Nicotine liquid formulations for aerosol devices and methods thereof

Abstract

The invention relates to nicotine liquid formulations for aerosol devices and methods thereof. A nicotine liquid formulation comprising nicotine, an acid, and a biologically acceptable liquid carrier wherein heating an amount of the nicotine liquid formulation using a low temperature electronic vaporizing device, i.e. An electronic cigarette, produces an inhalable aerosol, and wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

Description

[0001] This application is a divisional application of an application with an application date of November 7, 2014, application number 202110396804.8, and invention name “Nicotine liquid preparation for aerosol device and method thereof”.

[0002] The application with the application date of November 7, 2014, the application number of 202110396804.8, and the invention name of “Nicotine liquid preparation for aerosol device and method thereof” is a divisional application of the application with the application date of November 7, 2014, the application number of 201480074976.1, and the invention name of “Nicotine liquid preparation for aerosol device and method thereof”.

[0003] Cross-references

[0004] This application claims the benefit of U.S. Provisional Patent Application Serial No. 61 / 912,507, filed December 5, 2013, which is incorporated herein by reference in its entirety. SUMMARY OF THE INVENTION

[0006] In certain aspects, provided herein is a method for generating an inhalable aerosol comprising nicotine for delivery to a user, the method comprising using a low-temperature electronic vaporization device, i.e., an electronic cigarette, the low-temperature electronic vaporization device comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises the nicotine, an acid, and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing an amount of the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0007] In certain embodiments, the amount includes about 4 μL of the nicotine liquid formulation. In certain embodiments, the amount includes about 4.5 mg of the nicotine liquid formulation. In certain embodiments, the concentration of the nicotine is from about 0.5% (w / w) to about 20% (w / w). In certain embodiments, the molar ratio of the acid to the nicotine is from about 0.25:1 to about 4:1. In certain embodiments, the acid includes one or more acidic functional groups, and wherein the molar ratio of the acidic functional group to the nicotine is from about 0.25:1 to about 4:1. In certain embodiments, the acid and the nicotine form a nicotine salt. In certain embodiments, the nicotine is stabilized in the inhalable aerosol in the form of the nicotine salt. In certain embodiments of the method described herein, the inhalable aerosol includes one or more of the nicotine, the acid, the carrier, and the nicotine salt. In certain embodiments of the methods described herein, one or more particles in the inhalable aerosol are sized for delivery to the alveoli in the lungs of the user. In certain embodiments of the methods described herein, the acid is selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, succinic acid, and citric acid. In certain embodiments of the methods described herein, the acid is selected from the group consisting of benzoic acid, pyruvic acid, and salicylic acid. In certain embodiments of the methods described herein, the acid is benzoic acid. In certain embodiments of the methods described herein, the concentration is from about 2% (w / w) to about 6% (w / w). In certain embodiments of the methods described herein, the concentration is about 5% (w / w). In certain embodiments of the methods described herein, the biologically acceptable liquid carrier comprises from about 20% to about 50% propylene glycol and from about 80% to about 50% vegetable glycerin. In certain embodiments of the methods described herein, the biologically acceptable liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin. In certain embodiments of the methods described herein, the heater heats the amount of the nicotine liquid formulation from about 150°C to about 250°C. In certain embodiments of the methods described herein, the heater heats the amount of the nicotine liquid formulation from about 180°C to about 220°C. In certain embodiments of the methods described herein, the heater heats the amount of the nicotine liquid formulation to about 200°C. In certain embodiments of the methods described herein, the nicotine liquid formulation further comprises an additional acid selected from the group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid. In certain embodiments of the methods described herein, the additional acid forms an additional nicotine salt. In certain embodiments of the methods described herein, at least about 60% to about 90% of the acid in the amount is in the aerosol.In certain embodiments of the methods described herein, at least about 70% to about 90% of the acid in the amount is in the aerosol. In certain embodiments of the methods described herein, at least about 80% to about 90% of the acid in the amount is in the aerosol. In certain embodiments of the methods described herein, more than about 90% of the acid in the amount is in the aerosol.

[0008] In some aspects, provided herein is a method for generating an inhalable aerosol comprising nicotine for delivery to a user, the method comprising using a low temperature electronic vaporization device, i.e., an electronic cigarette, comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises: the nicotine at a concentration from about 0.5% (w / w) to about 20% (w / w); an acid at a molar ratio of the acid to the 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 the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0009] In certain aspects, provided herein is a method for generating an inhalable aerosol comprising nicotine for delivery to a user, the method comprising using a 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 the acid to the 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 the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0010] In some aspects, provided herein is a method for generating an inhalable aerosol comprising nicotine for delivery to a user, the method comprising using a 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 the acid to the 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 the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 90% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0011] In certain aspects, provided herein is a method for generating an inhalable aerosol comprising nicotine for delivery to a user, the method comprising using a 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 about 1:1 of the benzoic acid to the nicotine; and a biologically acceptable liquid carrier; wherein using the electronic cigarette comprises: providing a certain amount of the nicotine liquid formulation to the heater; the heater forms an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 90% of the benzoic acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0012] In some aspects, provided herein is a cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment comprising a nicotine formulation, the nicotine formulation comprising the nicotine, an acid, and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing an amount of the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0013] In certain embodiments of the cartridges described herein, the amount includes about 4 μL of the nicotine liquid formulation. In certain embodiments of the cartridges described herein, the amount includes about 4.5 mg of the nicotine liquid formulation. In certain embodiments of the cartridges described herein, the concentration of the nicotine is from about 0.5% (w / w) to about 20% (w / w). In certain embodiments of the cartridges described herein, the molar ratio of the acid to the nicotine is from about 0.25:1 to about 4:1. In certain embodiments of the cartridges described herein, the acid comprises one or more acidic functional groups, and wherein the molar ratio of the acidic functional groups to the nicotine is from about 0.25:1 to about 4:1. In certain embodiments of the cartridges described herein, the acid and the nicotine form a nicotine salt. In certain embodiments of the cartridges described herein, the nicotine is stabilized in the inhalable aerosol in the form of the nicotine salt. In certain embodiments of the cartridges described herein, the inhalable aerosol comprises one or more of the nicotine, the acid, the carrier, and the nicotine salt. In certain embodiments of the cartridges described herein, one or more particles in the inhalable aerosol are sized for delivery to the alveoli in the lungs of the user. In certain embodiments of the cartridges described herein, the acid is selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, succinic acid, and citric acid. In certain embodiments of the cartridges described herein, the acid is selected from the group consisting of benzoic acid, pyruvic acid, and salicylic acid. In certain embodiments of the cartridges described herein, the acid is benzoic acid. In certain embodiments of the cartridges described herein, the concentration is from about 2% (w / w) to about 6% (w / w). In certain embodiments of the cartridges described herein, the concentration is about 5% (w / w). In certain embodiments of the cartridges described herein, the biologically acceptable liquid carrier comprises from about 20% to about 50% propylene glycol and from about 80% to about 50% vegetable glycerin. In certain embodiments of the cartridges described herein, the biologically acceptable liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin. In certain embodiments of the cartridges described herein, the heater heats the amount of the nicotine liquid formulation from about 150°C to about 250°C. In certain embodiments of the cartridges described herein, the heater heats the amount of the nicotine liquid formulation from about 180°C to about 220°C. In certain embodiments of the cartridges described herein, the heater heats the amount of the nicotine liquid formulation to about 200°C. In certain embodiments of the cartridges described herein, the nicotine liquid formulation further comprises an additional acid selected from the group consisting of: benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.In certain embodiments of the cartridges described herein, the additional acid forms an additional nicotine salt. In certain embodiments of the cartridges described herein, at least about 60% to about 90% of the acid in the amount is in the aerosol. In certain embodiments of the cartridges described herein, at least about 70% to about 90% of the acid in the amount is in the aerosol. In certain embodiments of the cartridges described herein, at least about 80% to about 90% of the acid in the amount is in the aerosol. In certain embodiments of the cartridges described herein, more than about 90% of the acid in the amount is in the aerosol.

[0014] In some aspects, provided herein is a cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment comprising a nicotine formulation, the nicotine formulation comprising: the nicotine at a concentration from about 0.5% (w / w) to about 20% (w / w); an acid at a molar ratio of the acid to the 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 the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0015] In some aspects, provided herein is a cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment comprising a nicotine formulation, the nicotine formulation comprising: the nicotine at a concentration from about 2% (w / w) to about 6% (w / w); an acid at a molar ratio of the acid to the 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 the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0016] In some aspects, provided herein is a cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment comprising a nicotine formulation, the nicotine formulation comprising: the nicotine at a concentration from about 2% (w / w) to about 6% (w / w); an acid at a molar ratio of the acid to the 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 the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 90% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0017] In some aspects, provided herein is a cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment comprising a nicotine formulation, the nicotine formulation comprising: the nicotine at a concentration from about 2% (w / w) to about 6% (w / w); benzoic acid at a molar ratio of the benzoic acid to the nicotine of about 1:1; and a biologically acceptable liquid carrier; wherein using the electronic cigarette comprises: providing an amount of the nicotine liquid formulation to the heater; the heater forming an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 90% of the benzoic acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0018] In some aspects, provided herein is a formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a heater, the formulation comprising nicotine, an acid, and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing a certain amount of the nicotine liquid formulation to the heater; the heater forms an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0019] In certain embodiments of the formulations described herein, the amount includes about 4 μL of the nicotine liquid formulation. In certain embodiments of the formulations described herein, wherein the amount includes about 4.5 mg of the nicotine liquid formulation. In certain embodiments of the formulations described herein, the concentration of the nicotine is from about 0.5% (w / w) to about 20% (w / w). In certain embodiments of the formulations described herein, the molar ratio of the acid to the nicotine is from about 0.25:1 to about 4:1. In certain embodiments of the formulations described herein, the acid comprises one or more acidic functional groups, and wherein the molar ratio of the acidic functional groups to the nicotine is from about 0.25:1 to about 4:1. In certain embodiments of the formulations described herein, the acid and the nicotine form a nicotine salt. In certain embodiments of the formulations described herein, wherein the nicotine is stabilized in the inhalable aerosol in the form of the nicotine salt. In certain embodiments of the formulations described herein, the inhalable aerosol comprises one or more of the nicotine, the acid, the carrier, and the nicotine salt. In certain embodiments of the formulations described herein, one or more particles in the inhalable aerosol are sized for delivery to the alveoli in the lungs of the user. In certain embodiments of the formulations described herein, the acid is selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, succinic acid, and citric acid. In certain embodiments of the formulations described herein, the acid is selected from the group consisting of benzoic acid, pyruvic acid, and salicylic acid. In certain embodiments of the formulations described herein, the acid is benzoic acid. In certain embodiments of the formulations described herein, the concentration is from about 2% (w / w) to about 6% (w / w). In certain embodiments of the formulations described herein, the concentration is about 5% (w / w). In certain embodiments of the formulations described herein, the biologically acceptable liquid carrier comprises from about 20% to about 50% propylene glycol and from about 80% to about 50% vegetable glycerin. In certain embodiments of the formulations described herein, the biologically acceptable liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin. In certain embodiments of the formulations described herein, the heater heats the amount of the nicotine liquid formulation from about 150° C. to about 250° C. In certain embodiments of the formulations described herein, the heater heats the amount of the nicotine liquid formulation from about 180° C. to about 220° C. In certain embodiments of the formulations described herein, the heater heats the amount of the nicotine liquid formulation to about 200° C. In certain embodiments of the formulations described herein, the nicotine liquid formulation further comprises an additional acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.In certain embodiments of the formulations described herein, the additional acid forms an additional nicotine salt. In certain embodiments of the formulations described herein, at least about 60% to about 90% of the acid in the amount is in the aerosol. In certain embodiments of the formulations described herein, at least about 70% to about 90% of the acid in the amount is in the aerosol. In certain embodiments of the formulations described herein, at least about 80% to about 90% of the acid in the amount is in the aerosol. In certain embodiments, wherein more than about 90% of the acid in the amount is in the aerosol.

[0020] In some aspects, provided herein is a formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a heater, the formulation comprising: the nicotine at a concentration from about 0.5% (w / w) to about 20% (w / w); an acid at a molar ratio of the acid to the 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 the nicotine liquid formulation to the heater; and the heater forms an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0021] In certain aspects, provided herein is a formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device 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 the acid to the 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 the nicotine liquid formulation to the heater; and the heater forms an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0022] In some aspects, provided herein is a formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device 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 the acid to the 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 the nicotine liquid formulation to the heater; and the heater forms an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 90% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0023] In certain aspects, provided herein is a formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device 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 about 1:1 of the benzoic acid to the nicotine; and a biologically acceptable liquid carrier; wherein using the electronic cigarette comprises: providing an amount of the nicotine liquid formulation to the heater; and the heater forms an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 90% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the aerosol.

[0024] Incorporated by Reference

[0025] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description which sets forth illustrative embodiments in which the principles of the invention are employed, and in the accompanying drawings in which:

[0028] Figure 1 A non-limiting example of the results of measuring heart rate data for six minutes starting from puffing is shown. The Y-axis is heart rate (bpm) and the X-axis represents the duration of the test (-60 seconds to 180 seconds);

[0029] Figure 2 The results of heart rate data measured for ten minutes from the start of the puff are shown. The Y-axis is the heart rate (bpm) and the X-axis represents the duration of the test (0 minutes to 10 minutes);

[0030] Figure 3 illustrates non-limiting examples of calculated vapor pressures of various acids relative to nicotine;

[0031] Figure 4 Depicting a non-limiting example of a low temperature electronic vaporization device, i.e., an electronic cigarette, having a fluid storage compartment containing a nicotine liquid formulation of an embodiment described herein; and

[0032] Figure 5 Depicted is a non-limiting example of a low temperature electronic vaporization device, i.e., an electronic cigarette, a cartomizer, having a fluid storage compartment, a heater, and comprising a nicotine liquid formulation of the embodiments described herein.

[0033] Figure 6 Non-limiting examples of pharmacokinetic profiles of four test articles in a plasma study are depicted.

[0034] Figure 7 Figure 2. C of the four test articles in the plasma study. 最大 Non-limiting example of.

[0035] Figure 8 Figure 2. T of the four test articles in the plasma study. 最大 Non-limiting example of.

[0036] Fig. 9 Depicted is a non-limiting example of a correlation between a molar ratio of benzoic acid to nicotine and a percentage of nicotine captured from at least a portion of an aerosol generated using a low temperature electronic vaporization device, i.e., an electronic cigarette, and a nicotine liquid formulation.

[0037] Fig.10 Depicted are non-limiting examples of percentages of nicotine captured from at least a portion of an aerosol generated using a low temperature electronic vaporization device, i.e., an electronic cigarette, and a nicotine liquid formulation.

[0038] Fig.11 Depicted is a non-limiting example of a correlation between the molar ratio of acid functional groups to nicotine and the percentage of nicotine captured from at least a portion of an aerosol generated using a low temperature electronic vaporization device, i.e., an electronic cigarette, and a nicotine liquid formulation. DETAILED DESCRIPTION OF THE INVENTION

[0040] Nicotine is a chemical stimulant and increases heart rate and blood pressure when provided to individuals and animals. Nicotine transfer to individuals is associated with a sense of physical and / emotional satisfaction. Contradictory reports have been published regarding the transfer efficiency of free base nicotine compared to single or double protonated nicotine salts. Studies on the transfer efficiency of free base nicotine and nicotine salts are complex and have produced unpredictable results. In addition, such transfer efficiency studies have been conducted under extremely high temperature conditions (similar to smoking); therefore, these studies do not provide sufficient guidance regarding the transfer efficiency of free base nicotine and nicotine salts under low temperature evaporation conditions, such as low temperature evaporation devices, i.e., electronic cigarettes. Some reports have indicated that nicotine free base should cause greater satisfaction in users than any corresponding nicotine salt.

[0041] It has been unexpectedly found herein that some nicotine liquid preparations provide satisfaction that is superior to free base nicotine in an individual and more similar to the satisfaction in the individual of smoking a traditional cigarette.Satisfying effect is consistent with the rapid rise of the absorption of nicotine in blood plasma as shown in the non-limiting examples at least in embodiment 8, embodiment 13 and embodiment 14 of the transfer efficiency of the alveoli of the lung of individual nicotine to the lung.It has also been unexpectedly found herein that some nicotine liquid preparations provide greater satisfaction than other nicotine liquid preparations.Such effect is shown in the blood plasma level of the exemplary nicotine liquid preparations herein at least in embodiment 3 and embodiment 8 as non-limiting examples.These results confirm that for nicotine liquid preparations such as nicotine salt liquid preparations, the rate of nicotine intake in blood is higher than nicotine free base preparations.In addition, research described herein confirms that the transfer efficiency of nicotine liquid preparations such as nicotine salts depends on the acid used in the preparation. As demonstrated in at least non-limiting Example 13, certain acids used in nicotine liquid formulations produce better transfer from the liquid formulation to vapor and / or aerosol. Thus, described herein are nicotine liquid formulations, such as nicotine salt liquid formulations, for use in low temperature electronic vaporization devices, i.e., electronic cigarettes, or the like, which provide a general satisfaction effect consistent with efficient transfer of nicotine to the lungs of an individual and a rapid rise in nicotine absorption in plasma. Thus, provided herein are devices for inhaling an aerosol generated from a nicotine salt liquid formulation in a low temperature vaporization device, i.e., a low temperature electronic vaporization device, i.e., an electronic cigarette, through the mouth or nose, nicotine liquid formulations comprising one or more nicotine salts, systems, cartridge atomizers, kits, and methods, as described herein or as will be apparent to one skilled in the art after reading the disclosure herein.

[0042] Consistent with these satisfying effects, we have unexpectedly found that compared to conventional cigarettes, C 最大and T 最大 (Plasma nicotine levels are similarly measured). When measuring plasma nicotine levels of a free base nicotine liquid formulation inhaled using a low temperature vaporization device, i.e., an electronic cigarette, C 最大 (maximum concentration) and T 最大 Also consistent with these satisfying effects, it has been unexpectedly discovered herein that compared to the C of a nicotine liquid formulation, such as a nicotine salt liquid formulation, inhaled using a low temperature vaporization device, i.e., an electronic cigarette, 最大 and T 最大 (Plasma nicotine levels are similarly measured). When measuring plasma nicotine levels of a free base nicotine liquid formulation inhaled using a low temperature vaporization device, i.e., an electronic cigarette, C 最大 and T 最大 In addition, it has been unexpectedly discovered that there is a difference in the rate of nicotine uptake in the plasma of users who inhale freebase nicotine liquid formulations using a low temperature vaporization device, i.e., an electronic cigarette, compared to the rate of nicotine uptake in the plasma of users who inhale smoke from conventional cigarettes. In addition, it has been unexpectedly discovered that there is a difference in the rate of nicotine uptake in the plasma of users who inhale freebase nicotine liquid formulations using a low temperature vaporization device, i.e., an electronic cigarette, compared to the rate of nicotine uptake in the plasma of users who inhale nicotine liquid formulations, such as nicotine salt liquid formulations, using a low temperature vaporization device, i.e., an electronic cigarette.

[0043] In certain embodiments, the inhalation of a vapor and / or aerosol generated using a freebase nicotine composition in a low temperature vaporization device, i.e., an electronic cigarette, is at a plasma level (C 最大 and T 最大 ) is not necessarily comparable to the delivery of nicotine to the blood of conventional cigarettes when inhaled. In addition, the inhalation of vapor and / or aerosol generated by the free base nicotine composition used in a low temperature vaporization device, i.e., an electronic cigarette, is at a plasma level (C 最大 and T 最大) is not necessarily comparable to the inhalation of vapor and / or aerosol containing nicotine generated from a nicotine liquid formulation, such as a nicotine salt liquid formulation. In addition, when measuring the rate of nicotine uptake in the blood within the first 0-8 minutes, the inhalation of vapor and / or aerosol generated by a freebase nicotine composition used in a low temperature vaporization device, i.e., an electronic cigarette, is not necessarily comparable to the delivery of nicotine to the blood of a conventional cigarette when inhaled in terms of plasma levels. In addition, when measuring the rate of nicotine uptake in the blood within the first 0-8 minutes, the inhalation of vapor and / or aerosol generated by a freebase nicotine composition used in a low temperature vaporization device, i.e., an electronic cigarette, is not necessarily comparable to the inhalation of vapor and / or aerosol containing nicotine generated from a nicotine liquid formulation, such as a nicotine salt liquid formulation, in terms of plasma levels.

[0044] Consistent with the differences observed in nicotine plasma levels when using freebase nicotine as a nicotine source in a low temperature vaporization device, i.e., an electronic cigarette (compared to a nicotine liquid formulation, such as 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 aerosol. As demonstrated, in non-limiting Example 13, freebase nicotine as a nicotine source in a low temperature electronic vaporization device, i.e., an electronic cigarette, results in less nicotine being present in the aerosol compared to using a nicotine liquid formulation, such as a nicotine salt liquid formulation, as a nicotine source in a low temperature electronic vaporization device, i.e., an electronic cigarette. In addition, this is consistent with the differences observed in nicotine plasma levels when using freebase nicotine as a nicotine source in a low temperature vaporization device, i.e., an electronic cigarette (compared to using a nicotine liquid formulation, such as a nicotine salt liquid formulation), wherein the higher transfer efficiency of the nicotine liquid formulation from the liquid to the vapor and / or aerosol results in a higher rate of nicotine uptake in the blood. One explanation for this observation is that aerosols, such as droplets of aerosols, containing nicotine are more easily delivered to the user's lungs and / or alveoli therein, which results in more efficient uptake into the user's bloodstream. In addition, aerosols are delivered in the form of particles that are sized to be delivered through the oral or nasal cavity and delivered to the user's lungs, such as alveoli of the user's lungs.

[0045] Compared to vaporized nicotine, aerosolized nicotine is more likely to travel to the user's lungs and be absorbed in the alveoli. One reason that aerosolized nicotine has a greater chance of being absorbed in the lungs than vaporized nicotine is that, for example, vaporized nicotine has a greater chance of being absorbed in the user's oral tissue and upper respiratory tract tissue. In addition, it is possible that nicotine will be absorbed in the mouth and upper respiratory tract at a slower rate than nicotine absorbed in lung tissue, thus producing a less satisfactory effect for the user. As shown in at least non-limiting Examples 8 and 13, nicotine is delivered to the user using a low-temperature electronic vaporization device, i.e., an electronic cigarette, and at the time of reaching the maximum concentration of nicotine in the blood (T 最大 ) and the amount of aerosolized nicotine delivered to the aerosol. For example, the use of free base nicotine liquid formulations resulted in a significant reduction 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). In addition, as shown in non-limiting Example 8, for free base, the T is caused by less aerosolized nicotine compared to nicotine benzoate and nicotine malate. 最大 Longer and therefore less rapid uptake in the user's lungs.

[0046] Compared to the acid that does not degrade at room temperature and / or the operating temperature of the device, the acid that degrades at room temperature and / or the operating temperature of the device requires a higher molar ratio of acid to nicotine to transfer the same molar amount of acid from the liquid to the aerosol. Therefore, in some embodiments, compared to the acid that does not degrade, twice the molar amount of acid that degrades at room temperature and / or the operating temperature of the device is required to produce an aerosol containing the same molar amount of nicotine in the aerosol (in some embodiments, in the non-gas phase (e.g., droplets) of the aerosol). As shown in non-limiting Example 13, the correlation between the molar ratio of benzoic acid to nicotine and the percentage of the acid captured confirms that the more acid is in the aerosol (in some embodiments, in the non-gas phase of the aerosol), and therefore, the more nicotine may be present in the aerosol (in some embodiments, in the non-gas phase of the aerosol). In addition, malic acid is known to decompose at about 150°C, which is lower than the temperature at which the low-temperature electronic vaporization device, i.e., the electronic cigarette, operates, and as shown in non-limiting Example 13, when malic acid is used in a nicotine liquid formulation, less than 50% of the malic acid is recovered in the liquid formulation. This is significantly different from when benzoic acid is used in a nicotine liquid formulation, 90% of the benzoic acid is recovered in the liquid formulation. The lower recovery percentage of malic acid may be due to the degradation of malic acid. Therefore, as shown in Example 13, compared to benzoic acid, about twice the amount of malic acid is required to produce an aerosol containing the same molar amount of acid in the aerosol (in some embodiments in the non-gas phase of the aerosol), and therefore, twice the amount of malic acid may be required to produce an aerosol containing the same amount of nicotine in the aerosol (in some embodiments in the non-gas phase of the aerosol). In addition, degradation products of malic acid may be present in the aerosol, which can cause the user to have an unpleasant experience when using the device and the malic acid nicotine liquid formulation. In certain embodiments, the unpleasant experience includes taste, nerve reactions, and / or irritation of one or more of the oral cavity, upper respiratory tract, and / or lungs.

[0047] The presence of the acid in the aerosol stabilizes the nicotine and / or delivers the nicotine to the 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 the nicotine is stabilized in the aerosol generated by a 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 the nicotine is stabilized in the aerosol generated by a 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 because 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. Additionally, as shown in Example 14, nicotine was aerosolized at a 0.5:1 ratio of moles of succinic acid to moles of nicotine, and because succinic acid contains two carboxylic acid functional groups, nicotine was 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 is therefore likely protonated by the acid. Additionally, this demonstrates that nicotine may be delivered to the user's lungs in a protonated form in an aerosol.

[0048] Some reasons for not using acid in nicotine liquid preparations are listed below. Other reasons for using certain acids in nicotine liquid preparations are not related to the nicotine uptake rate. In some embodiments, acids that are corrosive or otherwise incompatible with electronic vaporization device materials are not used in nicotine liquid preparations. As a non-limiting example, sulfuric acid will corrode device components and / or react with device components, making sulfuric acid unsuitable for inclusion in nicotine liquid preparations. In some embodiments, acids that are toxic to users of electronic vaporization devices cannot be used in nicotine liquid preparations because the acid is incompatible with human consumption, ingestion, or inhalation. As a non-limiting example, sulfuric acid is an example of such an acid, which may not be suitable for users of low-temperature electronic vaporization devices, i.e., electronic cigarette devices, depending on the embodiment of the composition. In some embodiments, acids that are bitter or otherwise bad-tasting to users in liquid preparations cannot be used in nicotine liquid preparations. Non-limiting examples of such acids are acetic acid or citric acid at high concentrations. In some embodiments, acids that oxidize at room temperature and / or at the operating temperature of the device are not included in nicotine liquid preparations. Non-limiting examples of such acids include sorbic acid and malic acid that are unstable at room temperature and / or the operating temperature of the device. The decomposition of the acid at room temperature or operating temperature may indicate that the acid is not suitable for the formulation of the embodiment. As a non-limiting example, citric acid decomposes at 175°C and malic acid decomposes at 140°C, so these acids may be inappropriate for devices operating at 200°C. In certain embodiments, acids with poor solubility in the composition ingredients are not suitable for certain embodiments of the compositions herein. As a non-limiting example, nicotine bitartrate with a composition of nicotine and tartaric acid in a 1:2 molar ratio will not produce a solution with 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 under ambient conditions. As used herein, weight percentage (w / w) refers to the weight of a separate component relative to the weight of the total formulation.

[0049] In certain embodiments, nicotine liquid formulations, such as nicotine salt liquid formulations, made with acids having a vapor pressure between 20-300 mmHg @ 200°C, or a vapor pressure of >20 mmHg @ 200°C, or a vapor pressure from 20 mmHg to 300 mmHg @ 200°C, or a vapor pressure from 20 mmHg to 200 mmHg @ 200°C, or a vapor pressure between 20 mmHg and 300 mmHg @ 200°C, provide satisfaction similar to or close to that of traditional cigarettes (compared to other nicotine salt formulations or compared to nicotine free base formulations). For non-limiting examples, acids that meet one or more criteria of the present proposition include salicylic acid, sorbic acid, benzoic acid, lauric acid, and levulinic acid. In some embodiments, a nicotine liquid preparation made with an acid having a difference between a boiling point and a melting point of at least 50°C, a boiling point greater than 160°C, and a melting point less than 160°C, such as a nicotine salt liquid preparation, provides satisfaction similar to or close to traditional cigarettes (compared to other nicotine salt preparations or compared to nicotine free base preparations) with a traditional cigarette. For non-limiting examples, acids that meet the criteria of the existing proposition include salicylic acid, sorbic acid, benzoic acid, pyruvic acid, lauric acid, and levulinic acid. In some embodiments, a nicotine liquid preparation prepared with an acid having a difference between a boiling point and a melting point of at least 50°C, a boiling point less than the operating temperature of at most 40°C, and a melting point less than the operating temperature of at least 40°C, such as a nicotine salt liquid preparation, provides satisfaction similar to or close to traditional cigarettes (compared to other nicotine salt preparations or compared to nicotine free base preparations). In some embodiments, the operating temperature may 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 examples, acids that meet the aforementioned criteria include salicylic acid, sorbic acid, benzoic acid, pyruvic acid, lauric acid, and levulinic acid. In some embodiments, combinations of these criteria are contemplated herein for preferred certain nicotine salt formulations.

[0050] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0051] As used in this specification and claims, the term "vapor" refers to the gas or vapor phase of a material. As used in this specification and claims, the term "aerosol" refers to a colloidal suspension of particles, such as droplets, dispersed in air or a gas.

[0052] As used herein, the term "organic acid" refers to an organic compound that has acidic properties (e.g., Common organic acids are carboxylic acids, whose acidity is related to their carboxyl group -COOH. Dicarboxylic acids have two carboxylic acid groups. The relative acidity of an organic compound is determined by its pK a The pK values ​​of organic acids are determined by the skilled person and the skilled person knows how to determine the pK values ​​of organic acids based on the given pK values ​​of organic acids. a The acidity of an organic acid is determined by the value of keto acid. As used herein, the term "keto acid" refers to an organic compound comprising a carboxylic acid group and a ketone group. Common types of keto acids include α-keto acids or 2-oxo acids, such as pyruvic acid or oxaloacetic acid, with a keto group adjacent to the carboxylic acid; β-keto acids or 3-oxo acids, such as acetoacetic acid, with a keto group at the second carbon from the carboxylic acid; γ-keto acids or 4-oxo acids, such as levulinic acid, with a keto group at the third carbon from the carboxylic acid.

[0053] As used herein, the term "electronic cigarette" or "low temperature vaporization device" refers to an electronic inhaler that evaporates a liquid solution into an aerosol mist, simulating the act of smoking. The liquid solution contains a preparation containing nicotine. There are many low temperature vaporization devices, i.e., electronic cigarettes, that are not like conventional cigarettes at all. The amount of nicotine contained can be selected by the user through inhalation. Typically, a low temperature electronic vaporization device, i.e., an electronic cigarette, includes three important components: a plastic cartridge that acts as a mouthpiece and a reservoir for liquid, an "atomizer" that vaporizes the liquid, and a battery. The low temperature vaporization device of other embodiments, i.e., an electronic cigarette, includes a combined atomizer and a reservoir (referred to as a "cartridge atomizer" (which may or may not be disposable), a mouthpiece that may be integrated or not integrated with the cartridge atomizer, and a battery.

[0054] As used in the specification and claims, unless otherwise stated, the term "about" refers to a variation of 1%, 2%, 3%, 4%, 5%, 10%, 15%, or 25%, depending on the embodiment.

[0055] Suitable carriers (e.g., liquid solvents) for nicotine salts described herein include a medium in which the nicotine salt is soluble under ambient conditions so 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, and combinations thereof. In certain embodiments, the liquid carrier comprises from about 0% to about 100% propylene glycol and from about 100% to about 0% vegetable glycerin. In certain embodiments, the liquid carrier comprises from about 10% to about 70% propylene glycol and from about 90% to about 30% vegetable glycerin. In certain embodiments, the liquid carrier comprises from about 20% to about 50% propylene glycol and from about 80% to about 50% vegetable glycerin. In certain embodiments, the liquid carrier comprises about 30% propylene glycol and about 70% vegetable glycerin.

[0056] Preparations described herein vary in nicotine concentration. In some preparations, the concentration of nicotine in the preparation is dilute. In some preparations, the concentration of nicotine in the preparation is less dilute. In some preparations, the concentration of nicotine in nicotine liquid preparations is from about 1% (w / w) to about 25% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is from about 1% (w / w) to about 20% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is from about 1% (w / w) to about 18% (w / w). In certain embodiments, the concentration of nicotine in nicotine liquid preparations is from about 1% (w / w) to about 15% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is from about 4% (w / w) to about 12% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is from about 2% (w / w) to about 6% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is about 5% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is about 4% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is about 3% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is about 2% (w / w). In some embodiments, the concentration of nicotine in nicotine liquid preparations is about 1% (w / w). In some preparations, the concentration of nicotine in nicotine liquid preparations is from about 1% (w / w) to about 25% (w / w).

[0057] Preparations described herein vary in terms of nicotine salt concentration. In some preparations, the concentration of nicotine salt in nicotine liquid preparations is dilute. In some preparations, the concentration of nicotine salt in preparations is less dilute. In some preparations, the concentration of nicotine salt in nicotine liquid preparations is from about 1% (w / w) to about 25% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparations is from about 1% (w / w) to about 20% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparations is from about 1% (w / w) to about 18% (w / w). In some embodiments, the concentration of nicotine salt in nicotine liquid preparations is from about 1% (w / w) to about 15% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparations is from about 4% (w / w) to about 12% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparation is from about 2% (w / w) to about 6% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparation is about 5% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparation is about 4% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparation is about 3% (w / w). In some preparations, the concentration of nicotine salt in nicotine liquid preparation is about 2% (w / w).

[0058] In some embodiments, the concentration of nicotine salt in the nicotine liquid preparation is about 1% (w / w). In some preparations, a nicotine salt of less dilute concentration is used together with a second nicotine salt of dilute concentration. In some preparations, the concentration of nicotine in the first nicotine liquid preparation is from about 1% to about 20%, and is combined with a second nicotine liquid preparation of nicotine with a concentration from about 1% to about 20% or any range or concentration therein. In some preparations, the concentration of nicotine salt in the first nicotine liquid preparation is from about 1% to about 20%, and is combined with a second nicotine liquid preparation of nicotine with a concentration from 1% to 20% or any range or concentration therein. In some preparations, the concentration of nicotine salt in the first nicotine liquid preparation is from about 1% to about 20%, and is combined with a second nicotine liquid preparation of nicotine salt with a concentration from 1% to 20% or any range or concentration therein. As used with respect to the concentration of nicotine in a nicotine liquid formulation, the term "about" refers to a range of 0.05% (i.e., if the concentration is from about 2%, the range is 1.95%-2.05%), a range of 0.1% (i.e., if the concentration is from about 2%, the range is 1.9%-2.1%), a range of 0.25% (i.e., if the concentration is from about 2%, the range is 1.75%-2.25%), a range of 0.5% (i.e., if the concentration is from about 2%, the range is 1.5%-2.5%), or a range of 1% (i.e., if the concentration is from about 4%, the range is 3%-5%), depending on the embodiment.

[0059] In certain embodiments, preparation comprises organic acid and / or inorganic acid.In certain embodiments, suitable organic acid comprises carboxylic acid.In certain embodiments, organic carboxylic acid disclosed herein is monocarboxylic acid, dicarboxylic acid (organic acid comprising two carboxylic acid groups) and carboxylic acid comprising aromatic group such as benzoic acid, hydroxycarboxylic acid, heterocyclic carboxylic acid, terpenoid acid (terpenoid acid) and sugar acid such as pectic acid, amino acid, cycloaliphatic acid, aliphatic carboxylic acid, ketocarboxylic acid and analog.In certain embodiments, suitable acid comprises 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, salicylic acid, sorbic acid, malonic acid, malic acid or its combination. In certain embodiments, suitable acid comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid. In certain embodiments, suitable acid comprises one or more of benzoic acid, pyruvic acid, and salicylic acid. In certain embodiments, suitable acid comprises benzoic acid.

[0060] Nicotine salts are formed by adding a suitable acid (including an organic acid or an inorganic acid). In certain embodiments, suitable organic acids include carboxylic acids. In certain embodiments, the organic carboxylic acids disclosed herein are monocarboxylic acids, dicarboxylic acids (organic acids containing two carboxylic acid groups), carboxylic acids containing aromatic groups such as benzoic acids, hydroxycarboxylic acids, heterocyclic carboxylic acids, tert-butyl acids, sugar acids such as pectic acids, amino acids, cycloaliphatic acids, aliphatic carboxylic acids, ketocarboxylic acids, and the like. In certain embodiments, the organic acid used herein is a monocarboxylic acid. Nicotine salts are formed by adding a suitable acid to nicotine. In certain embodiments, suitable acid comprises formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, sad, 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, salicylic acid, sorbic acid, malonic acid, malic acid or its combination. In certain embodiments, suitable acid comprises one or more in benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid and citric acid. In certain embodiments, suitable acid comprises one or more in benzoic acid, pyruvic acid and salicylic acid. In certain embodiments, suitable acid comprises benzoic acid.

[0061] In certain embodiments, the formulation comprises various stoichiometric ratios and / or molar ratios of acid to nicotine, acidic functional groups to nicotine, and acidic functional group hydrogen to nicotine. In certain embodiments, the stoichiometric ratio of nicotine to acid (nicotine: acid) is 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 certain formulations provided herein, the stoichiometric ratio of nicotine to acid is 1: 1, 1: 2, 1: 3, or 1: 4. In certain 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 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.

[0062] Nicotine is an alkaloid molecule containing two basic nitrogens. It can exist in different protonation states. For example, if no protonation is present, nicotine is called "free base". If one nitrogen is protonated, then nicotine is "monoprotonated".

[0063] In some embodiments, the nicotine liquid formulation is formed by adding a suitable acid to nicotine, stirring the neat mixture at ambient temperature or at an elevated temperature, and then diluting the neat mixture with a carrier mixture such as a mixture of propylene glycol and glycerol. In some embodiments, the suitable acid is completely dissolved by the nicotine before dilution. The suitable acid may not be completely dissolved by the nicotine before dilution. Adding a suitable acid to nicotine to form a neat mixture may cause an exothermic reaction. Adding a suitable acid to nicotine to form a neat mixture may be performed at 55°C. Adding a suitable acid to nicotine to form a neat mixture may be performed at 90°C. The purging mixture may be cooled to ambient temperature before dilution. Dilution may be performed at an elevated temperature.

[0064] In certain embodiments, the nicotine liquid formulation is prepared by combining nicotine and a suitable acid in a mixture of a carrier mixture such as propylene glycol and glycerol. The mixture of nicotine and a first carrier mixture is combined with a mixture of a suitable acid in a second carrier mixture. In certain embodiments, the first carrier mixture and the second carrier mixture are identical in composition. In certain embodiments, the first carrier mixture and the second carrier mixture are not identical in composition. In certain embodiments, it is necessary to heat the nicotine / acid / carrier mixture to facilitate complete dissolution. In certain embodiments, stirring the nicotine / acid / carrier mixture is sufficient to facilitate complete dissolution.

[0065] In certain embodiments, a nicotine liquid formulation is prepared and added to a solution of propylene glycol (PG) / vegetable glycerin (VG) in a ratio of 3:7 by weight, and is thoroughly mixed. Although described herein as producing 10 g of each formulation, all procedures noted below are scalable. Other modes of formulation may also be employed to form the formulation noted below without departing from the disclosure herein, and will be known to those skilled in the art after reading the disclosure herein.

[0066] In some embodiments, the acid contained in the nicotine liquid formulation is determined by the vapor pressure of the acid. In some embodiments, the nicotine liquid formulation comprises an acid having a vapor pressure similar to the vapor pressure of free base nicotine. In some embodiments, the nicotine liquid formulation is formed from an acid having a vapor pressure similar to the vapor pressure of free base nicotine at the heating temperature of the device. As a non-limiting example, Figure 3This trend is illustrated. Nicotine salts formed from nicotine and benzoic acid; nicotine and pyruvic acid; nicotine and salicylic acid; or nicotine and levulinic acid are salts that produce satisfaction in individual users consistent with efficient transfer of nicotine and rapid rise in nicotine plasma levels. This pattern may be due to the mechanism of action during the heating of the nicotine liquid formulation. Nicotine salts can dissociate at or just below the heating temperature of the device, producing a mixture of free base nicotine and the individual acids. At that time, if both nicotine and the acid have the same vapor pressure, they can be aerosolized at the same time, causing both free base nicotine and the component acid to be transferred to the user. In certain embodiments, a nicotine liquid formulation, such as a nicotine salt liquid formulation, for producing an inhalable aerosol after heating in a low temperature electronic vaporization device, i.e., an electronic cigarette, can include a nicotine salt in a biologically acceptable liquid carrier; wherein the acid used to form the nicotine salt is characterized by a vapor pressure between 20-4000 mmHg at 200°C. In some embodiments, the acid used to form the nicotine salt is characterized by a vapor pressure between 20-2000 mmHg at 200° C. In some embodiments, the acid used to form the nicotine salt is characterized by a vapor pressure between 100-300 mmHg at 200° C.

[0067] Unexpectedly, different nicotine liquid preparations produce different degrees of satisfaction in individuals. In certain embodiments, the protonation degree of nicotine salt affects satisfaction, so that more protonation is less satisfying than less protonation. In certain embodiments, nicotine in preparation, steam and / or aerosol, such as nicotine salt is monoprotonated. In certain embodiments, nicotine in preparation, steam and / or aerosol, such as nicotine salt is diprotonated. In certain embodiments, nicotine in preparation, steam and / or aerosol, such as nicotine salt exists with more than one protonation state, such as the balance of monoprotonated nicotine salt and diprotonated nicotine salt. In certain embodiments, the protonation degree of nicotine depends on the nicotine used in the salt formation reaction: the stoichiometric ratio of acid. In certain embodiments, the protonation degree of nicotine depends on the solvent. In certain embodiments, the protonation degree of nicotine is unknown.

[0068] In certain embodiments, monoprotonated nicotine salts produce a high degree of satisfaction in users. For example, nicotine benzoate and nicotine salicylate are monoprotonated nicotine salts and produce a high degree of satisfaction in users. The reason for this trend can be explained by the following mechanism of action: wherein nicotine is first deprotonated before being transferred to the vapor with the component acid, then stabilized by the acid in the aerosol after re-protonation, and transported downstream to the user's lungs by the acid. In addition, the satisfaction of the lack of free base nicotine indicates that the second factor may be important. Depending on the salt, nicotine salts can perform best when they are protonated at their optimal degree. For example, as described in non-limiting Example 13, nicotine benzoate transfers the maximum amount of nicotine to the aerosol with benzoic acid and nicotine at a ratio of 1:1. Lower molar ratios produce less nicotine transferred to the aerosol, and benzoic acid and nicotine above a 1:1 molar ratio do not cause any additional nicotine to be transferred to the aerosol. This can 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 associated with all nicotine molecules, the remaining unprotonated free base nicotine in the formulation is evaporated, thus reducing satisfaction for the user.

[0069] In some embodiments, acids that degrade at room temperature or at the operating temperature of a low-temperature electronic vaporization device, i.e., a low-temperature electronic cigarette, do not provide the same degree of satisfaction to the user. For example, compared to benzoic acid, twice the amount of malic acid that degrades at the operating temperature of a low-temperature electronic cigarette is required to transfer the same molar amount of acid from the liquid to the aerosol. Therefore, in some embodiments, compared to benzoic acid, twice the molar amount of malic acid is required to produce an aerosol containing the same molar amount of nicotine in the aerosol (in some embodiments in the non-gas phase of the aerosol). In addition, because malic acid contains two carboxylic acid groups and benzoic acid contains one, compared to benzoic acid in a nicotine liquid formulation, four times the amount of acidic functional groups are required when malic acid is used. In addition, because malic acid contains two carboxylic acid groups and benzoic acid contains one, compared to benzoic acid in a nicotine liquid formulation, four times the amount of acidic functional group hydrogen is required when malic acid is used. In some embodiments, one or more chemicals produced when the acid degrades produce an unpleasant experience for the user. In certain embodiments, the unpleasant experience includes taste, nerve response, and / or irritation of one or more of the oral cavity, upper respiratory tract, and / or lungs.

[0070] In some embodiments, provided herein are methods, systems, devices, formulations, and kits for generating an inhalable aerosol, the inhalable aerosol comprising nicotine for delivery to a user, the method comprising using a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a nicotine liquid formulation and a heater, wherein the nicotine liquid formulation comprises the nicotine, an acid, and a biologically acceptable liquid carrier, wherein using the electronic cigarette comprises: providing a certain amount of the nicotine liquid formulation to the heater; the heater forms an aerosol by heating the amount of the nicotine liquid formulation, wherein at least about 50% of the acid in the amount is in the aerosol, and wherein at least about 90% of the nicotine in the amount is in the 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 about 95%, or at least about 99% of the acid in the amount is in the aerosol. In certain embodiments, at least about 50% to about 99% of the acid in the amount is in the aerosol. In certain embodiments, at least about 50% to about 95% of the acid in the amount is in the aerosol. In certain embodiments, at least about 50% to about 90% of the acid in the amount is in the aerosol. In certain embodiments, at least about 50% to about 80% of the acid in the amount is in the aerosol. In certain embodiments, at least about 50% to about 70% of the acid in the amount is in the aerosol. In certain embodiments, at least about 50% to about 60% of the acid in the amount is in the aerosol. In certain embodiments, at least about 60% to about 99% of the acid in the amount is in the aerosol. In certain embodiments, at least about 60% to about 95% of the acid in the amount is in the aerosol. In certain embodiments, at least about 60% to about 90% of the acid in the amount is in the aerosol. In certain embodiments, at least about 60% to about 80% of the acid in the amount is in the aerosol. In certain embodiments, at least about 60% to about 70% of the acid in the amount is in the aerosol. In certain embodiments, at least about 70% to about 99% of the acid in the amount is in the aerosol. In certain embodiments, at least about 70% to about 95% of the acid in the amount is in the aerosol. In certain embodiments, at least about 70% to about 90% of the acid in the amount is in the aerosol. In certain embodiments, at least about 70% to about 80% of the acid in the amount is in the aerosol.

[0071] In some embodiments, the aerosol is delivered with particles sized to be delivered through the oral cavity or nasal cavity and delivered to the user's lungs (e.g., alveoli of the user's lungs). In some embodiments, a nicotine liquid formulation, such as an aerosol produced by a nicotine salt liquid formulation (the nicotine liquid formulation is produced using a low-temperature electronic vaporization device, such as a low-temperature electronic cigarette) is delivered with particles sized to be delivered through the oral cavity or nasal cavity and delivered to the user's lungs (e.g., alveoli of the user's lungs). In some embodiments, the uptake rate in the user's lungs, such as in the alveoli of the user's lungs, is affected by the size of the aerosol particles. In certain embodiments, the aerosol particles are sized from about 0.1 micron to about 5 microns, from about 0.1 micron to about 4.5 microns, from about 0.1 micron to about 4 microns, from about 0.1 micron to about 3.5 microns, from about 0.1 micron to about 3 microns, from about 0.1 micron to about 2.5 microns, from about 0.1 micron to about 2 microns, from about 0.1 micron to about 1.5 microns, from about 0.1 micron to about 1 micron, from about 0.1 micron to about 0.9 microns, from about 0.1 micron to about 0.8 microns, from about 0.1 micron to about 0.7 microns ...7 microns, from about 0.1 micron to about 0.7 microns, from about 0.1 micron to about 0.7 microns, from about 0.1 micron to about 0.7 microns, from about 0.1 micron to about 0.7 microns, from about 0.1 micron to about 0.7 microns, from about 0.1 micron to about 0.7 microns, from about 0.1 micron to about 0.7 microns, from about 0.1 micron to about 0.7 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 micron, from about 0.2 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 micron, from 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 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 2.5 microns, from about 0.3 microns to about 4.5 microns, from about 0.3 microns to about 4.5 microns, from about 0.3 microns to about 4.5 microns, from about 0.3 microns to about 4.5 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 ...2 microns to about 0.4 microns, from about 0.2 microns to about From about 0.2 microns, from about 0.3 microns to about 1.5 microns, from about 0.3 microns to about 1 micron, 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 microns, 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 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 micron, 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 micron, 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 micrometers, from about 0.6 micrometers to about 1 micrometer, from about 0.6 micrometers to about 0.9 micrometers, from about 0.6 micrometers to about 0.8 micrometers, from about 0.6 micrometers to about 0.7 micrometers, from about 0.8 micrometers to about 5 micrometers, from about 0.8 micrometers to about 4.5 micrometers, from about 0.8 micrometers to about 4 micrometers, from about 0.8 micrometers to about 3.5 micrometers, from about 0.8 micrometers to about 3 micrometers, from about 0.8 micrometers to about 2.5 micrometers, from about 0.8 micrometers to about 2 micrometers, from about 0.8 micrometers to about 1.5 micrometers, from about 0.8 micrometers to about 1 micrometer, from about 0.8 micrometers to about 0.9 micrometers, from about 0.9 micrometers to about 5 micrometers, from about 0.9 micrometers to about 4.5 micrometers, from about 0.9 micrometers to about 4 micrometers, from about 0.9 micrometers to about 3.5 micrometers, from about 0.9 micrometers to about 3 micrometers, from about 0.9 micrometers to about 2.5 micrometers, from about 0.9 micrometers to about 2 micrometers, from about 0.9 micrometers to about 1.5 micrometers, from about 0.9 micrometers to about 1 micrometer, from about 1 micrometer to about 5 micrometers, from about 1 micrometer to about 4.5 micrometers, from about 1 micrometer to about 4 micrometers, from about 1 micrometer to about 3.5 micrometers, from about 1 micrometer to about 3 micrometers, from about 1 micrometer to about 2.5 micrometers, from about 1 micrometer to about 2 micrometers, from about 1 micrometer to about 1.5 micrometers. .

[0072] In some embodiments, the amount of the nicotine liquid preparation provided to the heater includes volume or mass. In some embodiments, the amount is "per puff" quantified. In some embodiments, the amount includes 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 a volume greater than about 100 μL. In certain 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.

[0073] The taste of the component acid used in the salt formation can be a consideration in the selection of the acid. Suitable acids can have minimal or no toxicity to humans within the concentration used. Suitable acids can be compatible with the electronic cigarette components that are in contact or may be in contact with it at the concentration used. That is, such an acid does not degrade the electronic cigarette components that are in contact or may be in contact with it or does not otherwise react with the electronic cigarette components that are in contact or may be in contact with it. The smell of the component acid used in the salt formation can be a consideration in the selection of a suitable acid. The concentration of nicotine salt in the carrier can affect the satisfaction in an individual user. In some embodiments, the taste of the preparation is adjusted by changing the acid. In some embodiments, the taste of the preparation is adjusted by adding exogenous flavorings. In some embodiments, acids that taste or smell unpleasant are used in minimal amounts to mitigate such characteristics. In some embodiments, exogenous acids that smell or taste pleasant are added to the preparation. Examples of salts that may 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.

[0074] The nicotine liquid formulation can generate an inhalable aerosol after being heated in a low temperature electronic vaporization device, i.e., an electronic cigarette. The amount of nicotine aerosol or nicotine salt aerosol inhaled can be user-determined. The user can, for example, modify the amount of nicotine or nicotine salt inhaled by adjusting the intensity of the inhalation.

[0075] Formulations are described herein that include two or more nicotine salts. In certain embodiments where the formulation includes two or more nicotine salts, each individual nicotine salt is formed as described herein.

[0076] As used herein, nicotine liquid formulations refer to nicotine salts alone or nicotine salts and other suitable chemical components used for electronic cigarettes, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In some embodiments, the nicotine liquid formulation is stirred for 20 minutes at ambient conditions. In some embodiments, the nicotine liquid formulation is heated at 55°C and stirred for 20 minutes. In some embodiments, the nicotine liquid formulation is heated at 90°C and stirred for 60 minutes. In some embodiments, the formulation facilitates the administration of nicotine to organic tissues (e.g., lungs).

[0077] The nicotine in the nicotine liquid preparation provided herein is naturally occurring nicotine (for example, from the extract of nicotine species such as tobacco), or synthetic nicotine. In certain embodiments, nicotine is (-)-nicotine, (+)-nicotine or its mixture. In certain embodiments, nicotine is used in a relatively pure form (for example, greater than about 80% pure, 85% pure, 90% pure, 95% pure or 99% pure). In certain embodiments, the nicotine for the nicotine liquid preparation provided herein is " water clear " in appearance, so as to avoid or minimize the formation of tarry residues during the subsequent salt formation step.

[0078] In certain embodiments, the nicotine liquid preparation for low temperature vaporization device, i.e., electronic cigarette, described herein has a nicotine concentration of about 0.5% (w / w) to about 20% (w / w), wherein the concentration is the weight of nicotine to the total solution weight, i.e. (w / w). In certain embodiments, the nicotine liquid preparation provided herein has a nicotine concentration of about 1% (w / w) to about 20% (w / w). In certain embodiments, the nicotine liquid preparation provided herein has a nicotine concentration of about 1% (w / w) to about 18% (w / w). In certain embodiments, the nicotine liquid preparation provided herein has a nicotine concentration of about 1% (w / w) to about 15% (w / w). In certain embodiments, the nicotine liquid preparation provided herein has a nicotine concentration of about 4% (w / w) to about 12% (w / w). In certain embodiments, provided herein is a nicotine liquid formulation having 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, provided herein is a nicotine liquid formulation having a nicotine concentration of about 0.5% (w / w) to about 10% (w / w). In certain embodiments, provided herein is a nicotine liquid formulation having a nicotine concentration of about 0.5% (w / w) to about 5% (w / w). In certain embodiments, provided herein is a nicotine liquid formulation having a nicotine concentration of about 0.5% (w / w) to about 4% (w / w). In certain embodiments, provided herein is a nicotine liquid formulation having a nicotine concentration of about 0.5% (w / w) to about 3% (w / w). In certain embodiments, the nicotine liquid preparations provided herein have a nicotine concentration of about 0.5% (w / w) to about 2% (w / w). In certain embodiments, the nicotine liquid preparations provided herein have a nicotine concentration of about 0.5% (w / w) to about 1% (w / w). In certain embodiments, the nicotine liquid preparations provided herein have a nicotine concentration of about 1% (w / w) to about 10% (w / w). In certain embodiments, the nicotine liquid preparations provided herein have a nicotine concentration of about 1% (w / w) to about 5% (w / w). In certain embodiments, the nicotine liquid preparations provided herein have a nicotine concentration of about 1% (w / w) to about 4% (w / w). In certain embodiments, the nicotine liquid preparations provided herein have a nicotine concentration of about 1% (w / w) to about 3% (w / w). In certain embodiments, the nicotine liquid preparations provided herein have a nicotine concentration of about 1% (w / w) to about 2% (w / w). In certain embodiments, the nicotine liquid formulations provided herein have a nicotine concentration of about 2% (w / w) to about 10% (w / w). In certain embodiments, the nicotine liquid formulations provided herein have a nicotine concentration of about 2% (w / w) to about 5% (w / w).In certain embodiments, the nicotine liquid formulations provided herein have a nicotine concentration of about 2% (w / w) to about 4% (w / w). Certain embodiments provide nicotine liquid formulations 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%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.1%, 8. In some embodiments, the nicotine liquid preparation has a nicotine concentration of about 5% (w / w). In some embodiments, the nicotine liquid preparation has a nicotine concentration of about 4% (w / w). In some embodiments, the nicotine liquid preparation has 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).

[0079] In some embodiments, the nicotine liquid formulations described herein for low temperature vaporization devices, i.e., electronic cigarettes, 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 described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine content of 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) nicotine concentration. In some embodiments, the nicotine liquid formulations described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of 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 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 described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of 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 described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of 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 described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of 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 described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of 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 described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of 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 described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of from about 2% (w / w) to about 6% (w / w). In some embodiments, the nicotine liquid formulations described herein for low temperature vaporization devices, i.e., electronic cigarettes, have a nicotine concentration of about 5% (w / w).

[0080] In certain embodiments, the preparation can also include one or more flavorings. In certain embodiments, the taste of the preparation is adjusted by changing the acid. In certain embodiments, the taste of the preparation is adjusted by adding exogenous flavorings. In certain embodiments, the acid that tastes or smells unpleasant is used in a minimum amount to alleviate such characteristics. In certain embodiments, exogenous smells or tastes pleasant acid are added to the preparation. The example of the salt that can provide taste and fragrance to the mainstream aerosol at certain levels includes nicotine acetate, nicotine oxalate, nicotine malate, nicotine isovalerate, nicotine lactate, nicotine citrate, nicotine phenylacetate and nicotine myristate.

[0081] In some embodiments, suitable acids for nicotine liquid formulations have a vapor pressure of >20 mmHg at 200°C and are non-corrosive to electronic cigarettes or non-toxic to humans. In some embodiments, suitable acids for nicotine salt formation are selected from the group consisting of salicylic acid, formic acid, sorbic acid, acetic acid, benzoic acid, pyruvic acid, lauric acid, and levulinic acid.

[0082] In some embodiments, suitable acids for nicotine liquid formulations have a vapor pressure of about 20 mmHg to 200 mmHg at 200° C. and are non-corrosive to electronic cigarettes or non-toxic to humans. In some embodiments, suitable acids for nicotine salt formation are selected from the group consisting of salicylic acid, benzoic acid, lauric acid, and levulinic acid.

[0083] In some embodiments, a suitable acid for nicotine liquid formulation has a melting point of <160°C, a boiling point of >160°C, a difference of at least 50 degrees between the melting point and the boiling point, and is non-corrosive to the electronic cigarette or non-toxic to humans. In some embodiments, a suitable acid for nicotine salt formation has a melting point of at least 40 degrees below the operating temperature of the electronic cigarette, a boiling point no greater than 40 degrees below the operating temperature of the electronic cigarette, a difference of at least 50 degrees between the melting point and the boiling point, and is non-corrosive to the electronic cigarette or non-toxic to humans; wherein the operating temperature is 200°C. In some embodiments, a 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.

[0084] In some embodiments, suitable acids for nicotine liquid formulations do not decompose at the operating temperature of the electronic cigarette. In some embodiments, suitable acids for nicotine salt formation do not oxidize at the operating temperature of the electronic cigarette. In some embodiments, suitable acids for nicotine salt formation do not oxidize at room temperature. In some embodiments, suitable acids for nicotine salt formation do not provide an unpleasant taste. In some embodiments, suitable acids for nicotine salt formation have good solubility in liquid formulations used in low temperature electronic vaporization devices, i.e., electronic cigarettes.

[0085] Provided herein is a low temperature electronic vaporization device, i.e., an electronic cigarette 2, having a fluid storage compartment 4, the fluid storage compartment containing an exemplary nicotine liquid formulation of any embodiment described herein within the fluid storage compartment described herein. Figure 4 is shown in . Figure 4 The electronic cigarette 2 includes a mouth end 6, and a charging end 8. The mouth end 6 includes a mouthpiece 10. The charging end 8 can be connected to a battery or a charger or both, wherein the battery is within the body of the electronic cigarette, and the charger is separate from the battery and coupled to the body or the battery to charge the battery. In some embodiments, the electronic cigarette includes a rechargeable battery within the body 14 of the electronic cigarette and the charging end 8 includes a connection 12 for charging the rechargeable battery. In some embodiments, the electronic cigarette includes a cartridge atomizer including a fluid storage compartment and an atomizer. In some embodiments, the atomizer includes a heater. In some embodiments, the fluid storage compartment 4 is separable from the atomizer. In some embodiments, the fluid storage compartment 4 is replaceable as part of a replaceable cartridge. In some embodiments, the fluid storage compartment 4 is refillable. In some embodiments, the mouthpiece 10 is replaceable.

[0086] Provided herein is a cartomizer 18 for a low temperature electronic vaporization device, ie, an electronic cigarette 2, having a fluid storage compartment 4 containing an exemplary nicotine liquid formulation of any of the embodiments described herein within the fluid storage compartment described herein. Figure 5 The cartridge nebulizer 18 embodiment includes a mouth end 6 and a connecting end 16. Figure 5 The connecting end 16 in the embodiment couples the cartridge atomizer 18 to the body of the low temperature electronic vaporization device, i.e., the electronic cigarette, or to the battery of the electronic cigarette, or both. The mouth end 6 includes a mouthpiece 10. In some embodiments, the cartridge atomizer does not include a mouthpiece, and in such embodiments, the cartridge atomizer can be coupled to the mouthpiece of the low temperature electronic vaporization device, i.e., the electronic cigarette, or the cartridge atomizer can be coupled to the battery or body of the low temperature electronic vaporization device, i.e., the electronic cigarette, while the mouthpiece is also coupled to the battery or body of the electronic cigarette. In some embodiments, the mouthpiece is integral with the body of the electronic cigarette. In the embodiment including Figure 5 In certain embodiments of the embodiments of the present invention, the cartridge nebulizer 18 includes a fluid storage compartment 4 and a nebulizer (not shown). In certain embodiments, the nebulizer includes a heater (not shown). Example

[0087] Example 1: Preparation of nicotine liquid preparation

[0088] Various nicotine liquid formulations were prepared and added to a solution of propylene glycol (PG) / vegetable glycerin (VG) in a 3:7 ratio by weight and mixed thoroughly. The examples shown below were used to prepare 10 g of each formulation. All procedures are scalable.

[0089] For example, to prepare nicotine liquid formulations having a final nicotine freebase equivalent concentration of 2% (w / w), the following procedure was applied to each individual formulation.

[0090] - Nicotine benzoate formulation: 0.15 g benzoic acid was added to a beaker followed by 0.2 g nicotine to the same beaker. The mixture was stirred at 55°C for 20 minutes until the benzoic acid was completely dissolved and an orange oily mixture was formed. The mixture was cooled to ambient conditions. 9.65 g PG / VG (3:7) solution was added to the orange nicotine benzoate and the mixture was stirred until a visually homogeneous formulation solution was obtained.

[0091] - Nicotine benzoate formulation can also be prepared by adding 0.15g benzoic acid to a beaker followed by adding 0.2g nicotine and 9.65g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 55°C for 20 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0092] - Nicotine citrate formulation was prepared by adding 0.47g citric acid to a beaker followed by adding 0.2g nicotine and 9.33g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogenous formulation solution was obtained with no undissolved chemicals.

[0093] - Nicotine malate formulation was prepared by adding 0.33g malic acid to a beaker followed by adding 0.2g nicotine and 9.47g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogenous formulation solution was obtained with no undissolved chemicals.

[0094] - Nicotine succinate formulation was prepared by adding 0.29g succinic acid to a beaker followed by adding 0.2g nicotine and 9.51g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0095] - Nicotine salicylate formulation was prepared by adding 0.17g salicylic acid to a beaker followed by adding 0.2g nicotine and 9.63g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0096] - Nicotine salicylate formulation can also be prepared by adding 0.17 g salicylic acid to a beaker, followed by adding 0.2 g nicotine to the same beaker. The mixture was stirred at 90°C for 60 minutes until salicylic acid was completely dissolved and an orange oily mixture was formed. When 9.63 g PG / VG (3:7) solution was added, the mixture was cooled to ambient conditions or kept at 90°C. The mixture was then stirred at 90°C until a visually uniform formulation solution was obtained with no undissolved chemicals.

[0097] - Nicotine free base formulation was prepared by adding 0.2 g nicotine to a beaker followed by adding 9.8 g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at ambient conditions for 10 minutes until a visually homogenous formulation solution was obtained.

[0098] For example, to prepare nicotine liquid formulations having a final nicotine freebase equivalent concentration of 3% (w / w), the following procedure was applied to each individual formulation.

[0099] - Nicotine benzoate formulation: 0.23 g benzoic acid was added to a beaker followed by 0.3 g nicotine to the same beaker. The mixture was stirred at 55°C for 20 minutes until the benzoic acid was completely dissolved and an orange oily mixture was formed. The mixture was cooled to ambient conditions. 9.47 g PG / VG (3:7) solution was added to the orange nicotine benzoate and the blend was stirred until a visually homogeneous formulation solution was obtained.

[0100] - Nicotine benzoate formulation can also be prepared by adding 0.23g benzoic acid to a beaker followed by adding 0.3g nicotine and 9.47g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 55°C for 20 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0101] - Nicotine citrate formulation was prepared by adding 0.71 g citric acid to a beaker followed by adding 0.3 g nicotine and 8.99 g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogenous formulation solution was obtained with no undissolved chemicals.

[0102] - Nicotine malate formulation was prepared by adding 0.5g malic acid to a beaker followed by adding 0.3g nicotine and 9.2g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogenous formulation solution was obtained with no undissolved chemicals.

[0103] - Nicotine levulinate formulation was prepared by adding melted 0.64g levulinic acid to a beaker, followed by adding 0.3g nicotine to the same beaker. The mixture was stirred for 10 minutes at ambient conditions. An exothermic reaction occurred and an oily product was produced. The mixture was allowed to cool to ambient temperature and 9.06g PG / VG (3:7) solution was added to the same beaker. The mixture was then stirred for 20 minutes at ambient conditions until a visually uniform formulation solution was obtained.

[0104] - Nicotine pyruvate formulation was prepared by adding 0.33 g pyruvic acid to a beaker, followed by adding 0.3 g nicotine to the same beaker. The mixture was stirred at ambient conditions for 10 minutes. An exothermic reaction occurred and an oily product was produced. The mixture was allowed to cool to ambient temperature and 9.37 g PG / VG (3:7) solution was added to the same beaker. The mixture was then stirred at ambient conditions for 20 minutes until a visually uniform formulation solution was obtained.

[0105] - Nicotine succinate formulation was prepared by adding 0.44g succinic acid to a beaker followed by adding 0.3g nicotine and 9.26g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogenous formulation solution was obtained with no undissolved chemicals.

[0106] - Nicotine salicylate formulation was prepared by adding 0.26g salicylic acid to a beaker followed by adding 0.3g nicotine and 9.44g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0107] - Nicotine salicylate formulation can also be prepared by adding 0.26g salicylic acid to a beaker, followed by adding 0.3g nicotine to the same beaker. The mixture was stirred at 90°C for 60 minutes until salicylic acid was completely dissolved and an orange oily mixture was formed. When 9.44g PG / VG (3:7) solution was added, the mixture was cooled to ambient conditions or kept at 90°C. The blend was then stirred at 90°C until a visually uniform formulation solution was obtained with no undissolved chemicals.

[0108] - Nicotine free base formulation was prepared by adding 0.3 g nicotine to a beaker followed by adding 9.7 g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at ambient conditions for 10 minutes until a visually homogenous formulation solution was obtained.

[0109] For example, to prepare nicotine liquid formulations having a final nicotine freebase equivalent concentration of 4% (w / w), the following procedure was applied to each individual formulation.

[0110] - Nicotine benzoate formulation: 0.3 g benzoic acid was added to a beaker followed by 0.4 g nicotine to the same beaker. The mixture was stirred at 55°C for 20 minutes until the benzoic acid was completely dissolved and an orange oily mixture was formed. The mixture was cooled to ambient conditions. 9.7 g PG / VG (3:7) solution was added to the orange nicotine benzoate and the blend was stirred until a visually homogeneous formulation solution was obtained.

[0111] - Nicotine benzoate formulation can also be prepared by adding 0.3g benzoic acid to a beaker followed by adding 0.4g nicotine and 9.7g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 55°C for 20 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0112] For example, to prepare nicotine liquid formulations having a final nicotine freebase equivalent concentration of 5% (w / w), the following procedure was applied to each individual formulation.

[0113] - Nicotine benzoate formulation: 0.38 g benzoic acid was added to a beaker followed by 0.5 g nicotine to the same beaker. The mixture was stirred at 55°C for 20 minutes until the benzoic acid was completely dissolved and an orange oily mixture was formed. The mixture was cooled to ambient conditions. 9.12 g PG / VG (3:7) solution was added to the orange nicotine benzoate and the blend was stirred until a visually homogeneous formulation solution was obtained.

[0114] - Nicotine benzoate formulation can also be prepared by adding 0.38g benzoic acid to a beaker followed by adding 0.5g nicotine and 9.12g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 55°C for 20 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0115] - Nicotine malate formulation was prepared by adding 0.83g malic acid to a beaker followed by adding 0.5g nicotine and 8.67g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogenous formulation solution was obtained with no undissolved chemicals.

[0116] - Nicotine levulinate formulation was prepared by adding 1.07 g levulinic acid melted to a beaker, followed by adding 0.5 g nicotine to the same beaker. The mixture was stirred for 10 minutes at ambient conditions. An exothermic reaction occurred and an oily product was produced. The mixture was allowed to cool to ambient temperature and 8.43 g PG / VG (3:7) solution was added to the same beaker. The mixture was then stirred for 20 minutes at ambient conditions until a visually uniform formulation solution was obtained.

[0117] - Nicotine pyruvate formulation was prepared by adding 0.54 g pyruvic acid to a beaker, followed by adding 0.5 g nicotine to the same beaker. The mixture was stirred for 10 minutes at ambient conditions. An exothermic reaction occurred and an oily product was produced. The mixture was allowed to cool to ambient temperature and 8.96 g PG / VG (3:7) solution was added to the same beaker. The mixture was then stirred for 20 minutes at ambient conditions until a visually uniform formulation solution was obtained.

[0118] - Nicotine succinate formulation was prepared by adding 0.73g succinic acid to a beaker followed by adding 0.5g nicotine and 8.77g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0119] - Nicotine salicylate formulation was prepared by adding 0.43g salicylic acid to a beaker followed by adding 0.5g nicotine and 9.07g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at 90°C for 60 minutes until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0120] - Nicotine salicylate formulation can also be prepared by adding 0.43g salicylic acid to a beaker, followed by adding 0.5g nicotine to the same beaker. The mixture was stirred at 90°C for 60 minutes until salicylic acid was completely dissolved and an orange oily mixture was formed. When 9.07g PG / VG (3:7) solution was added, the mixture was cooled to ambient conditions or kept at 90°C. The blend was then stirred at 90°C until a visually homogeneous formulation solution was obtained with no undissolved chemicals.

[0121] - Nicotine free base formulation was prepared by adding 0.5 g nicotine to a beaker followed by adding 9.5 g PG / VG (3:7) solution to the same beaker. The mixture was then stirred at ambient conditions for 10 minutes until a visually homogenous formulation solution was obtained.

[0122] Various formulations containing different nicotine salts may be similarly prepared, or different concentrations of the above-noted nicotine liquid formulations or other nicotine liquid formulations may be prepared as would be known to one of skill in the art after reading the disclosure herein.

[0123] Various formulations containing two or more nicotine salts can be similarly prepared in a solution of propylene glycol (PG) / vegetable glycerin (VG) in a 3:7 ratio. For example, 0.43 g (2.5% w / w nicotine) of nicotine levulinate and 0.34 g (2.5% w / w nicotine) of nicotine acetate are added to 9.23 g of PG / VG solution to produce a 5% w / w nicotine liquid formulation.

[0124] Another exemplary formulation is also provided. For example, 0.23 g (1.33% w / w nicotine) of nicotine benzoate (molar ratio 1:1 nicotine / benzoic acid), 0.25 g (1.33% w / w nicotine) of nicotine salicylate (molar ratio 1:1 nicotine / salicylic acid), and 0.28 g (1.34% w / w nicotine) of nicotine pyruvate (molar ratio 1:2 nicotine / pyruvic acid) are added to 9.25 g of PG / VG solution to produce a 5% w / w nicotine liquid formulation.

[0125] Example 2: Heart rate study of nicotine solution via electronic cigarette

[0126] Exemplary formulations of nicotine levulinate, nicotine benzoate, nicotine succinate, nicotine salicylate, nicotine malate, nicotine pyruvate, nicotine citrate, nicotine free base, and a control of propylene glycol were prepared as noted in Example 1 as 3% w / w solutions and administered to the same human subjects in the same manner by a low temperature electronic vaporization device, i.e., an electronic cigarette. About 0.5 mL of each solution was loaded into the "eRoll" cartridge atomizer (joyetech.com) 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.

[0127] Heart rate measurements were taken for 6 minutes; starting 1 minute before the start of puffing, for 3 minutes during puffing, and continuing until 2 minutes after the end of puffing. In each case, the test participants took 10 puffs in 3 minutes. The basal heart rate was the average heart rate during the initial 1 minute before the start of puffing. The heart rate after the start of puffing was averaged over 20 second intervals. Puffing (inhalation) occurred every 20 seconds for a total of 3 minutes. The normalized heart rate was defined as the ratio between the individual heart rate data points and the basal heart rate. The final result was taken as the Figure 1 The normalized heart rate shown in the first 4 minutes is presented.

[0128] Figure 1 Results from heart rate measurements performed on various nicotine liquid formulations are summarized. Figure 1, at the 180 second time point, from top to bottom (highest normalized heart rate to lowest normalized heart rate), the nicotine liquid preparations are as follows: nicotine salicylate preparation, nicotine malate preparation, nicotine levulinate preparation (at 180 seconds, almost the same as nicotine malate, so as a second reference point: the nicotine malate preparation curve is lower than the nicotine levulinate preparation at the 160 second time point), nicotine pyruvate preparation, nicotine benzoate preparation, nicotine citrate preparation, nicotine succinate preparation, and nicotine free base preparation. The bottom curve at the 180 second time point (lowest normalized heart rate) is related to the placebo (100% propylene glycol). The test preparations containing nicotine salts cause a faster and more obvious increase in heart rate than the placebo. When compared with nicotine free base preparations with the same amount of nicotine by weight, the test preparations containing nicotine salts also cause a faster and more obvious increase. In addition, nicotine salts (e.g., nicotine benzoate and nicotine pyruvate) prepared from acids having a calculated vapor pressure between 20-200 mmHg at 200°C (benzoic acid (171.66 mmHg), respectively, in addition to pyruvic acid (having a boiling point of 165°C)) caused a more rapid increase in heart rate than the rest. Nicotine salts (e.g., nicotine levulinate, nicotine benzoate, and nicotine salicylate) prepared from acids (benzoic acid, levulinic acid, and salicylic acid, respectively) also caused a more significant increase in heart rate. Therefore, other suitable nicotine salts formed by acids with similar vapor pressures and / or similar boiling points can be used in accordance with the practice of the present invention. This experience of an elevated heart rate that is theoretically close to or theoretically comparable to that of a traditional burning cigarette has not been demonstrated or identified in other electronic cigarette devices. This has not been demonstrated or identified in low temperature tobacco vaporization devices (electronic cigarettes) that do not burn tobacco, even when nicotine salts (20% (w / w) or greater nicotine salt solutions) are used as additives to tobacco. Therefore, the results from this experiment are surprising and unexpected.

[0129] Example 3: Study on the Satisfaction of Nicotine Salt Solution by Electronic Cigarette

[0130] In addition to the heart rate study shown in Example 2, a nicotine liquid formulation (using a 3% w / w nicotine liquid formulation as described in Example 1) was used to conduct a satisfaction study using 11 test participants. Test participants, low-temperature electronic vaporization devices, i.e., electronic cigarettes, and / or traditional cigarette users were required to have no nicotine intake for at least 12 hours before the test. In each case, the participant took 10 puffs in 3 minutes using a low-temperature electronic vaporization device, i.e., an electronic cigarette (the same as used in Example 2), and was then asked to rate the level of physical satisfaction and emotional satisfaction he or she felt on a scale of 0-10, where 0 was no physical satisfaction or emotional satisfaction. The formulations were then graded from 1-8 using the ratings provided for each formulation, with 1 having the highest rating and 8 having the lowest rating. The ratings for each acid were then averaged across the 11 participants to produce the average ratings in Table 1. Nicotine benzoate, nicotine pyruvate, nicotine salicylate, and nicotine levulinate all performed well, followed by nicotine malate, nicotine succinate, and nicotine citrate.

[0131] Table 1

[0132]

[0133]

[0134] Based on the satisfaction study, nicotine salt formulations containing acids with a vapor pressure range between >20 mmHg@200°C, or 20-200 mmHg@200°C, or 100-300 mmHg@200°C provide more satisfaction than the rest (except for pyruvic acid which has a 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.

[0135] In addition, based on the satisfaction study, nicotine liquid formulations containing acids that degrade at the operating temperature of the device (i.e., malic acid), such as nicotine salt liquid formulations, are rated low. However, nicotine liquid formulations containing acids that do not degrade at the operating temperature of the device (i.e., benzoic acid), such as nicotine salt liquid formulations, are rated high. Therefore, acids that are easily degraded at the operating temperature of the device are less favorable than acids that are not easily degraded at the operating temperature of the device.

[0136] Example 4: Test Formulation 1 (TF1) :

[0137] Nicotine levulinate in glycerol The solution comprising nicotine salt used: 1.26 g (12.6% w / w) 1:3 nicotine levulinate, 8.74 g (87.4% w / w) glycerol - total weight 10.0 g.

[0138] Pure nicotine levulinate is added to glycerol and mixed thoroughly. L-Nicotine has a molar mass of 162.2 g and the molar mass of levulinic acid is 116.1 g. At a 1:3 molar ratio, the percentage of nicotine by weight in nicotine levulinate is given by: 162.2 g / (162.2 g + (3 x 116.1 g)) = 31.8% (w / w).

[0139] Example 5: Test Formulation 2 (TF2):

[0140] A solution of free base nicotine in glycerol containing 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.

[0141] Example 6: Heart rate study of nicotine solution via electronic cigarette:

[0142] Both formulations (TF1 and TF2) were administered to the same human subject in the same manner via a low temperature electronic vaporization device, i.e., an electronic cigarette: approximately 0.6 mL of each solution was loaded into an "eGo-C" cartridge atomizer (joyetech.com). The atomizer was then attached to an "eVic" 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.

[0143] The atomizer in both cases had a resistance of 2.4 ohms and the electronic cigarette was set to 4.24V, producing a power of 7.49W. (P = V^2 / R)

[0144] Heart rate was measured at 30-second intervals for ten minutes from the start of the puff. In each case, the test participants took 10 puffs in 3 minutes (solid line (2nd highest peak)): cigarette, dark dashed line (highest peak): test formulation 1 (TF1-nicotine liquid formulation), light dashed line: test formulation 2 (TF2-nicotine liquid formulation). Comparison between cigarette, TF1, and TF2 Figure 2 is shown in .

[0145] exist Figure 2It is clearly shown in that the test formulation (TF1) with nicotine levulinate causes a faster heart rate increase than nicotine alone (TF2). In addition, TF1 is closer to the rate of increase similar to cigarettes. Other salts were tested and also found to increase heart rate relative to pure nicotine solution. Therefore, other suitable nicotine salts that cause similar effects can be used according to the practice of the present invention. For example, other keto acids (α-keto acids, β-keto acids, γ-keto acids, and the like), such as pyruvic acid, oxaloacetic acid, acetoacetyl and the like. This experience of increased heart rate comparable to the increased heart rate of traditional burning cigarettes has neither been confirmed or identified in other electronic cigarette devices, nor in low-temperature tobacco vaporization devices that do not burn tobacco, even when nicotine salts (20% (W / W) or greater nicotine salt solutions) are used as additives for tobacco. Therefore, the results from this experiment are surprising and unexpected.

[0146] Furthermore, the data appear to be consistent with Figure 2 The previous findings shown in are well correlated.

[0147] As previously noted in the gratification study, with the exception of the nicotine liquid formulation prepared with pyruvic acid having a boiling point of 165°C, the nicotine salt formulations containing acids with vapor pressures between 20-300 mmHg @ 200°C provided more gratification than the rest, as shown in Figure 3 In the description. In addition, based on the study, nicotine liquid preparations containing acids that degrade at the operating temperature of the device (i.e., malic acid), such as nicotine salt liquid preparations, are rated low, and nicotine liquid preparations containing acids that do not degrade at the operating temperature of the device (i.e., benzoic acid), such as nicotine salt liquid preparations, are rated high. Therefore, acids that are easily degraded at the operating temperature of the device are less favorable than acids that are not easily degraded at the operating temperature of the device. Based on the findings herein, these nicotine liquid preparations are expected to have one or more of the following properties:

[0148] - Vapor pressure between 20-300 mmHg @ 200°C,

[0149] -> 20mmHg@200℃ vapor pressure,

[0150] - 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,

[0151] - 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,

[0152] - a difference between boiling point and melting point of at least 50°C, and a boiling point at most 40°C below the operating temperature, and a melting point at least 40°C below the operating temperature, and

[0153] - Resistance to degradation at the operating temperature of the device.

[0154] T 最大 - Time to maximum blood concentration: Based on the results determined herein, users of low temperature electronic vaporization devices, i.e., electronic cigarettes, containing nicotine liquid formulations will experience similar levels of physical and emotional satisfaction from using formulations containing a mixture of nicotine salts prepared with a suitable acid, which is at least 1.2X to 3X faster than using formulations containing free base nicotine. Figure 1 As shown in the figure: Nicotine from a nicotine salt formulation appears to produce a heartbeat of almost 1.2 times the normal heart rate for an individual approximately 40 seconds after starting to puff; while nicotine from a nicotine freebase formulation appears to produce a heartbeat of almost 1.2 times the normal heart rate for an individual approximately 110 seconds after starting to puff; a 2.75X difference in the time to obtain a similar initial satisfaction level.

[0155] Again, this will be consistent with the Figure 2 The data is inconsistent. Figure 2 The data illustrate that at about 120 seconds (2 minutes), the heart rate of the test participants reached a maximum of 105-110bpm using either a regular cigarette or a nicotine liquid formulation (TF1); whereas using a nicotine freebase formulation (TF2), those same participants' heart rates only reached a maximum of about 86bpm at about 7 minutes; furthermore, nicotine salts (and regular cigarettes) had a 1.2-fold greater effect difference relative to freebase nicotine.

[0156] Additionally, when considering the peak satisfaction level (obtained at approximately 120 seconds from the start of the puff (time = 0)) and observing the slope of the line to normalized heart rate, the approximate slope range for those nicotine liquid formulations that exceed the freebase nicotine liquid formulation is within 0.0054 hours. n / second and 0.0025 hours n By comparison, the slope of the line for the freebase nicotine liquid formulation is about 0.002. This would indicate that the concentration of available nicotine would be delivered to the user at a rate between 1.25 and 2.7 times faster than the freebase formulation.

[0157] In another performance measure; C 最大- Maximum blood nicotine concentration; it is expected that similar rates of rise will be measured in blood nicotine concentrations as those exemplified above. That is, it is expected based on the findings herein and unexpected based on currently known technology that there will be similar C between common cigarettes and certain nicotine liquid formulations. 最大 , but with a lower C in free base nicotine solution 最大 .

[0158] Similarly, it is expected based on the findings herein and unexpected based on currently known technology that certain nicotine liquid formulations will have higher levels of nicotine uptake levels in the blood at an early stage. In fact, Example 8 presents data for two salt formulations that are consistent with these predictions made based on the findings and testing noted herein and unexpected compared to currently available technology.

[0159] Example 7: Heart rate study of nicotine solution via electronic cigarette

[0160] Exemplary formulations of nicotine levulinate, nicotine benzoate, nicotine succinate, nicotine salicylate, nicotine malate, nicotine pyruvate, nicotine citrate, nicotine sorbate, nicotine laurate, nicotine free base, and a control of propylene glycol were prepared as noted in Example 1 and administered to the same human subjects in the same manner by a low-temperature electronic vaporization device, i.e., an electronic cigarette. About 0.5 mL of each solution was loaded into the "eRoll" cartridge atomizer (joyetech.com) used in the study. The atomizer was then attached to an "eRoll" electronic cigarette (same manufacturer). The operating temperature of the electronic cigarette was from about 150°C to about 250°C, or from about 180°C to about 220°C.

[0161] Heart rate measurements were taken for 6 minutes; from 1 minute before the start of the puff, for 3 minutes during the puff, and continued until 2 minutes after the end of the puff. In each case, the test participant took 10 puffs in 3 minutes. The basal heart rate is the average heart rate within the first 1 minute before the start of the puff. The heart rate after the start of the puff is averaged in 20 second intervals. The normalized heart rate is defined as the ratio between the individual heart rate data points and the basal heart rate. The final result is presented as the normalized heart rate.

[0162] Example 8: Plasma Testing

[0163] Plasma testing was performed on 24 subjects (n=24). In this study, four test articles were used: a reference cigarette and three nicotine liquid formulations used in low temperature electronic vaporization devices, i.e., electronic cigarettes, with 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 electronic cigarettes: 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.

[0164] The concentration of nicotine in each preparation is confirmed using a UV spectrophotometer (Cary 60, manufactured by Agilent). The sample solution for UV analysis is prepared by dissolving 20 mg of each preparation in 20 mL of 0.3% HCl in water. Then, the sample solution is scanned in a UV spectrophotometer and the characteristic nicotine peak at 259 nm is used to quantify the nicotine in the sample relative to a standard solution of 19.8 μg / mL nicotine in the same diluent. The standard solution is prepared by first dissolving 19.8 mg of nicotine in 10 mL of 0.3% HCl in water, followed by a 1:100 dilution with 0.3% HCl in water. The nicotine concentration reported for all preparations is within the range of 95%-105% of the concentration claimed.

[0165] All subjects were able to consume 30-55 mg of the liquid formulation of each blend tested using an e-cigarette.

[0166] References: C. Bullen et al., Tobacco Control 2010, 19: 98-103

[0167] Cigarettes (5 min adlib, n = 9): T 最大 =14.3(8.8-19.9),C 最大 =13.4(6.5-20.3)

[0168] 1.4% E-cig (5min impromptu speech, n=8): T 最大 =19.6(4.9-34.2),C 最大 =1.3(0.0-2.6)

[0169] Nicotine inhaler (20 mg / 20 min, n = 10): T 最大=32.0(18.7-45.3),C 最大 =2.1(1.0-3.1)

[0170] Evaluating the C of 2% Nicotine Blend 最大 :

[0171] C 最大 = Mass consumed * Strength * Bioavailability / (Volume of Distribution * Body weight) = 40 mg * 2% * 80% / (2.6 L / kg * 75 kg) = 3.3 ng / mL

[0172] Evaluating the 4% Nicotine Blend C 最大 :

[0173] C 最大 = Mass consumed * Strength * Bioavailability / (Volume of distribution * Body weight) = 40 mg * 4% * 80% / (2.6 L / kg * 75 kg) = 6.6 ng / mL

[0174] The pharmacokinetic profile of the plasma test was Figure 6 ; shows the blood nicotine concentration (ng / mL) over time after the first puff (inhalation) of the aerosol from the electronic cigarette or the smoke of the reference cigarette. Ten puffs were taken at 30 second intervals starting at time = 0 and continuing for 4.5 minutes. Based on Figure 6 It is possible that the data shown in other studies in this article are consistent with the data on C 最大 , the free base formulation is statistically different from the salt formulation and / or the reference cigarette because the free base appears lower than the other formulations tested at several time points. In addition, those skilled in the art, after reviewing the disclosure herein, can appropriately power a test to determine the actual statistically based differences between one or more formulations and cigarettes, or between the formulations themselves in a low temperature electronic vaporization device, i.e., an electronic cigarette. For ease of reference, Table 2 presents the amount of nicotine detected for each formulation and reference cigarette presented in ng / mL (as an average of all users), together with C 最大 and T 最大 Therefore, data from these tables are used along with the original data to generate Figure 6 , Figure 7 ,as well as Figure 8 .

[0175] Table 2

[0176] time Pall Mall 2% Free Base 2% Benzoate 2% Malate -2 0.07 -0.14 0.02 0.10 0 -0.03 0.14 -0.03 -0.15 1.5 4.54 0.22 1.43 1.91 3 17.12 1.50 5.77 5.18 5 24.85 2.70 7.35 7.65 7.5 16.36 2.60 4.73 4.79 10 13.99 2.87 3.90 3.71 12.5 12.80 2.79 3.11 3.10 15 11.70 2.30 2.79 2.64 30 7.65 1.14 1.64 1.06 60 4.47 0.04 0.37 0.06 <![CDATA[T 最大 (min)]]> 6.15 9.48 8.09 5.98 <![CDATA[C 最大 (ng / mL)]]> 29.37 4.56 9.27 8.75

[0177] C of three nicotine liquid preparations and a reference cigarette 最大 and T最大 The comparison is Figure 7 Due to the time constraints of the wash-period, the baseline blood nicotine concentration (at t = -2 min and t = 0 min) was higher for samples consumed later in the test day. Figure 6-7 The data in show corrected blood nicotine concentration values ​​(ie, the apparent blood nicotine concentration at each time point minus the baseline nicotine concentration of the same sample). Figure 8 Describes T calculated using corrected blood nicotine concentration 最大 The reference cigarette, the nicotine liquid formulation containing nicotine benzoate, and the nicotine liquid formulation containing nicotine malate all exhibited higher C values ​​than the nicotine liquid formulation containing free base nicotine. 最大 and lower T 最大 The superior performance of nicotine liquid formulations comprising nicotine benzoate and nicotine malate compared to freebase nicotine may be due to the superior transfer efficiency of nicotine salts from liquid to aerosol compared to freebase nicotine, which allows nicotine to be more effectively delivered to the user's lungs and / or the alveoli of the user's lungs.

[0178] The contents of the nicotine liquid formulations and the nature of the acids tested provide a plausible explanation for how the plasma test data confirms the lower rating of malic acid compared to benzoic acid as described in Example 1. In the plasma experiments, the nicotine malate formulation contained a 1:2 molar ratio of nicotine to malic acid and the nicotine benzoate formulation contained a 1:1 molar ratio of nicotine to benzoic acid. As explained below, additional malic acid is required to aerosolize the nicotine because malic acid degrades at the operating temperature of the electronic cigarette. Therefore, it is possible that the aerosol generated using malic acid contains degradation products, which may produce an unpleasant experience for the user, thus resulting in a lower rating. For example, the unpleasant experience includes taste, neurological response, and / or irritation of one or more of the oral cavity, upper respiratory tract, and / or lungs.

[0179] Example 9: Blood plasma testing

[0180] Plasma testing was performed on 24 subjects (n=24). In this study, eight test articles were used: a reference cigarette and seven blends delivered to the user as an aerosol in a low-temperature electronic vaporization device, i.e., an electronic cigarette. The operating temperature of the electronic cigarette was from about 150°C to about 250°C, or from about 180°C to about 220°C. The reference cigarette was PallMall (New Zealand). Seven blends were tested: 2% free base, 2% benzoate, 4% benzoate, 2% citrate, 2% malate, 2% salicylate, and 2% succinate. The seven blends were liquid formulations prepared according to a similar protocol as described below and in Example 1.

[0181] All subjects will consume 30-55 mg of the liquid formulation of each blend tested. Ten puffs will be taken at 30 second intervals starting at time = 0 and continuing for 4.5 minutes. Plasma testing will occur for at least 60 minutes from the first puff (t = 0). For pharmacokinetic data of nicotine in the plasma of users (e.g., C 最大 , T 最大 , AUC), along with the rate of nicotine absorption within the first 90 seconds for each test article were obtained at various time periods during those 60 minutes.

[0182] Example 10: Blood plasma testing

[0183] Twenty-four subjects (n=24) were tested for plasma. In this study, eleven test articles were used: a reference cigarette and ten blends delivered to the user as an aerosol in a low temperature electronic vaporization device, i.e., an electronic cigarette. The reference cigarette was Pall Mall (New Zealand). The operating temperature of the electronic cigarette was from about 150°C to about 250°C, or from about 180°C to about 220°C. Ten blends were 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 were liquid formulations prepared according to a similar protocol as described below and in Example 1.

[0184] All subjects will consume 30-55 mg of the liquid formulation of each blend tested. Ten puffs will be taken at 30 second intervals starting at time = 0 and continuing for 4.5 minutes. Plasma testing will occur for at least 60 minutes from the first puff (t = 0). Pharmacokinetic data for nicotine in the plasma of users (e.g., C 最大 , T 最大, AUC) were obtained at various time periods during those 60 minutes, along with the rate of nicotine absorption within the first 90 seconds for each test article.

[0185] Example 11: Blood plasma testing

[0186] Twenty-four subjects (n=24) were tested for plasma. In this study, twenty-one test articles were used: a reference cigarette and twenty blends delivered to the user as an aerosol in a low-temperature electronic vaporization device, i.e., an electronic cigarette. The reference cigarette was Pall Mall (New Zealand). The operating temperature of the electronic cigarette was from about 150°C to about 250°C, or from about 180°C to about 220°C. Twenty blends were 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. Twenty blends were liquid formulations prepared according to a similar protocol to that described below and in Example 1.

[0187] All subjects will consume 30-55 mg of the liquid formulation of each blend tested. Ten puffs will be taken at 30 second intervals starting at time = 0 and continuing for 4.5 minutes. Plasma testing will occur for at least 60 minutes from the first puff (t = 0). Pharmacokinetic data for nicotine in the plasma of users (e.g., C 最大 , T 最大 , AUC), along with the rate of nicotine absorption within the first 90 seconds for each test article were obtained at various time periods during those 60 minutes.

[0188] Example 12: Plasma Testing

[0189] Twenty-four subjects (n=24) were tested for plasma. In this study, twenty-one test articles were used: one reference cigarette and twenty blends delivered to the user as an aerosol in a low-temperature electronic vaporization device, i.e., an electronic cigarette. The reference cigarette was Pall Mall (New Zealand). The operating temperature of the electronic cigarette was from about 150°C to about 250°C, or from about 180°C to about 220°C. Twenty blends were 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. Twenty blends were liquid formulations prepared according to a similar protocol to that described below and in Example 1.

[0190] All subjects will consume 30-55 mg of the liquid formulation of each blend tested. Ten puffs will be taken at 30 second intervals starting at time = 0 and continuing for 4.5 minutes. Plasma testing will occur for at least 60 minutes from the first puff (t = 0). For pharmacokinetic data of nicotine in the plasma of users (e.g., C 最大 , T 最大 , AUC), along with the rate of nicotine absorption within the first 90 seconds for each test article were obtained at various time periods during those 60 minutes.

[0191] Example 13: Aerosolized Nicotine Salt Testing

[0192] The experimental system included a glass bubbler (bubbler-1), a Cambridge filter pad, and 2 glass bubblers (trap-1 and trap-2 connected in sequence) to capture any volatiles passing through the filter pad. A low temperature electronic vaporization device, i.e., an electronic cigarette, was connected to the inlet of bubbler 1 and activated by a smoking machine connected to the outlet of trap 2 under a designed puffing scheme. The puffing scheme included: number of puffs per sample = 30, puff size = 60cc, puff duration = 4s. The trap solvent included 0.3% HCl in water. The nicotine liquid formulations tested were: free base 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 produced using the procedure described in Example 1. In the experimental system, gaseous (ie, vapor) analytes were trapped by a bubbler.

[0193] The program includes:

[0194] Before starting to draw, weigh the following parts: the electronic cigarette filled with nicotine liquid formulation, the bubbler-1 filled with 35 mL of capture solvent, the clean filter pad and pad holder, the trap-1 filled with 20 mL of capture solvent, and the trap-2 filled with 20 mL of capture solvent;

[0195] Connect in the following order: electronic cigarette, bubbler-1, filter pad, trap-1, trap-2, and smoking machine;

[0196] Smoking was performed under the aforementioned puffing regimen. Clean air puffs of the same puff size and duration were performed after each smoking puff;

[0197] After the end of the aspiration protocol, all parts were weighed. The inlet tube of the bubbler-1 was assayed with 10 mL of capture solvent in 1 mL aliquots. After aspiration, the total amount of solvent in the bubbler-1 was calculated with correction for water loss from 60 aspirations. The filter pad was cut in half and each half was extracted in 20 mL of capture solvent for 2 hours. The pad extract was filtered through a 0.2 μm nylon syringe filter. The front half of the pad holder was assayed with 5 mL of capture solvent. The back half of the pad holder was assayed with 3 mL of capture solvent.

[0198] The solution was analyzed by UV-Vis spectroscopy. The absorbance at 259 nm was used to calculate the nicotine concentration. The absorbance at 230 nm was used to calculate the benzoic acid concentration. Malic acid was quantified using the Malic Acid UV Test Kit from NZYTech Inc.

[0199] Results and discussion

[0200] Analyte recovery

[0201] The total recovery of each analyte (nicotine, benzoic acid, and malic acid) was calculated as the sum of the measured amounts from all parts. No analytes were detected in trap-1 and trap-2. The recovery percentage was calculated by dividing the total recovery by the theoretical amount produced by the electronic cigarette. Table 3 shows the recovery percentage of nicotine in the free base liquid formulation, nicotine benzoate liquid formulation, and nicotine malate liquid formulation. Table 3 also shows the recovery percentage of benzoic acid in the nicotine benzoate liquid formulation and the recovery percentage of malic acid in the nicotine malate liquid formulation.

[0202] Table 3

[0203] Analyte being measured % Recovery Nicotine (nicotine free base liquid preparation) 80.2±1.3 Nicotine (nicotine benzoate liquid preparation) 90.4±3.4 Benzoic acid (nicotine benzoate liquid preparation) 91.8±3.5 Nicotine (nicotine malate liquid preparation) 92.1±4.9 Malic Acid (nicotine malate liquid preparation) 46.4±8.1

[0204] The recovery percentage of malic acid is significantly lower than that of nicotine and benzoic acid, with large variations across sample replicates. Malic acid is reported to thermally decompose at 150°C, which is lower than common electronic cigarette operating temperatures. The low recovery of malic acid found in the aerosol is consistent with the thermal instability of malic acid. This results in an inefficient nicotine to malic acid ratio in the aerosol compared to the ratio in the nicotine liquid formulation. Therefore, the protonation state of nicotine is also lower in the aerosol, which will actually result in less nicotine being present in the aerosol produced with the nicotine malate liquid formulation. The lower nicotine recovery in the case of the free base nicotine liquid formulation compared to the nicotine liquid formulation may be caused by the sample collection and measurement procedures for escaping a small portion of the gaseous nicotine from the smoking system.

[0205] Volatile nicotine in aerosol

[0206] The amount of nicotine in the aerosol leaving the low temperature vaporization device, i.e., the electronic cigarette, is examined by calculating the percentage of nicotine captured in the bubbler-1 compared to the total recovered nicotine. Benzoic acid is expected to reside in particles (i.e., droplets) in the aerosol because benzoic acid is non-volatile. Therefore, benzoic acid is used as a particle marker for nicotine because it is expected that benzoic acid protonates nicotine at a 1:1 molar ratio, which will result in nicotine being present in the aerosol, in certain embodiments in the non-gas phase of the aerosol. The amount of aerosolized nicotine is calculated by comparing the difference between the amount of benzoic acid captured in the bubbler-1 and the amount of benzoic acid in the nicotine liquid formulation.

[0207] A linear relationship was found between the amount of nicotine trapped in bubbler-1 and the molar ratio of benzoic acid to nicotine in the nicotine liquid formulation ( Fig. 9 ). At a 1:1 molar ratio of nicotine to benzoic acid, the minimum amount of nicotine that became fully protonated and vapor collected in bubbler-1 was measured. Furthermore, at a 1:1.5 molar ratio of nicotine to benzoic acid, no further decrease in the amount of aerosolized nicotine was detected. It should also be noted that a higher percentage of freebase nicotine was collected by bubbler-1, indicating that a higher concentration of vapor phase nicotine is nicotine produced when freebase nicotine is used in the nicotine liquid formulation.

[0208] In theory, diprotic malic acid 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. Therefore, considering the low transfer efficiency of malic acid, the effective nicotine to malic acid ratio in the aerosol is 0.23 when a nicotine liquid formulation containing a molar ratio of 1:0.5 of nicotine to malic acid is produced, and the effective nicotine to malic acid ratio in the aerosol is 0.87 when a nicotine liquid formulation containing a molar ratio of 1:2 of nicotine to malic acid is produced. As expected, the percentage of acid captured in the bubbler-1 when using a nicotine liquid formulation containing a nicotine to malic acid molar ratio of 1:0.5 falls between the percentage of acid recovered when using a nicotine liquid formulation containing a nicotine to benzoic acid molar ratio of 1:0.4 and 1:0.7. The nicotine liquid formulation containing a 1:2 molar ratio of nicotine to malic acid delivered an aerosol containing a 1:0.87 molar ratio of nicotine to malic acid, thus containing excess malic acid than required to fully protonate the nicotine, leaving only 14.7% of the nicotine trapped in bubbler-1.

[0209] Aerosolized nicotine that stays in the particles is more likely to travel to the alveoli and enter the user's blood. Gaseous nicotine has a better chance of being deposited in the upper respiratory tract and absorbed at a different rate than the deep lung gas exchange zone. Therefore, using a nicotine liquid formulation 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 will be delivered to the user's lungs. This is consistent with the T described in Example 8. 最大 The data is consistent.

[0210] Example 14: Acidic functional group requirement test

[0211] The experimental system included a glass bubbler (bubbler-1), a Cambridge filter pad, and 2 glass bubblers (well 1 and well 2 connected in sequence) to capture any volatiles passing through the filter pad. A low-temperature electronic vaporization device, i.e., an electronic cigarette, was connected to the inlet of bubbler 1 and activated by a smoking machine connected to the outlet of well 2 under a designed puffing scheme. The puffing scheme included: number of puffs per sample = 30, puff size = 60cc, puff duration = 4s. The capture solvent included 0.3% HCl in water. The nicotine liquid formulations tested were: free base nicotine, nicotine benzoate at a molar ratio of nicotine to acid of 1:0.4, 1:0.7, 1:1, and 1:1.5, and nicotine malate at a molar ratio of nicotine to acid of 1:0.5 and 1:2. The formulations were generated using the procedure described in Example 1. In the experimental system, gaseous (i.e., vapor) analytes were captured by the bubbler.

[0212] The program includes:

[0213] Before starting to draw, weigh the following parts: the electronic cigarette filled with nicotine liquid formulation, the bubbler-1 filled with 35 mL of capture solvent, the clean filter pad and pad holder, the trap-1 filled with 20 mL of capture solvent, and the trap-2 filled with 20 mL of capture solvent;

[0214] Connect in the following order: electronic cigarette, bubbler-1, filter pad, trap-1, trap-2, and smoking machine;

[0215] Smoking was performed under the aforementioned puffing regimen. Clean air puffs of the same puff size and duration were performed after each smoking puff;

[0216] After the end of the aspiration protocol, all parts were weighed. The inlet tube of the bubbler-1 was assayed with 10 mL of capture solvent in 1 mL aliquots. After aspiration, the total amount of solvent in the bubbler-1 was calculated with correction for water loss from 60 aspirations. The filter pad was cut in half and each half was extracted in 20 mL of capture solvent for 2 hours. The pad extract was filtered through a 0.2 μm nylon syringe filter. The front half of the pad holder was assayed with 5 mL of capture solvent. The back half of the pad holder was assayed with 3 mL of capture solvent.

[0217] The solution was analyzed by UV-Vis spectroscopy. The absorbance at 259 nm was used to calculate the nicotine concentration. The absorbance at 230 nm was used to calculate the benzoic acid concentration. Malic acid was quantified using the Malic Acid UV Test Kit from NZYTech Inc.

[0218] Results and discussion

[0219] The amount of nicotine in the aerosol leaving the low temperature vaporization device, i.e., the electronic cigarette, is examined by calculating the percentage of nicotine captured in the bubbler-1 compared to the total recovered nicotine. Benzoic acid is expected to reside in particles (i.e., droplets) in the aerosol because benzoic acid is non-volatile. Therefore, benzoic acid is used as a particle marker for nicotine because it is expected that benzoic acid protonates nicotine at a 1:1 molar ratio, which will result in nicotine being present in the aerosol, in certain embodiments in the non-gas phase of the aerosol. The amount of aerosolized nicotine is calculated by comparing the difference between the amount of benzoic acid captured in the bubbler-1 and the amount of benzoic acid in the nicotine liquid formulation.

[0220] A linear relationship was found between the amount of nicotine trapped in bubbler-1 and the molar ratio of benzoic acid to nicotine in the nicotine liquid formulation ( Fig. 9). At a 1:1 molar ratio of nicotine to benzoic acid, the minimum amount of nicotine that became fully protonated and vapor collected in bubbler-1 was measured. In addition, at a 1:1.5 molar ratio of nicotine to benzoic acid, no further decrease in the amount of nicotine that was aerosolized was detected. It should also be noted that a higher percentage of freebase nicotine was collected by bubbler-1, indicating that a higher concentration of vapor phase nicotine is nicotine produced when freebase nicotine is used in the nicotine liquid formulation.

[0221] 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 decomposing. Therefore, nicotine liquid formulations produced using either acid will behave similarly and produce an aerosol with about the same molar amount of nicotine in the aerosol. Therefore, it is likely that when either acid is used in a nicotine liquid formulation, the same total amount of acid will be collected. In other words, it is likely that when a nicotine succinate liquid formulation is used in an electronic cigarette, about the same percentage of succinic acid will be recovered compared to the percentage of benzoic acid recovered when a nicotine benzoate liquid formulation as described in Example 13 is used. Therefore, the same percentage of nicotine will also likely be trapped in bubbler-1 when succinic acid or benzoic acid is used in a nicotine liquid formulation.

[0222] Here, different molar ratios of acidic functional groups to nicotine moles were investigated. Because succinic acid is a diprotic acid, it is expected that a molar ratio of 1:0.25 of nicotine to succinic acid will 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. In addition, it is expected that a molar ratio of 1:0.5 of nicotine to succinic acid will 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 expected, when a molar ratio of 1:0.25 of nicotine to succinic acid is used in the nicotine liquid formulation, about the same percentage of acid is collected in bubbler-1, as would be expected based on the amount of nicotine captured using 1:0.4 and 1:0.7 molar ratios of nicotine to benzoic acid ( Fig.11 In addition, as expected, when a 1:0.5 molar ratio of nicotine to succinic acid was used in the nicotine liquid formulation, about the same percentage of acid was collected in bubbler-1 compared to when a 1:1 molar ratio of nicotine to benzoic acid was used ( Fig.11 ).

[0223] Therefore, because succinic acid is diprotic, one mole of succinic acid may protonate two moles of nicotine, thereby stabilizing two moles of nicotine in the aerosol. In other words, compared to the benzoic acid used in the nicotine liquid preparation used in the low-temperature electronic vaporization device, i.e., the electronic cigarette, half the molar amount of succinic acid in the nicotine liquid preparation used in the low-temperature electronic vaporization device, i.e., the electronic cigarette, is required to completely protonate the nicotine and stabilize the nicotine in the aerosol. In addition, it seems credible that succinic acid is rated low in the satisfaction study described in Example 3 because an excess of succinic acid (1:2 molar ratio of nicotine to succinic acid) is included in the preparation and therefore it is possible that an excess of succinic acid is delivered to the user, thereby producing an unpleasant experience for the user. For example, an unpleasant experience includes taste, neural response, and / or stimulation of one or more of the oral cavity, upper respiratory tract, and / or lungs.

[0224] Further understanding may be gained by contemplating the numbered embodiments below.

[0225] 1. A method of delivering nicotine to a user, the method comprising using a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a nicotine preparation, the nicotine preparation comprising:

[0226] a. from about 0.5% (w / w) to about 20% (w / w) nicotine;

[0227] b. a molar ratio of acid to nicotine from about 0.25:1 to about 4:1; and

[0228] c. a biologically acceptable liquid carrier,

[0229] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0230] 2. The method of embodiment 1, wherein the molar ratio of acidic functional groups to nicotine is from about 0.25:1 to about 4:1.

[0231] 3. The method of any one of embodiments 1-2, wherein the acid and the nicotine form a nicotine salt.

[0232] 4. The method of embodiments 1-3, wherein the nicotine formulation comprises monoprotonated nicotine.

[0233] 5. The method of any one of embodiments 1-4, wherein the aerosol comprises monoprotonated nicotine.

[0234] 6. The method of any one of embodiments 1-5, wherein the aerosol is delivered to the lungs of a user.

[0235] 7. The method of embodiment 6, wherein the aerosol is delivered to alveoli in the lungs of the user.

[0236] 8. The method of any one of embodiments 1-10, wherein nicotine is stabilized in the aerosol in salt form.

[0237] 9. The method of any one of embodiments 1-10, wherein nicotine is delivered in the aerosol in the form of a salt.

[0238] 10. The method of any one of embodiments 1-9, wherein the acid comprises a carboxylic acid functional group.

[0239] 11. The method of any one of embodiments 1-9, wherein the acid comprises more than one carboxylic acid functional group.

[0240] 12. The method of any one of embodiments 1-9, wherein the acid is selected from the group consisting of 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, salicylic acid, sorbic acid, malonic acid, or malic acid.

[0241] 13. The method of any one of embodiments 1-9, wherein the acid comprises one or more of a carboxylic acid, a dicarboxylic acid, and a keto acid.

[0242] 14. The method of any one of embodiments 1-9, wherein the acid comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.

[0243] 15. The method of any one of embodiments 1-9, wherein the acid comprises benzoic acid.

[0244] 16. The method of any one of the embodiments 1-11, wherein 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.

[0245] 17. The method of any one of the embodiments 1-11, wherein 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.

[0246] 18. The method of any one of the embodiments 1-11, wherein 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.

[0247] 19. The method of any one of the embodiments 1-11, wherein 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.

[0248] 20. The method of any one of the embodiments 1-11, wherein 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.

[0249] 21. The method of any one of the embodiments 1-11, wherein 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.

[0250] 22. A method as described in any of the embodiments 1-

[0054] , wherein the nicotine concentration is 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).

[0251] 23. The method of any one of embodiments 1-

[0054] , wherein the nicotine concentration is 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 ...5% (w / w), from about 0.5% (w / w) to about 1 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).

[0252] 24. A method as described in any of embodiments 1-

[0054] , wherein the nicotine concentration is 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 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).

[0253] 25. A method as described in any of embodiments 1-

[0054] , wherein the nicotine concentration is 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).

[0254] 26. A method as described in any of embodiments 1-

[0054] , wherein the nicotine concentration is 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).

[0255] 27. A method as described in any of embodiments 1-

[0054] , wherein the nicotine concentration is 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).

[0256] 28. A method as described in any of embodiments 1-

[0054] , wherein the nicotine concentration is 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).

[0257] 29. A method as described in any of embodiments 1-

[0054] , wherein the nicotine concentration is 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).

[0258] 30. The method of any one of embodiments 1-

[0054] , wherein the nicotine concentration is from about 2% (w / w) to about 6% (w / w).

[0259] 31. The method of any one of embodiments 1-

[0054] , wherein the nicotine concentration is about 5% (w / w).

[0260] 32. The method of any one of embodiments 1-

[0072] , wherein the molar concentration of nicotine in the aerosol is approximately the same as the molar concentration of the acid in the aerosol.

[0261] 33. The method of any one of the embodiments 1-32, wherein the aerosol comprises about 50% of the nicotine in the formulation, about 60% of the nicotine in the formulation, about 70% of the nicotine in the formulation, about 75% of the nicotine in the formulation, about 80% of the nicotine in the formulation, about 85% of the nicotine in the formulation, about 90% of the nicotine in the formulation, about 95% of the nicotine in the formulation, or about 99% of the nicotine in the formulation.

[0262] 34. The method of any one of the embodiments 1-33, wherein the aerosol comprises condensate in a particle size of 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 micron, 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, or from about 0.3 microns to about 0.4 microns.

[0263] 35. The method of embodiments 1-34, wherein the aerosol comprises a concentrate of nicotine salt.

[0264] 36. The method of embodiments 1-34, wherein the aerosol comprises a concentrate comprising one or more of the carrier, the nicotine salt, the free base nicotine, and the free acid.

[0265] 37. The method of embodiments 1-9, wherein the acid does not decompose at room temperature and does not decompose at the operating temperature of the electronic cigarette.

[0266] 38. The method of any one of embodiments 1-37, wherein the operating temperature is from 150°C to 250°C.

[0267] 39. The method of any one of embodiments 1-37, wherein the operating temperature is from 180°C to 220°C.

[0268] 40. The method of any one of embodiments 1-37, wherein the operating temperature is about 200°C.

[0269] 41. The method of any one of embodiments 1-40, wherein the acid is stable at and below operating temperature or about 200°C.

[0270] 42. The method of any one of embodiments 1-40, wherein the acid does not decompose at and below operating temperature or about 200°C.

[0271] 43. The method of any one of embodiments 1-40, wherein the acid does not oxidize at and below operating temperature or about 200°C.

[0272] 44. The method of any one of embodiments 1-43, wherein the formulation is non-toxic to a user of the electronic cigarette.

[0273] 45. The method of any one of embodiments 1-44, wherein the formulation is non-corrosive to the electronic cigarette.

[0274] 46. ​​The method of any one of embodiments 1-45, wherein the formulation comprises a flavorant.

[0275] 47. The method of any one of embodiments 1-46, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a five minute period produces a nicotine plasma T of from about 1 minute to about 8 minutes. 最大 .

[0276] 48. The method of embodiment 47, wherein the nicotine plasma T 最大 is from about 1 minute to about 7 minutes, from about 1 minute to about 6 minutes, from about 1 minute to about 5 minutes, from about 1 minute to about 4 minutes, from about 1 minute to about 3 minutes, from about 1 minute to about 2 minutes, from about 2 minutes to about 8 minutes, from about 2 minutes to about 7 minutes, from about 2 minutes to about 6 minutes, from about 2 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 8 minutes, from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 3 minutes. From about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute.

[0277] 49. The method of any one of embodiments 1-46, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T of from about 2 minutes to about 8 minutes. 最大 .

[0278] 50. The method of embodiment 49, wherein the nicotine plasma T 最大 is from about 2 minutes to about 8 minutes, from about 2 minutes to about 7 minutes, from about 2 minutes to about 6 minutes, from about 2 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 8 minutes, from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 7 minutes, from about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, or about 2 minutes.

[0279] 51. The method of any one of embodiments 1-46, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T of from about 3 minutes to about 8 minutes. 最大 .

[0280] 52. The method of embodiment 51, wherein the nicotine plasma T 最大 is from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 8 minutes, from about 4 minutes to about 7 minutes, from about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, or about 3 minutes.

[0281] 53. The method of any one of embodiments 1-46, wherein the T 最大 Less than about 8 minutes.

[0282] 54. The method of any one of embodiments 47-53, wherein the T 最大 Determined based on at least three independent data sets.

[0283] 55. A method as described in embodiment 47-53, wherein the T 最大 is a series of at least three independent data sets.

[0284] 56. A method as described in embodiment 47-53, wherein the T 最大 are the means ± SD of at least three independent data sets.

[0285] 57. The method of any one of embodiments 1-56, wherein the liquid carrier comprises glycerol, propylene glycol, trimethylene glycol, water, ethanol, or a combination thereof.

[0286] 58. The method of any one of embodiments 1-56, wherein the liquid carrier comprises propylene glycol and vegetable glycerin.

[0287] 59. The method of any one of embodiments 1-56, wherein the liquid carrier comprises 20% to 50% propylene glycol and 80% to 50% vegetable glycerin.

[0288] 60. The method of any one of embodiments 1-56, wherein the liquid carrier comprises 30% propylene glycol and 70% vegetable glycerin.

[0289] 61. The method of any one of embodiments 1-17, wherein the formulation further comprises one or more additional acids.

[0290] 62. The method of embodiment 21, wherein the one or more additional acids comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.

[0291] 63. The method of embodiment 21, wherein the one or more additional acids comprises benzoic acid.

[0292] 64. The method of any one of embodiments 21-63, wherein the one or more additional acids forms one or more additional nicotine salts.

[0293] 65. A method of delivering nicotine to a user, the method comprising using a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a nicotine formulation, the nicotine formulation comprising:

[0294] a. from about 0.5% (w / w) to about 20% (w / w) nicotine;

[0295] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 0.25:1 to about 4:1; and

[0296] c. a biologically acceptable liquid carrier,

[0297] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0298] 66. A method of delivering nicotine to a user, the method comprising using a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a nicotine formulation, the nicotine formulation comprising:

[0299] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0300] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 0.25:1 to about 4:1; and

[0301] c. a biologically acceptable liquid carrier,

[0302] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0303] 67. A method of delivering nicotine to a user, the method comprising using a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a nicotine formulation, the nicotine formulation comprising:

[0304] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0305] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 1:1 to about 2:1; and

[0306] c. a biologically acceptable liquid carrier,

[0307] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0308] 68. A method of delivering nicotine to a user, the method comprising using a low temperature electronic vaporization device, i.e., an electronic cigarette, the low temperature electronic vaporization device comprising a nicotine formulation, the nicotine formulation comprising:

[0309] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0310] b. a molar ratio of benzoic acid to nicotine of about 1:1; and

[0311] c. a biologically acceptable liquid carrier,

[0312] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0313] 69. A formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, comprising:

[0314] a. from about 0.5% (w / w) to about 20% (w / w) nicotine;

[0315] b. a molar ratio of acid to nicotine from about 0.25:1 to about 4:1; and

[0316] c. a biologically acceptable liquid carrier,

[0317] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0318] 70. The formulation of embodiment 69, wherein the molar ratio of acidic functional groups to nicotine is from about 1:1 to about 4:1.

[0319] 71. The formulation of any one of embodiments 69-70, wherein the acid and the nicotine form a nicotine salt.

[0320] 72. The formulation of embodiments 69-71, comprising monoprotonated nicotine.

[0321] 73. The formulation of any one of embodiments 69-72, wherein the aerosol comprises monoprotonated nicotine.

[0322] 74. The formulation of any one of embodiments 69-73, wherein the aerosol is delivered to the lungs of a user.

[0323] 75. The formulation of embodiment 74, wherein the aerosol is delivered to alveoli in the lungs of a user.

[0324] 76. The formulation of any one of embodiments 69-75, wherein nicotine is stabilized in the aerosol in salt form.

[0325] 77. The formulation of any one of embodiments 69-75, wherein nicotine is delivered in the aerosol in salt form.

[0326] 78. The formulation of any one of embodiments 69-77, wherein the acid comprises a carboxylic acid functional group.

[0327] 79. The formulation of any one of embodiments 69-77, wherein the acid comprises more than one carboxylic acid functional group.

[0328] 80. The formulation of any one of embodiments 69-77, wherein the acid is selected from the group consisting of 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, salicylic acid, sorbic acid, malonic acid, or malic acid.

[0329] 81. The formulation of any one of embodiments 69-77, wherein the acid comprises one or more of a carboxylic acid, a dicarboxylic acid, and a keto acid.

[0330] 82. The formulation of any one of embodiments 69-77, wherein the acid comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.

[0331] 83. The formulation of any one of embodiments 69-77, wherein the acid comprises nicotine benzoate.

[0332] 84. The formulation of any one of the embodiments 69-83, wherein 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.

[0333] 85. The formulation of any one of the embodiments 69-83, wherein 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.

[0334] 86. The formulation of any one of the embodiments 69-83, wherein 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.

[0335] 87. The formulation of any one of the embodiments 69-83, wherein 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.

[0336] 88. The formulation of any one of the embodiments 69-83, wherein 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.

[0337] 89. The formulation of any one of the embodiments 69-83, wherein 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.

[0338] 90. The formulation of any one of the embodiments 69-89, wherein the nicotine concentration is 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 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).

[0339] 91. A formulation as described in any of the embodiments 69-89, wherein the nicotine concentration is about 0.5% (w / w), about 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).

[0340] 92. A formulation as described in any of the embodiments 69-89, wherein the nicotine concentration is 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 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).

[0341] 93. A formulation as described in any of the embodiments 69-89, wherein the nicotine concentration is 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).

[0342] 94. A formulation as described in any of the embodiments 69-89, wherein the nicotine concentration is 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).

[0343] 95. A formulation as described in any of the embodiments 69-89, wherein the nicotine concentration is 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).

[0344] 96. A formulation as described in any of the embodiments 69-89, wherein the nicotine concentration is 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).

[0345] 97. A formulation as described in any of the embodiments 69-87, wherein the nicotine concentration is 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).

[0346] 98. The formulation of any one of the embodiments 69-89, wherein the nicotine concentration is from about 2% (w / w) to about 6% (w / w).

[0347] 99. The formulation of any one of embodiments 69-89, wherein the nicotine concentration is about 5% (w / w).

[0348] 100. The formulation of any one of embodiments 69-99, wherein the molar concentration of nicotine in the aerosol is about the same as the molar concentration of the acid in the aerosol.

[0349] 101. The formulation of any one of the embodiments 69-100, wherein the aerosol comprises about 50% of the nicotine in the formulation, about 60% of the nicotine in the formulation, about 70% of the nicotine in the formulation, about 75% of the nicotine in the formulation, about 80% of the nicotine in the formulation, about 85% of the nicotine in the formulation, about 90% of the nicotine in the formulation, about 95% of the nicotine in the formulation, or about 99% of the nicotine in the formulation.

[0350] 102. The formulation of any one of embodiments 69-101, wherein the aerosol comprises a condensate in a particle size of 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 micron, 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, or from about 0.3 microns to about 0.4 microns.

[0351] 103. The formulation of embodiments 69-102, wherein the aerosol comprises a concentrate of nicotine salt.

[0352] 104. The formulation of embodiments 69-102, wherein the aerosol comprises a concentrate comprising one or more of the carrier, the nicotine salt, the free base nicotine, and the free acid.

[0353] 105. The formulation of embodiments 69-104, wherein the acid does not decompose at room temperature and does not decompose at the operating temperature of the electronic cigarette.

[0354] 106. The formulation of any one of embodiments 69-105, wherein the operating temperature of the electronic cigarette is from 150°C to 250°C.

[0355] 107. The formulation of any one of embodiments 69-105, wherein the operating temperature of the electronic cigarette is from 180°C to 220°C.

[0356] 108. The formulation of any one of embodiments 69-105, wherein the operating temperature of the electronic cigarette is about 200°C.

[0357] 109. The formulation of any one of embodiments 69-108, wherein the acid is stable at and below the operating temperature of the electronic cigarette or about 200°C.

[0358] 110. The formulation of any one of embodiments 69-108, wherein the acid does not decompose at and below the operating temperature of the electronic cigarette or about 200°C.

[0359] 111. The formulation of any one of embodiments 69-108, wherein the acid does not oxidize at and below the operating temperature of the electronic cigarette or about 200°C.

[0360] 112. The formulation of any one of embodiments 69-108, wherein the formulation is non-toxic to a user of the electronic cigarette.

[0361] 113. The formulation of any one of embodiments 69-112, wherein the formulation is non-corrosive to the electronic cigarette.

[0362] 114. The formulation of any one of embodiments 69-113, wherein the formulation comprises a flavorant.

[0363] 115. The formulation of any one of embodiments 69-114, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T from about 1 minute to about 8 minutes. 最大 .

[0364] 116. A formulation as described in embodiment 115, wherein the nicotine plasma T 最大is from about 1 minute to about 7 minutes, from about 1 minute to about 6 minutes, from about 1 minute to about 5 minutes, from about 1 minute to about 4 minutes, from about 1 minute to about 3 minutes, from about 1 minute to about 2 minutes, from about 2 minutes to about 8 minutes, from about 2 minutes to about 7 minutes, from about 2 minutes to about 6 minutes, from about 2 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 8 minutes, from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 3 minutes. From about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute.

[0365] 117. The formulation of any one of embodiments 69-114, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T of from about 2 minutes to about 8 minutes. 最大 .

[0366] 118. A formulation as described in embodiment 117, wherein the nicotine plasma T 最大 is from about 2 minutes to about 8 minutes, from about 2 minutes to about 7 minutes, from about 2 minutes to about 6 minutes, from about 2 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 8 minutes, from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 7 minutes, from about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, or about 2 minutes.

[0367] 119. The formulation of any one of embodiments 69-114, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T of from about 3 minutes to about 8 minutes. 最大 .

[0368] 120. A formulation as described in embodiment 119, wherein the nicotine plasma T 最大 is from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 8 minutes, from about 4 minutes to about 7 minutes, from about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, or about 3 minutes.

[0369] 121. A formulation as described in any one of embodiments 69-114, wherein the T 最大 Less than about 8 minutes.

[0370] 122. A formulation as described in any one of embodiments 115-121, wherein the T 最大 Determined based on at least three independent data sets.

[0371] 123. A formulation as described in any one of embodiments 115-121, wherein the T 最大 is a series of at least three independent data sets.

[0372] 124. A formulation as described in any one of embodiments 115-121, wherein the T 最大 are the means ± SD of at least three independent data sets.

[0373] 125. The formulation of any one of embodiments 69-124, wherein the liquid carrier comprises glycerol, propylene glycol, trimethylene glycol, water, ethanol, or a combination thereof.

[0374] 126. The formulation of any one of embodiments 69-124, wherein the liquid carrier comprises propylene glycol and vegetable glycerin.

[0375] 127. The formulation of any one of embodiments 69-124, wherein the liquid carrier comprises 20% to 50% propylene glycol and 80% to 50% vegetable glycerin.

[0376] 128. The formulation of any one of embodiments 69-124, wherein the liquid carrier comprises 30% propylene glycol and 70% vegetable glycerin.

[0377] 129. The formulation of any one of embodiments 69-128, further comprising one or more additional acids.

[0378] 130. The formulation of any one of embodiments 129, wherein the one or more additional acids comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.

[0379] 131. The formulation of embodiment 129, wherein the one or more additional acids comprises benzoic acid.

[0380] 132. The formulation of any one of embodiments 129-131, wherein the one or more additional acids form one or more additional nicotine salts.

[0381] 133. A formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, comprising:

[0382] a. from about 0.5% (w / w) to about 20% (w / w) nicotine;

[0383] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 0.25:1 to about 4:1; and

[0384] c. a biologically acceptable liquid carrier,

[0385] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0386] 134. A formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, comprising:

[0387] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0388] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 0.25:1 to about 4:1; and

[0389] c. a biologically acceptable liquid carrier,

[0390] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0391] 135. A formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, comprising:

[0392] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0393] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 1:1 to about 2:1; and

[0394] c. a biologically acceptable liquid carrier,

[0395] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0396] 136. A formulation for use in a low temperature electronic vaporization device, i.e., an electronic cigarette, comprising:

[0397] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0398] b. a molar ratio of benzoic acid to nicotine of about 1:1; and

[0399] c. a biologically acceptable liquid carrier,

[0400] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0401] 137. A cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment containing a nicotine formulation, the nicotine formulation comprising:

[0402] a. from about 0.5% (w / w) to about 20% (w / w) nicotine;

[0403] b. a molar ratio of acid to nicotine from about 0.25:1 to about 4:1; and

[0404] c. a biologically acceptable liquid carrier,

[0405] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0406] 138. The cartridge of embodiment 137, wherein the molar ratio of acidic functional groups to nicotine is from about 1:1 to about 4:1.

[0407] 139. The cartridge of any one of embodiments 137-138, wherein the acid and the nicotine form a nicotine salt.

[0408] 140. The cartridge of embodiments 137-139, wherein the nicotine formulation comprises monoprotonated nicotine.

[0409] 141. The cartridge of any one of embodiments 137-140, wherein the aerosol comprises monoprotonated nicotine.

[0410] 142. The cartridge of any one of embodiments 137-141, wherein the aerosol is delivered to the lungs of a user.

[0411] 143. The cartridge of embodiment 142, wherein the aerosol is delivered to alveoli in the lungs of a user.

[0412] 144. The cartridge of any one of embodiments 137-143, wherein nicotine is stabilized in the aerosol in salt form.

[0413] 145. The cartridge of any one of embodiments 137-143, wherein nicotine is delivered in the aerosol in salt form.

[0414] 146. The cartridge of any one of embodiments 137-145, wherein the acid comprises a carboxylic acid functional group.

[0415] 147. The cartridge of any one of embodiments 137-145, wherein the acid comprises more than one carboxylic acid functional group.

[0416] 148. The cartridge of any one of embodiments 137-145, wherein the acid is selected from the group consisting of 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, salicylic acid, sorbic acid, malonic acid, or malic acid.

[0417] 149. The cartridge of any one of embodiments 137-145, wherein the acid comprises one or more of a carboxylic acid, a dicarboxylic acid, and a keto acid.

[0418] 150. The cartridge of any one of embodiments 137-145, wherein the acid comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.

[0419] 151. The cartridge of any one of embodiments 137-145, wherein the acid comprises benzoic acid.

[0420] 152. The cartridge of any one of the embodiments 137-151, wherein 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.

[0421] 153. The cartridge of any one of the embodiments 137-151, wherein 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.

[0422] 154. The cartridge of any one of the embodiments 137-151, wherein 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.

[0423] 155. The cartridge of any one of the embodiments 137-151, wherein 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.

[0424] 156. The cartridge of any one of the embodiments 137-151, wherein 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.

[0425] 157. The cartridge of any one of the embodiments 137-151, wherein 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.

[0426] 158. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is about 0.5% (w / w), about 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).

[0427] 159. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is 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 ...5% (w / w), from about 0.5% (w / w) to about 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).

[0428] 160. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is 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 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).

[0429] 161. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is 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).

[0430] 162. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is 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).

[0431] 163. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is 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).

[0432] 164. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is 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).

[0433] 165. The cartridge of any one of the embodiments 137-157, wherein the nicotine concentration is 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).

[0434] 166. The cartridge of any one of embodiments 137-157, wherein the nicotine concentration is from about 2% (w / w) to about 6% (w / w).

[0435] 167. The cartridge of any one of embodiments 137-157, wherein the nicotine concentration is about 5% (w / w).

[0436] 168. The cartridge of any one of embodiments 137-167, wherein the molar concentration of nicotine in the aerosol is about the same as the molar concentration of the acid in the aerosol.

[0437] 169. The cartridge of any one of the embodiments 137-168, wherein the aerosol comprises about 50% of the nicotine in the formulation, about 60% of the nicotine in the formulation, about 70% of the nicotine in the formulation, about 75% of the nicotine in the formulation, about 80% of the nicotine in the formulation, about 85% of the nicotine in the formulation, about 90% of the nicotine in the formulation, about 95% of the nicotine in the formulation, or about 99% of the nicotine in the formulation.

[0438] 170. The cartridge of any one of the embodiments 137-169, wherein the aerosol comprises a condensate in a particle size of 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 micron, 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, or from about 0.3 microns to about 0.4 microns.

[0439] 171. The cartridge of embodiments 137-170, wherein the aerosol comprises a concentrate of nicotine salt.

[0440] 172. The cartridge of embodiments 137-170, wherein the aerosol comprises a concentrate comprising one or more of the carrier, the nicotine salt, the free base nicotine, and the free acid.

[0441] 173. The cartridge of embodiments 137-172, wherein the acid does not decompose at room temperature and does not decompose at the operating temperature of the electronic cigarette.

[0442] 174. The cartridge of any one of embodiments 137-173, wherein the operating temperature is from 150°C to 250°C.

[0443] 175. The cartridge of any one of embodiments 137-173, wherein the operating temperature is from 180°C to 220°C.

[0444] 176. The cartridge of any one of embodiments 137-173, wherein the operating temperature is about 200°C.

[0445] 177. The cartridge of any one of embodiments 137-176, wherein the acid is stable at and below operating temperature or about 200°C.

[0446] 178. The cartridge of any one of embodiments 137-176, wherein the acid does not decompose at and below operating temperature or about 200°C.

[0447] 179. The cartridge of any one of embodiments 137-176, wherein the acid does not oxidize at and below operating temperature or about 200°C.

[0448] 180. The cartridge of any one of embodiments 137-179, wherein the formulation is non-toxic to a user of the electronic cigarette.

[0449] 181. The cartridge of any one of embodiments 137-180, wherein the formulation is non-corrosive to the electronic cigarette.

[0450] 182. The cartridge of any one of embodiments 137-181, wherein the formulation comprises a flavorant.

[0451] 183. The cartridge of any one of embodiments 137-182, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T of from about 1 minute to about 8 minutes. 最大 .

[0452] 184. The cartridge of embodiment 183, wherein the nicotine plasma T 最大is from about 1 minute to about 7 minutes, from about 1 minute to about 6 minutes, from about 1 minute to about 5 minutes, from about 1 minute to about 4 minutes, from about 1 minute to about 3 minutes, from about 1 minute to about 2 minutes, from about 2 minutes to about 8 minutes, from about 2 minutes to about 7 minutes, from about 2 minutes to about 6 minutes, from about 2 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 8 minutes, from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 3 minutes. From about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute.

[0453] 185. The cartridge of any one of embodiments 137-182, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T from about 2 minutes to about 8 minutes. 最大 .

[0454] 186. The cartridge of embodiment 185, wherein the nicotine plasma T 最大 is from about 2 minutes to about 8 minutes, from about 2 minutes to about 7 minutes, from about 2 minutes to about 6 minutes, from about 2 minutes to about 5 minutes, from about 2 minutes to about 4 minutes, from about 2 minutes to about 3 minutes, from about 3 minutes to about 8 minutes, from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 7 minutes, from about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, or about 2 minutes.

[0455] 187. The cartridge of any one of embodiments 137-182, wherein inhalation of the aerosol at a rate of about one inhalation every 30 seconds over a period of about five minutes produces a nicotine plasma T of from about 3 minutes to about 8 minutes. 最大 .

[0456] 188. The cartridge of embodiment 187, wherein the nicotine plasma T 最大 is from about 3 minutes to about 7 minutes, from about 3 minutes to about 6 minutes, from about 3 minutes to about 5 minutes, from about 3 minutes to about 4 minutes, from about 4 minutes to about 8 minutes, from about 4 minutes to about 7 minutes, from about 4 minutes to about 6 minutes, from about 4 minutes to about 5 minutes, from about 5 minutes to about 8 minutes, from about 5 minutes to about 7 minutes, from about 5 minutes to about 6 minutes, from about 6 minutes to about 8 minutes, from about 6 minutes to about 7 minutes, from about 7 minutes to about 8 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, or about 3 minutes.

[0457] 189. The cartridge of any one of embodiments 137-182, wherein the T 最大 Less than about 8 minutes.

[0458] 190. The cartridge of any one of embodiments 183-189, wherein the T 最大 Determined based on at least three independent data sets.

[0459] 191. The cartridge of embodiments 183-189, wherein the T 最大 is a series of at least three independent data sets.

[0460] 192. The cartridge of embodiments 183-189, wherein the T 最大 are the means ± SD of at least three independent data sets.

[0461] 193. The cartridge of any one of embodiments 137-192, wherein the liquid carrier comprises glycerin, propylene glycol, trimethylene glycol, water, ethanol, or a combination thereof.

[0462] 194. The cartridge of any one of embodiments 137-192, wherein the liquid carrier comprises propylene glycol and vegetable glycerin.

[0463] 195. The cartridge of any one of embodiments 137-192, wherein the liquid carrier comprises 20% to 50% propylene glycol and 80% to 50% vegetable glycerin.

[0464] 196. The cartridge of any one of embodiments 137-192, wherein the liquid carrier comprises 30% propylene glycol and 70% vegetable glycerin.

[0465] 197. The cartridge of any one of embodiments 137-196, wherein the formulation further comprises one or more additional acids.

[0466] 198. The cartridge of embodiment 197, wherein the one or more additional acids comprises one or more of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid.

[0467] 199. The cartridge of embodiment 197, wherein the one or more additional acids comprises nicotine benzoate.

[0468] 200. The cartridge of any one of embodiments 197-199, wherein the one or more additional acids form one or more additional nicotine salts.

[0469] 201. A cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment containing a nicotine formulation, the nicotine formulation comprising:

[0470] a. from about 0.5% (w / w) to about 20% (w / w) nicotine;

[0471] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 0.25:1 to about 4:1; and

[0472] c. a biologically acceptable liquid carrier,

[0473] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0474] 202. A cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment containing a nicotine formulation, the nicotine formulation comprising:

[0475] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0476] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 0.25:1 to about 4:1; and

[0477] c. a biologically acceptable liquid carrier,

[0478] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0479] 203. A cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment containing a nicotine formulation, the nicotine formulation comprising:

[0480] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0481] b. an acid selected from the group consisting of benzoic acid, pyruvic acid, salicylic acid, levulinic acid, malic acid, succinic acid, and citric acid, wherein the molar ratio of acid to nicotine is from about 1:1 to about 2:1; and

[0482] c. a biologically acceptable liquid carrier,

[0483] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0484] 204. A cartridge for use with a low temperature electronic vaporization device, i.e., an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heating element, the fluid compartment containing a nicotine formulation, the nicotine formulation comprising:

[0485] a. from about 2% (w / w) to about 6% (w / w) nicotine;

[0486] b. a molar ratio of benzoic acid to nicotine of about 1:1; and

[0487] c. a biologically acceptable liquid carrier,

[0488] Wherein operation of the electronic cigarette generates an inhalable aerosol comprising at least a portion of the nicotine in the formulation.

[0489] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. A large amount of changes, modifications and replacements will now be expected by those skilled in the art without departing from the present invention. It should be understood that each alternative of the embodiments of the present invention described herein can be used in practicing the present invention. It is intended that the following embodiments define the scope of the present invention and that methods and structures and equivalents thereof within the scope of these embodiments are thus covered.

Claims

1. A method of generating an inhalable aerosol comprising nicotine for delivery to a user, the method comprising forming the aerosol by heating an amount of a nicotine salt liquid formulation in an electronic cigarette, wherein: (a) the electronic cigarette comprises a cartridge, the cartridge comprising a fluid compartment configured to be in fluid communication with a heater, wherein the fluid compartment contains the nicotine salt liquid formulation; (b) the nicotine salt liquid formulation has a nicotine salt concentration of 1% w / w to 6% w / w in a biologically acceptable liquid carrier; and comprising (i) a salt of nicotine and lactic acid in a biologically acceptable liquid carrier, wherein the molar ratio of lactic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:1; (ii) a salt of nicotine and levulinic acid in a biologically acceptable liquid carrier, wherein the molar ratio of levulinic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 4:1; (iii) a salt of nicotine and salicylic acid in a biologically acceptable liquid carrier, wherein the molar ratio of salicylic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:1; (iv) a salt of nicotine and malic acid in a biologically acceptable liquid carrier, wherein the molar ratio of malic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 3:1; (v) a salt of nicotine and succinic acid in a biologically acceptable liquid carrier, wherein the molar ratio of succinic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 3:1; or (vi) a salt of nicotine and sorbic acid in a biologically acceptable liquid carrier, wherein the molar ratio of sorbic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:

1.

2. The method of claim 1, wherein the nicotine salt liquid formulation has a nicotine salt concentration of 1% w / w to 5% w / w in the biologically acceptable liquid carrier.

3. The method of claim 1, wherein the molar ratio of lactic acid to nicotine is from 0.9:1 to 1.2:1; the molar ratio of levulinic acid to nicotine is from 0.9:1 to 3.2:1; the molar ratio of salicylic acid to nicotine is from 0.9:1 to 1.2:1; the molar ratio of malic acid to nicotine is from 0.9:1 to 2.2:1; the molar ratio of succinic acid to nicotine is from 0.9:1 to 2.2:1; and the molar ratio of sorbic acid to nicotine is from 0.9:1 to 1.2:

1.

4. The method of claim 1, wherein the molar ratio of lactic acid to nicotine is 1:1; the molar ratio of levulinic acid to nicotine is 3:1; the molar ratio of salicylic acid to nicotine is 1:1; the molar ratio of malic acid to nicotine is 2:1; the molar ratio of succinic acid to nicotine is 2:1; and the molar ratio of sorbic acid to nicotine is 1:

1.

5. The method of claim 1, wherein the biologically acceptable liquid carrier comprises from 10% to 70% propylene glycol and from 30% to 90% vegetable glycerin.

6. The method of claim 1, wherein the heater heats the amount of the nicotine salt liquid formulation from 100°C to 300°C.

7. The method of claim 1, wherein the nicotine salt liquid formulation further comprises an additional acid selected from the group consisting of benzoic acid, pyruvic acid, lactic acid, levulinic acid, salicylic acid, succinic acid, malic acid, sorbic acid, and citric acid.

8. A cartridge for use with an electronic cigarette, the cartridge comprising a fluid compartment configured to be in fluid communication with a heater, wherein (a) the fluid compartment contains a nicotine salt liquid formulation; (b) the nicotine salt liquid formulation has a nicotine concentration of 1% w / w to 6% w / w in a biologically acceptable liquid carrier and comprises (i) a salt of nicotine and lactic acid in a biologically acceptable liquid carrier, wherein the molar ratio of lactic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:1; (ii) a salt of nicotine and levulinic acid in a biologically acceptable liquid carrier, wherein the molar ratio of levulinic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:1; (iii) a salt of nicotine and salicylic acid in a biologically acceptable liquid carrier, wherein the molar ratio of salicylic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:1; (iv) a salt of nicotine and malic acid in a biologically acceptable liquid carrier, wherein the molar ratio of malic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:1; (v) a salt of nicotine and succinic acid in a biologically acceptable liquid carrier, wherein the molar ratio of succinic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:1; or (vi) a salt of nicotine and sorbic acid in a biologically acceptable liquid carrier, wherein the molar ratio of sorbic acid to nicotine in the biologically acceptable liquid carrier is from 0.7:1 to 1.5:

1.

9. The cartridge of claim 8, wherein the nicotine salt liquid formulation has a nicotine salt concentration of 1% w / w to 5% w / w in the biologically acceptable liquid carrier.

10. The cartridge of claim 8, wherein the molar ratio of lactic acid to nicotine is from 0.9:1 to 1.2:1; the molar ratio of levulinic acid to nicotine is from 0.9:1 to 3.2:1; the molar ratio of salicylic acid to nicotine is from 0.9:1 to 1.2:1; the molar ratio of malic acid to nicotine is from 0.9:1 to 2.2:1; the molar ratio of succinic acid to nicotine is from 0.9:1 to 2.2:1; and the molar ratio of sorbic acid to nicotine is from 0.9:1 to 1.2:

1.

11. The cartridge of claim 8, wherein the molar ratio of lactic acid to nicotine is 1:1; the molar ratio of levulinic acid to nicotine is 3:1; the molar ratio of salicylic acid to nicotine is 1:1; the molar ratio of malic acid to nicotine is 2:1; the molar ratio of succinic acid to nicotine is 2:1; and the molar ratio of sorbic acid to nicotine is 1:

1.

12. The cartridge of claim 8, wherein the biologically acceptable liquid carrier comprises from 10% to 70% propylene glycol and from 30% to 90% vegetable glycerin.

13. The cartridge of claim 8, wherein the heater heats the amount of the nicotine salt liquid formulation from 100°C to 300°C.

14. The cartridge of claim 8, wherein the nicotine salt liquid formulation further comprises an additional acid selected from the group consisting of benzoic acid, pyruvic acid, lactic acid, levulinic acid, salicylic acid, succinic acid, malic acid, sorbic acid, and citric acid.

15. An electronic cigarette comprising the cartridge according to any one of claims 8 to 14.

16. A nicotine salt liquid formulation for use in an electronic cigarette, the formulation comprising nicotine and a salt of an organic acid in a biologically acceptable liquid carrier, wherein (a) the organic acid is lactic acid, levulinic acid, salicylic acid, malic acid, succinic acid or sorbic acid; (b) the nicotine salt liquid formulation has a nicotine salt concentration of 1% w / w to 6% w / w in the biologically acceptable liquid carrier; and (c) a molar ratio of lactic acid to nicotine in the biologically acceptable liquid carrier of from 0.7:1 to 1.5:1; a molar ratio of levulinic acid to nicotine in the biologically acceptable liquid carrier of from 0.7:1 to 4:1; a molar ratio of salicylic acid to nicotine in the biologically acceptable liquid carrier of from 0.7:1 to 1.5:1; a molar ratio of malic acid to nicotine in the biologically acceptable liquid carrier of from 0.7:1 to 3:1; a molar ratio of succinic acid to nicotine in the biologically acceptable liquid carrier of from 0.7:1 to 3:1; or a molar ratio of sorbic acid to nicotine in the biologically acceptable liquid carrier of from 0.7:1 to 1.5:

1.

17. The formulation of claim 16, wherein the nicotine salt liquid formulation has a nicotine salt concentration of 1% w / w to 5% w / w in the biologically acceptable liquid carrier.

18. The formulation of claim 16, wherein the molar ratio of lactic acid to nicotine is from 0.9:1 to 1.2:1; the molar ratio of levulinic acid to nicotine is from 0.9:1 to 3.2:1; the molar ratio of salicylic acid to nicotine is from 0.9:1 to 1.2:1; the molar ratio of malic acid to nicotine is from 0.9:1 to 2.2:1; the molar ratio of succinic acid to nicotine is from 0.9:1 to 2.2:1; and the molar ratio of sorbic acid to nicotine is from 0.9:1 to 1.2:

1.

19. The formulation of claim 16, wherein the molar ratio of lactic acid to nicotine is 1:1; the molar ratio of levulinic acid to nicotine is 3:1; the molar ratio of salicylic acid to nicotine is 1:1; the molar ratio of malic acid to nicotine is 2:1; the molar ratio of succinic acid to nicotine is 2:1; and the molar ratio of sorbic acid to nicotine is 1:

1.

20. The formulation of claim 16, wherein the biologically acceptable liquid carrier comprises from 10% to 70% propylene glycol and from 30% to 90% vegetable glycerin.

21. The formulation of claim 16, wherein the nicotine salt liquid formulation further comprises an additional acid selected from the group consisting of benzoic acid, pyruvic acid, lactic acid, levulinic acid, salicylic acid, succinic acid, malic acid, sorbic acid, and citric acid.

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