. In certain embodiments, the nicotine liquid formulation is heated and stirred at 55 C for 20 minutes. In certain embodiments, the nicotine liquid formulation is heated and stirred at 90 C for 60 minutes. In certain embodiments, the formulation facilitates administration of nicotine to an organism (e.g., lung).
The nicotine of nicotine liquid formulations provided herein is either naturally occurring nicotine (e.g., from extract of nicotineous species such as tobacco), or synthetic nicotine. In some embodiments, the nicotine is (−)-nicotine, (+)-nicotine, or a mixture thereof. In some embodiments, the nicotine is employed in relatively pure form (e.g., greater than about 80% pure, 85% pure, 90% pure, 95% pure, or 99% pure). In some embodiments, the nicotine for nicotine liquid formulation provided herein is “water clear” in appearance in order to avoid or minimize the formation of tarry residues during the subsequent salt formation steps.
Nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein, in some embodiments, have a nicotine concentration of about 0.5% (w/w) to about 20% (w/w), wherein the concentration is of nicotine weight to total solution weight, i.e. (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 20% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 18% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 15% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 4% (w/w) to about 12% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 18% (w/w), about 3% (w/w) to about 15% (w/w), or about 4% (w/w) to about 12% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 0.5% (w/w) to about 10% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 0.5% (w/w) to about 5% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 0.5% (w/w) to about 4% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 0.5% (w/w) to about 3% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 0.5% (w/w) to about 2% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 0.5% (w/w) to about 1% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 10% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 5% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 4% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 3% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 1% (w/w) to about 2% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 2% (w/w) to about 10% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 2% (w/w) to about 5% (w/w). In certain embodiments, nicotine liquid formulations provided herein have a nicotine concentration of about 2% (w/w) to about 4% (w/w). Certain embodiments provide a nicotine liquid formulation having a nicotine concentration of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% (w/w), or more, including any increments therein. Certain embodiments provide a nicotine liquid formulation having a nicotine concentration of about 5% (w/w). Certain embodiments provide a nicotine liquid formulation having a nicotine concentration of about 4% (w/w). Certain embodiments provide a nicotine liquid formulation having a nicotine concentration of about 3% (w/w). Certain embodiments provide a nicotine liquid formulation having a nicotine concentration of about 2% (w/w). Certain embodiments provide a nicotine liquid formulation having a nicotine concentration of about 1% (w/w). Certain embodiments provide a nicotine liquid formulation having a nicotine concentration of about 0.5% (w/w).
Nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein, in some embodiments, have a nicotine concentration of about 0.5% (w/w), 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w), about 18% (w/w), about 19% (w/w), or about 20% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 0.5% (w/w) to about 20% (w/w), from about 0.5% (w/w) to about 18% (w/w), from about 0.5% (w/w) to about 15% (w/w), from about 0.5% (w/w) to about 12% (w/w), from about 0.5% (w/w) to about 10% (w/w), from about 0.5% (w/w) to about 8% (w/w), from about 0.5% (w/w) to about 7% (w/w), from about 0.5% (w/w) to about 6% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about 0.5% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3% (w/w), or from about 0.5% (w/w) to about 2% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 1% (w/w) to about 20% (w/w), from about 1% (w/w) to about 18% (w/w), from about 1% (w/w) to about 15% (w/w), from about 1% (w/w) to about 12% (w/w), from about 1% (w/w) to about 0.10% (w/w), from about 1% (w/w) to about 8% (w/w), from about 1% (w/w) to about 7% (w/w), from about 1% (w/w) to about 6% (w/w), from about 1% (w/w) to about 5% (w/w), from about 1% (w/w) to about 4% (w/w), from about 1% (w/w) to about 3% (w/w), or from about 1% (w/w) to about 2% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 2% (w/w) to about 20% (w/w), from about 2% (w/w) to about 18% (w/w), from about 2% (w/w) to about 15% (w/w), from about 2% (w/w) to about 12% (w/w), from about 2% (w/w) to about 10% (w/w), from about 2% (w/w) to about 8% (w/w), from about 2% (w/w) to about 7% (w/w), from about 2% (w/w) to about 6% (w/w), from about 2% (w/w) to about 5% (w/w), from about 2% (w/w) to about 4% (w/w), or from about 2% (w/w) to about 3% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 3% (w/w) to about 20% (w/w), from about 3% (w/w) to about 18% (w/w), from about 3% (w/w) to about 15% (w/w), from about 3% (w/w) to about 12% (w/w), from about 3% (w/w) to about 10% (w/w), from about 3% (w/w) to about 8% (w/w), from about 3% (w/w) to about 7% (w/w), from about 3% (w/w) to about 6% (w/w), from about 3% (w/w) to about 5% (w/w), or from about 3% (w/w) to about 4% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 4% (w/w) to about 20% (w/w), from about 4% (w/w) to about 18% (w/w), from about 4% (w/w) to about 15% (w/w), from about 4% (w/w) to about 12% (w/w), from about 4% (w/w) to about 10% (w/w), from about 4% (w/w) to about 8% (w/w), from about 4% (w/w) to about 7% (w/w), from about 4% (w/w) to about 6% (w/w), or from about 4% (w/w) to about 5% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 5% (w/w) to about 20% (w/w), from about 5% (w/w) to about 18% (w/w), from about 5% (w/w) to about 15% (w/w), from about 5% (w/w) to about 12% (w/w), from about 5% (w/w) to about 10% (w/w), from about 5% (w/w) to about 8% (w/w), from about 5% (w/w) to about 7% (w/w), or from about 5% (w/w) to about 6% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 6% (w/w) to about 20% (w/w), from about 6% (w/w) to about 18% (w/w), from about 6% (w/w) to about 15% (w/w), from about 6% (w/w) to about 12% (w/w), from about 6% (w/w) to about 10% (w/w), from about 6% (w/w) to about 8% (w/w), or from about 6% (w/w) to about 7% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration from about 2% (w/w) to about 6% (w/w). In some embodiments, the nicotine liquid formulations used for a low temperature vaporization device, i.e. an electronic cigarette, described herein have a nicotine concentration of about 5% (w/w).
In some embodiments, the formulation further may comprise one or more flavorants. In some embodiments, the flavor of the formulation is adjusted by changing the acid. In some embodiments, the flavor of the formulation is adjusted by adding exogenous flavorants. In some embodiments, an unpleasant tasting or smelling acid is used in minimal quantities to mitigate such characteristics. In some embodiments, exogenous pleasant smelling or tasting acid is added to the formulation. Examples of salts which can provide flavor and aroma to the mainstream aerosol at certain levels include nicotine acetate, nicotine oxalate, nicotine malate, nicotine isovalerate, nicotine lactate, nicotine citrate, nicotine phenylacetate and nicotine myristate.
In some embodiments, the suitable acid for the nicotine liquid formulation has a vapor pressure >20 mmHg at 200° C., and is non-corrosive to the electronic cigarette or is non-toxic to humans. In some embodiments, the suitable acid for nicotine salt formation is selected from the group consisting of salicylic acid, formic acid, sorbic acid, acetic acid, benzoic acid, pyruvic acid, lauric acid, and levulinic acid.
In some embodiments, the suitable acid for the nicotine liquid formulation has a vapor pressure of about 20 to 200 mmHg at 200° C., and is non-corrosive to the electronic cigarette or is non-toxic to humans. In some embodiments, the suitable acid for nicotine salt formation is selected from the group consisting of salicylic acid, benzoic acid, lauric acid, and levulinic acid.
In some embodiments, the suitable acid for the nicotine liquid formulation has a melting point <160° C., a boiling point >160° C., at least a 50-degree difference between the melting point and the boiling point, and is non-corrosive to the electronic cigarette or is non-toxic to humans. In some embodiments, the suitable acid for nicotine salt formation has a melting point at least 40 degrees lower than the operating temperature of the electronic cigarette, a boiling point no more than 40 degrees lower than the operating temperature of the electronic cigarette, at least a 50-degree difference between the melting point and the boiling point, and is non-corrosive to the electronic cigarette or is non-toxic to humans; wherein the operating temperature is 200° C. In some embodiments, the suitable acid for nicotine salt formation is selected from the group consisting of salicylic acid, sorbic acid, benzoic acid, pyruvic acid, lauric acid, and levulinic acid.
In some embodiments, the suitable acid for the nicotine liquid formulation does not decompose at the operating temperature of the electronic cigarette. In some embodiments, the suitable acid for nicotine salt formation does not oxidize at the operating temperature of the electronic cigarette. In some embodiments, the suitable acid for nicotine salt formation does not oxidize at room temperature. In some embodiments, the suitable acid for nicotine salt formation does not provide an unpleasant taste. In some embodiments, the suitable acid for nicotine salt formation has good solubility in a liquid formulation for use in low temperature electronic vaporization device, i.e. an electronic cigarette.
Provided herein is low temperature electronic vaporization device, i.e. an electronic cigarette, 2 having a fluid storage compartment 4 comprising an embodiment nicotine liquid formulation of any embodiment described herein within the fluid storage compartment described herein. An embodiment is shown in
Provided herein is a cartomizer 18 for low temperature electronic vaporization device, i.e. an electronic cigarette, 2 having a fluid storage compartment 4 comprising an embodiment nicotine liquid formulation of any embodiment described herein within the fluid storage compartment described herein. The cartomizer 18 embodiment of
Various nicotine liquid formulations were prepared and added to a solution of 3:7 ratio by weight of propylene glycol (PG)/vegetable glycerin (VG), and mixed thoroughly. The examples shown below were used to make 10 g of each of the formulations. All procedures are scalable.
For example, in order to make nicotine liquid formulations with a final nicotine free base equivalent concentration of 2% (w/w), the following procedures were applied to each individual formulation.
For example, in order to make nicotine liquid formulations with a final nicotine free base equivalent concentration of 3% (w/w), the following procedures were applied to each individual formulation.
For example, in order to make nicotine liquid formulations with a final nicotine free base equivalent concentration of 4% (w/w), the following procedures were applied to each individual formulation.
For example, in order to make nicotine liquid formulations with a final nicotine free base equivalent concentration of 5% (w/w), the following procedures were applied to each individual formulation.
Various formulations comprising different nicotine salts can be prepared similarly, or different concentrations of the above-noted nicotine liquid formulations or other nicotine liquid formulations can be prepared as one of skill in the art would know to do upon reading the disclosure herein.
Various formulations comprising two or more nicotine salts can be prepared similarly in a solution of 3:7 ratio of propylene glycol (PG)/vegetable glycerin (VG). For example, 0.43 g (2.5% w/w nicotine) of nicotine levulinate salt and 0.34 g (2.5% w/w nicotine) of nicotine acetate salt are added to 9.23 g of PG/VG solution, to achieve a 5% w/w nicotine liquid formulation.
Also provided is another exemplary formulation. For example, 0.23 g (1.33% w/w nicotine) of nicotine benzoate salt (molar ratio 1:1 nicotine/benzoic acid), 0.25 g (1.33% w/w nicotine) of nicotine salicylate salt (molar ratio 1:1 nicotine/salicylic acid) and 0.28 g (1.34% w/w nicotine) of nicotine pyruvate salt (molar ratio 1:2 nicotine/pyruvic acid) are added to 9.25 g of PG/VG solution, to achieve a 5% w/w nicotine liquid formulation.
Exemplary formulations of nicotine levulinate, nicotine benzoate, nicotine succinate, nicotine salicylate, nicotine malate, nicotine pyruvate, nicotine citrate, nicotine freebase, and a control of propylene glycol were prepared as noted in Example 1 in 3% w/w solutions and were administered in the same fashion by low temperature electronic vaporization device, i.e. an electronic cigarette, to the same human subject. About 0.5 mL of each solution was loaded into an “eRoll” cartridge atomizer (joyetech.com) to be used in the study. The atomizer was then attached to an “eRoll” electronic cigarette (same manufacturer). The operating temperature was from about 150° C. to about 250° C., or from about 180° C. to about 220° C.
Heart rate measurements were taken for 6 minutes; from 1 minute before start of puffing, for 3 minutes during puffing, and continuing until 2 minutes after end of puffing. The test participant took 10 puffs over 3 minutes in each case. The base heart rate was the average heart rate over the first 1 minute before start of puffing. Heart rate after puffing started was averaged over 20-second intervals. Puffing (inhalation) occurred every 20 seconds for a total of 3 minutes. Normalized heart rate was defined as the ratio between individual heart rate data point and the base heart rate. Final results were presented as normalized heart rate, shown for the first 4 minutes in
In addition to the heart rate study shown in Example 2, nicotine liquid formulations (using 3% w/w nicotine liquid formulations as described in Example 1) were used to conduct a satisfaction study using 11 test participants. The test participant, low temperature electronic vaporization device. i.e. an electronic cigarette, and/or traditional cigarette user, was required to have no nicotine intake for at least 12 hour % before the test. The participant took 10 puffs using low temperature electronic vaporization device, i.e. an electronic cigarette, (same as used in Example 2) over 3 minutes in each case, and then was asked to rate the level of physical and emotional satisfaction he or she felt on a scale of 0-10, with 0 being no physical or emotional satisfaction. Using the ratings provided for each formulation, the formulations were then ranked from 1-8 with 1 having the highest rating and 8 having the lowest rating. The rankings for each acid were then averaged over the 11 participant to generate average rankings in Table 1. Nicotine benzoate, nicotine pyruvate, nicotine salicylate, and nicotine levulinate all performed well, followed by nicotine malate, nicotine succinate, and nicotine citrate.
Based on the Satisfaction Study, the nicotine salts formulations with acids having vapor pressure ranges between >20 mmHg @200° C., or 20-200 mmHg @200° C., or 100-300 mmHg @200° C. provide more Satisfaction than the rest (except the pyruvic acid which has boiling point of 165° C.). For reference, it has been determined that salicylic acid has a vapor pressure of about 135.7 mmHg @200° C., benzoic acid has a vapor pressure of about 171.7 mmHg @200° C., and levulinic acid has a vapor pressure of about 149 mmHg @200° C.
Further, based on the Satisfaction Study, nicotine liquid formulations, for example a nicotine salt liquid formulations, comprising acids that degrade at the operating temperature of the device (i.e. malic acid) were ranked low. However, nicotine liquid formulations, for example a nicotine salt liquid formulations, comprising acids that do not degrade at the operating temperature of the device (i.e. benzoic acid) were ranked high. Thus, acids prone to degradation at the operating temperature of the device are less favorable compared to acids not prone to degradation.
A solution of nicotine levulinate in glycerol comprising nicotine salt used: 1.26 g (12.6% w/w) of 1:3 nicotine levulinate 8.74 g (87.4% w/w) of glycerol—Total weight 10.0 g.
Neat nicotine levulinate was added to the glycerol, and mixed thoroughly. L-Nicotine has a molar mass of 162.2 g, and levulinic acid molar mass is 116.1 g. In a 1:3 molar ratio, the percentage of nicotine in nicotine levulinate by weight is given by: 162.2 g/(162.2 g+(3×116.1 g))=31.8% (w/w).
A solution of free base nicotine in glycerol comprising 0.40 g (4.00% w/w) of L-nicotine was dissolved in 9.60 g (96.0% w/w) of glycerol and mixed thoroughly.
Both formulations (TF1 and TF2) were administered in the same fashion by low temperature electronic vaporization device, i.e. an electronic cigarette, to the same human subject; about 0.6 mL of each solution was loaded into “eGo-C” cartridge atomizer (joyetech.com). The atomizer was then attached to an “Vic” electronic cigarette (same manufacturer). This model of electronic cigarette allows for adjustable voltage, and therefore wattage, through the atomizer. The operating temperature of the electronic cigarette is from about 150° C. to about 250° C., or from about 180° C. to about 220° C.
The atomizer in both cases has resistance 2.4 ohms, and the electronic cigarette was set to 4.24V, resulting in 7.49 W of power. (P=V{circumflex over ( )}2/R)
Heart rate was measured in a 30-second interval for ten minutes from start of puffing. Test participants took 10 puffs over 3 minutes in each case (solid line (2nd highest peak): cigarette, dark dotted line (highest peak): test formulation 1 (TF1—nicotine liquid formulation), light dotted line: test formulation 2 (TF2—nicotine liquid formulation). Comparison between cigarette, TF1, and TF2 is shown in
It is clearly shown in
In addition, the data appears to correlate well with the previous findings shown in
As previously noted in the Satisfaction Study, the nicotine salts formulations with acids having vapor pressures between 20-300 mmHg @200° C. provide more satisfaction than the rest, with the exception of the nicotine liquid formulation made with pyruvic acid, which has a boiling point of 165° C., as noted in
Tmax—Time to maximum blood concentration: Based on the results established herein, a user of low temperature electronic vaporization device, i.e. an electronic cigarette, comprising the nicotine liquid formulation will experience a comparable rate of physical and emotional satisfaction from using a formulation comprising a mixture of nicotine salts prepared with an appropriate acid at least 1.2× to 3× faster than using a formulation comprising a freebase nicotine. As illustrated in
Again this would not be inconsistent with the data from
Further, when considering peak satisfaction levels (achieved at approximately 120 seconds from the initiation of puffing (time=0) and looking at the slope of the line for a normalized heart rate, the approximate slope of those nicotine liquid formulations that exceeded the freebase nicotine liquid formulation range between 0.0054 hrn/sec and 0.0025 hrn/sec. By comparison, the slope of the line for the freebase nicotine liquid formulation is about 0.002. This would suggest that the concentration of available nicotine will be delivered to the user at a rate that is between 1.25 and 2.7 times faster than a freebase formulation.
In another measure of performance; Cmax—Maximum blood nicotine concentration; it is anticipated that similar rates of increase will be measured in blood nicotine concentration, as those illustrated above. That is, it was anticipated based on the findings herein, and unexpected based on the art known to date, that there would be comparable Cmax between the common cigarette and certain nicotine liquid formulations, but with a lower Cmax in a freebase nicotine solution.
Similarly, anticipated based on the findings herein, and unexpected based on the art known to date, that certain nicotine liquid formulations would have higher rate of nicotine uptake levels in the blood at early time periods. Indeed, Example 8 presents data for two salt formulations consistent with these predictions which were made based on the findings and tests noted herein, and unexpected compared to the art available to date.
Exemplary formulations of nicotine levulinate, nicotine benzoate, nicotine succinate, nicotine salicylate, nicotine malate, nicotine pyruvate, nicotine citrate, nicotine sorbate, nicotine laurate, nicotine freebase, and a control of propylene glycol are prepared as noted in Example 1 and are administered in the same fashion by low temperature electronic vaporization device, i.e. an electronic cigarette, to the same human subject. About 0.5 mL of each solution is loaded into an “eRoll” cartridge atomizer (joyetech.com) to be used in the study. The atomizer is then attached to an “eRoll” electronic cigarette (same manufacturer). The operating temperature of the electronic cigarette is from about 150° C. to about 250° C., or from about 180° C. to about 220° C.
Heart rate measurements are taken for 6 minutes; from 1 minute before start of puffing, for 3 minutes during puffing, and continuing until 2 minutes after end of puffing. The test participant takes 10 puffs over 3 minutes in each case. The base heart rate is the average heart rate over the first 1 minute before start of puffing. Heart rate after puffing started is averaged over 20-second intervals. Normalized heart rate is defined as the ratio between individual heart rate data point and the base heart rate. Final results are presented as normalized heart rate.
Blood plasma testing was conducted on 24 subjects (n=24). Four test articles were used in this study: one reference cigarette and three nicotine liquid formulations used in low temperature electronic vaporization device, i.e. an electronic cigarette, having an operating temperature of the electronic cigarette from about 150° C. to about 250° C., or from about 180° C. to about 220° C. The reference cigarette was Pall Mall (New Zealand). Three nicotine liquid formulations were tested in the electronic cigarette: 2% free base (w/w based on nicotine), 2% benzoate (w/w based on nicotine, 1:1 molar ratio of nicotine to benzoic acid), and 2% malate (w/w based on nicotine, 1:2 molar ratio of nicotine to malic acid). The three nicotine liquid formulations were liquid formulations prepared as described in Example 1.
The concentration of nicotine in each of the formulations was confirmed using UV spectrophotometer (Cary 60, manufactured by Agilent). The sample solutions for UV analysis were made by dissolving 20 mg of each of the formulations in 20 mL 0.3% HCl in water. The sample solutions were then scanned in UV spectrophotometer and the characteristic nicotine peak at 259 nm was used to quantify nicotine in the sample against a standard solution of 19.8 μg/mL nicotine in the same diluent. The standard solution was prepared by first dissolving 19.8 mg nicotine in 10 mL 0.3% HCl in water followed by a 1:100 dilution with 0.3% HCl in water. Nicotine concentrations reported for all formulations were within the range of 95%-105% of the claimed concentrations
All subjects were able to consume 30-55 mg of the liquid formulation of each tested blend using the electronic cigarette.
Literature results: C. Bullen et al, Tobacco Control 2010, 19:98-103
Cigarette (5 min adlib, n=9): Tmax=14.3 (8.8-19.9), Cmax=13.4 (6.5-20.3)
1.4% E-cig (5 min adlib, n=8): Tmax=19.6 (4.9-34.2), Cmax=1.3 (0.0-2.6)
Nicorette Inhalator (20 mg/20 min, n=10): Tmax=32.0 (18.7-45.3), Cmax=2.1 (1.0-3.1)
Estimated Cmax of 2% nicotine blends:
Cmax=Mass consumed*Strength*Bioavailability/(Vol of Distribution*Body Weight)=40 mg*2%*80%/(2.6 L/kg*75 kg)=3.3 ng/ml,
Estimated Cmax of 4% nicotine blends:
Cmax=Mass consumed*Strength*Bioavailability/(Vol of Distribution*Body Weight)=40 mg*4%*80%/(2.6 L/kg*75 kg)=6.6 ng/mL.
Pharmacokinetic profiles of the blood plasma testing are shown in
Comparison of and Cmax and Tmax of the three nicotine liquid formulations and reference cigarette are shown in
The nicotine liquid formulation contents and properties of the acids tested provide a plausible explanation as to how the blood plasma testing data corroborate the lower ranking of malic acid compared to benzoic acid as described in Example 1. In the blood plasma experiments the nicotine malate formulation comprised a 1:2 molar ratio of nicotine to malic acid and the nicotine benzoate formulation comprised a 1:1 molar ratio of nicotine to benzoic acid. As explained below, extra malic acid is needed to aerosolize nicotine because malic acid degrades at the operating temperature of the electronic cigarette. Thus, it is probable that the aerosol generated using malic acid comprises degradation products, which could result in an unfavorable experience for a user thus resulting in a lower ranking. For example, an unfavorable experience comprises a flavor, a nervous response, and/or an irritation of one or more of an oral cavity, an upper respiratory tract, and/or the lungs.
Blood plasma testing is conducted on 24 subjects (n=24). Eight test articles are used in this study: one reference cigarette and seven blends delivered to a user in low temperature electronic vaporization device, i.e. an electronic cigarette, as an aerosol. The operating temperature of the electronic cigarette is from about 150° C. to about 250° C., or from about 180° C. to about 220° C. The reference cigarette is Pall Mall (New Zealand). Seven blends are tested: 2% free base, 2% benzoate, 4% benzoate, 2% citrate, 2% malate, 2% salicylate, and 2% succinate. The seven blends are liquid formulations prepared according to protocols similar to that described infra and in Example 1.
All subjects are to consume 30-55 mg of the liquid formulation of each tested blend. Ten puffs are to be taken at 30 sec intervals starting at time=0 and continuing for 4.5 minutes. Blood plasma testing is to occur for at least 60 minutes from the first puff (t=0) Pharmacokinetic data (e.g., Cmax, Tmax, AUC) for nicotine in the plasma of users are obtained at various time periods during those 60 minutes, along with rates of nicotine absorption within the first 90 seconds for each test article.
Blood plasma testing is conducted on twenty-four subjects (n=24). Eleven test articles are used in this study: one reference cigarette and ten blends delivered to a user in low temperature electronic vaporization device, i.e. an electronic cigarette, as an aerosol. The reference cigarette is Pall Mall (New Zealand). The operating temperature of the electronic cigarette is from about 150° C. to about 250° C., or from about 180° C. to about 220° C. Ten blends are tested: 2% free base, 2% benzoate, 2% sorbate, 2% pyruvate, 2% laurate, 2% levulinate, 2% citrate, 2% malate, 2% salicylate, and 2% succinate. The ten blends are liquid formulations prepared according to protocols similar to that described infra and in Example 1.
All subjects are to consume 30-55 mg of the liquid formulation of each tested blend. Ten puffs are to be taken at 30 sec intervals starting at time=0 and continuing for 4.5 minutes. Blood plasma testing is to occur for at least 60 minutes from the first puff (t=0). Pharmacokinetic data (e.g., Cmax, Tmax, AUC) for nicotine in the plasma of users are obtained at various time periods during those 60 minutes, along with rates of nicotine absorption within the first 90 seconds for each test article.
Blood plasma testing is conducted on twenty-four subjects (n=24). Twenty-one test articles are used in this study: one reference cigarette and twenty blends delivered to a user in low temperature electronic vaporization device, i.e. an electronic cigarette, as an aerosol. The reference cigarette is Pall Mall (New Zealand). The operating temperature of the electronic cigarette is from about 150° C. to about 250° C., or from about 180° C. to about 220° C. Twenty blends are tested: 2% free base, 4% free base, 2% benzoate, 4% benzoate, 2% sorbate, 4% sorbate, 2% pyruvate, 4% pyruvate, 2% laurate, 4% laurate, 2% levulinate, 4% levulinate, 2% citrate, 4% citrate, 2% malate, 4% malate, 2% salicylate, 4% salicylate, 2% succinate, and 4% succinate. The twenty blends are liquid formulations prepared according to protocols similar to that described infra and in Example 1.
All subjects are to consume 30-55 mg of the liquid formulation of each tested blend. Ten puffs are to be taken at 30 sec intervals starting at time=0 and continuing for 4.5 minutes. Blood plasma testing is to occur for at least 60 minutes from the first puff (t=0). Pharmacokinetic data (e.g., Cmax, Tmax, AUC) for nicotine in the plasma of users are obtained at various time periods during those 60 minutes, along with rates of nicotine absorption within the first 90 seconds for each test article.
Blood plasma testing is conducted on twenty-four subjects (n=24). Twenty-one test articles are used in this study: one reference cigarette and twenty blends delivered to a user in low temperature electronic vaporization device, i.e. an electronic cigarette, as an aerosol. The reference cigarette is Pall Mall (New Zealand). The operating temperature of the electronic cigarette is from about 150° C. to about 250° C., or from about 180° C. to about 220° C. Twenty blends are tested: 2% free base, 1% free base, 2% benzoate, 1% benzoate, 2% sorbate, 1% sorbate, 2% pyruvate, 1% pyruvate, 2% laurate, 1% laurate, 2% levulinate, 1% levulinate, 2% citrate, 1% citrate, 2% malate, 1% malate, 2% salicylate, 1% salicylate, 2% succinate, and 1% succinate. The twenty blends are liquid formulations prepared according to protocols similar to that described infra and in Example 1.
All subjects are to consume 30-55 mg of the liquid formulation of each tested blend. Ten puffs are to be taken at 30 sec intervals starting at time=0 and continuing for 4.5 minutes. Blood plasma testing is to occur for at least 60 minutes from the first puff (t=0). Pharmacokinetic data (e.g., Cmax, Tmax, AUC) for nicotine in the plasma of users are obtained at various time periods during those 60 minutes, along with rates of nicotine absorption within the first 90 seconds for each test article.
The experimental system comprised a glass bubbler (bubbler-1), a Cambridge filter pad, and 2 glass bubblers (trap-1 and trap-2, connected in sequence) to trap any volatiles that pass through the filter pad. Low temperature electronic vaporization device, i.e. an electronic cigarette, was connected to the inlet of bubbler 1, and was activated by a smoking machine connected to the outlet of trap 2 under designed puffing regime. The puffing regime comprised: Number of puffs per sample=30, puff size=60 cc, puff duration=4 s. The trap solvent comprised 0.3% HCl in water. The nicotine liquid formulations tested were: freebase nicotine, nicotine benzoate at molar ratios of nicotine to acid of 1:0.4, 1:0.7, 1:1, and 1:1.5, and nicotine malate at molar ratios of nicotine to acid of 1:0.5 and 1:2. The formulations were generated using the procedures described in Example 1. In the experimental system gaseous (i.e. vapor) analytes were capture by the bubblers.
The procedure comprised:
The total recovered amount of each analyte (nicotine, benzoic acid, and malic acid) was calculated as the sum of the assayed amount from all parts. No analyte was detected in trap-1 or trap-2. The percent recovery was calculated by dividing the total recovered amount by the theoretical amount generated by the electronic cigarette. Table 3 shows the percent recovery of nicotine in nicotine freebase liquid formulations, nicotine benzoate liquid formulations, and nicotine malate liquid formulations. Table 3 also shows the percent recovery of benzoic acid in nicotine benzoate liquid formulations and the percent recovery of malic acid in nicotine malate liquid formulations.
The percent recovery of malic acid was significantly lower than that of nicotine and benzoic acid, with a larger variability across sample replicates. Malic acid was reported to thermally decompose at 150° C. a temperature that is lower than common electronic cigarette operating temperature. The low recovery of malic acid found in the aerosol agrees with the thermal instability of malic acid. This leads to low effective nicotine to malic ratio in the aerosol compared to the ratio in the nicotine liquid formulation. Thus the protonation state of nicotine is also lower in the aerosol which will result in effectively less nicotine being present in the aerosol generated with a nicotine malate liquid formulation. Lower nicotine recovery in the case of freebase nicotine liquid formulation compared to the nicotine liquid formulations might result from the sample collection and assay procedure that small portion of gaseous nicotine escaped from the smoking system.
Volatile Nicotine in Aerosol
The amount of nicotine in the aerosol exiting the a low temperature vaporization device, i.e. an electronic cigarette, was examined by calculating percent nicotine captured in bubbler-1 compared to the total recovered nicotine. Benzoic acid is expected to reside in the particles (i.e. liquid droplets) in aerosol as it is non-volatile. Benzoic acid was thus used as a particle marker for nicotine since it is expected to protonate nicotine at 1:1 molar ratio, which will result in nicotine being present in the aerosol, in some embodiments in a non-gas phase of the aerosol. The amount of aerosolized nicotine was calculated by comparing the difference between the amount of benzoic acid captured in bubbler-1 and the amount of benzoic acid in the nicotine liquid formulation.
A linear relationship was found between the amount of nicotine captured in bubbler-1 to the molar ratio of benzoic acid to nicotine in the nicotine liquid formulations (
Theoretically malic acid, which is diprotic, will protonate nicotine at a 0.5:1 molar ratio of malic acid to nicotine. However, malic acid is known to degrade at the operating temperature of the electronic cigarette resulting in a low transfer efficiency from the liquid formulation to the aerosol. Thus, given the low transfer efficiency of malic acid, the effective nicotine to malic ratio in the aerosol was 0.23 when generated using the nicotine liquid formulation comprising a molar ratio of 1:0.5 of nicotine to malic acid and 0.87 when generated using the nicotine liquid formulation comprising a molar ratio of 1:2 of nicotine to malic acid. As expected, the percent acid captured in bubbler-1 when using a nicotine liquid formulation comprising a 1:0.5 nicotine to malic acid molar ratio fell between the percent acid recovered when using nicotine liquid formulations comprising a nicotine to benzoic acid molar ratio of 1:0.4 and 1:0.7. The nicotine liquid formulation comprising a 1:2 molar ratio of nicotine to malic acid delivered an aerosol comprising a molar ratio of nicotine to malic acid of 1:0.87, thus containing excess malic acid than needed to fully protonate nicotine, leaving only 14.7% nicotine captured in bubbler-1 (
Aerosolized nicotine that stays in particles is more likely to travel down to alveoli and get into the blood of a user. Gaseous nicotine has greater chance to deposit in upper respiratory tract and be absorbed at a different rate from deep lung gas exchange region. Thus, using nicotine liquid formulations with a molar ratio of 1:1 nicotine to benzoic acid or 1:2 nicotine to malic acid, about the same molar amount of aerosolized nicotine in the non-gas phase would be delivered to a user's lungs. This is in agreement with the Tmax data described in Example 8.
The experimental system comprised a glass bubbler (bubbler-1), a Cambridge filter pad, and 2 glass bubblers (trap-1 and trap-2, connected in sequence) to trap any volatiles that pass through the filter pad. Low temperature electronic vaporization device, i.e. an electronic cigarette, was connected to the inlet of bubbler 1, and was activated by a smoking machine connected to the outlet of trap 2 under designed puffing regime. The puffing regime comprised: Number of puffs per sample=30, puff size=60 cc, puff duration=4 s. The trap solvent comprised 0.3% HCl in water. The nicotine liquid formulations tested were: freebase nicotine, nicotine benzoate at molar ratios of nicotine to acid of 1:0.4, 1:0.7, 1:1, and 1:1.5, and nicotine malate at molar ratios of nicotine to acid of 1:0.5 and 1:2. The formulations were generated using the procedures described in Example 1. In the experimental system gaseous (i.e. vapor) analytes were capture by the bubblers.
The procedure comprised:
The amount of nicotine in the aerosol exiting the a low temperature vaporization device, i.e. an electronic cigarette, was examined by calculating percent nicotine captured in bubbler-1 compared to the total recovered nicotine. Benzoic acid is expected to reside in the particles (i.e. liquid droplets) in aerosol as it is non-volatile. Benzoic acid was thus used as a particle marker for nicotine since it is expected to protonate nicotine at 1:1 molar ratio, which will result in nicotine being present in the aerosol, in some embodiments in a non-gas phase of the aerosol. The amount of aerosolized nicotine was calculated by comparing the difference between the amount of benzoic acid captured in bubbler-1 and the amount of benzoic acid in the nicotine liquid formulation.
A linear relationship was found between the amount of nicotine captured in bubbler-1 to the molar ratio of benzoic acid to nicotine in the nicotine liquid formulations (
Benzoic acid and succinic acid have similar boiling points, 249° C. for benzoic acid and 235° C. for succinic acid, and both acids melt and evaporate without decomposition. Thus a nicotine liquid formulation generated using either acid should behave similarly and generate an aerosol with about the same molar amount of nicotine in aerosol. Thus, it is likely that the same total amount of acid will be collected when using either acid in the nicotine liquid formulation. Stated differently, it is likely that about the same percentage of succinic acid would be recovered when using a nicotine succinate liquid formulation in the electronic cigarette as compared to the percentage benzoic acid recovered when using a nicotine benzoate liquid formulation as described in Example 13. As such, the same percentage of nicotine will also likely be captured in bubbler-1 when using either succinic acid or benzoic acid in a nicotine liquid formulation.
Here different molar ratios of acidic functional groups to moles of nicotine were investigated. Since succinic acid is a diprotic acid, it was expected that a molar ratio of 1:0.25 of nicotine to succinic acid would result in the same amount of acid captured in bubbler-1 as captured using a 1:0.5 molar ratio of nicotine to benzoic acid. Further, it was expected that a molar ratio of 1:0.5 of nicotine to succinic acid would result in about the same amount of nicotine captured in bubbler-1 as captured using a 1:1 molar ratio of nicotine to benzoic acid. As was expected about the same percentage of acid was collected in bubbler-1 when using a molar ratio of 1:0.25 of nicotine to succinic acid in the nicotine liquid formulation as would be expected based on the amount of nicotine captured using a 1:0.4 and 1:0.7 nicotine to benzoic acid molar ratio nicotine liquid formulation (
Thus, since succinic acid is diprotic, one mole of succinic acid likely protonates two moles of nicotine thus stabilizing the two moles of nicotine in the aerosol. Stated differently, half the molar amount of succinic acid in a nicotine liquid formulation used in low temperature electronic vaporization device, i.e. an electronic cigarette, is needed to fully protonate nicotine and stabilize nicotine in the aerosol compared to using benzoic acid in a nicotine liquid formulation used in low temperature electronic vaporization device, i.e. an electronic cigarette. Moreover, it is plausible that succinic acid was ranked low in the satisfaction study described in Example 3 because excess succinic acid (1:2 molar ratio of nicotine to succinic acid) was included in the formulation and thus it is likely the excess succinic acid was delivered to the user thus resulting in an unfavorable experience for the user. For example, an unfavorable experience comprises a flavor, a nervous response, and/or an irritation of one or more of an oral cavity, an upper respiratory tract, and/or the lungs.
Further understanding may be gained through contemplation of the numbered embodiments below.
Although preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be employed in practicing the invention. It is intended that the following embodiments define the scope of the invention and that methods and structures within the scope of these embodiments and their equivalents be covered thereby.
This application is a continuation of U.S. application Ser. No. 16/585,382 filed Sep. 27, 2019, issued as U.S. Pat. No. 11,510,433, which is a continuation of U.S. application Ser. No. 15/101,303 filed Jun. 2, 2016, issued as U.S. Pat. No. 10,463,069, which is a Section 371 US national phase of International Application No. PCT/US2014/64690 filed Nov. 7, 2014, which claims the benefit of U.S. Provisional Application Ser. No. 61/912,507, filed Dec. 5, 2013, which is incorporated herein by reference in its entirety.
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| Number | Date | Country | |
|---|---|---|---|
| 20230157347 A1 | May 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61912507 | Dec 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16585382 | Sep 2019 | US |
| Child | 17993459 | US | |
| Parent | 15101303 | US | |
| Child | 16585382 | US |
