JP7703445B2 - Aerosolizable Formulations - Google Patents

Description

FIELD OF THEINVENTION

The present disclosure relates to aerosolizable formulations, methods of making aerosolizable formulations, containers containing aerosolizable formulations, devices containing aerosolizable formulations, and methods and uses of aerosolizable formulations.

2. Background of the Invention

Electronic aerosol delivery systems, such as e-cigarettes, generally contain a reservoir of liquid to be vaporized, typically containing nicotine. When a user inhales on the device, a heater is activated to vaporize a small amount of the liquid, which is then inhaled by the user.

E-cigarette use in the UK is growing rapidly and it is now estimated that there are over one million e-cigarette users in the UK.

One challenge faced in providing such a system is to deliver an inhaled aerosol from the aerosol delivery device that provides an acceptable experience to the consumer. Some consumers may prefer e-cigarettes that generate an aerosol that "resembles" the smoke inhaled from tobacco products such as cigarettes. The aerosol from e-cigarettes and the smoke from tobacco products such as cigarettes provide the user with a complex sequence of flavors in the mouth, nicotine absorption in the mouth and throat, and subsequently nicotine absorption in the lungs. These various aspects are described by users in terms of flavor, strength/quality, impact, spiciness/smoothness, and nicotine reward. Nicotine contributes to several of these factors, and is strongly associated with factors such as impact, spiciness, and smoothness, which are easily perceived by consumers, and e-cigarettes may give consumers too much or too little of these parameters, depending on personal preferences. Nicotine reward is particularly complex because it is a result of both the amount and rate at which nicotine is absorbed through the oral mucosa (which is typically nicotine in the vapor phase) and the amount and rate at which nicotine is absorbed through the lungs (which is typically nicotine in the particle phase of the inhaled aerosol). Each of these factors, and the balance of factors, can strongly contribute to consumer acceptability of e-cigarettes. Thus, delivery means that optimize the overall vaping experience are desirable for e-cigarette manufacturers.

A further challenge facing such systems is the ongoing demand for harm reduction. The harm caused by cigarettes and e-cigarette devices comes primarily from toxins. It is therefore desirable to reduce or eliminate compounds that may produce toxins.

In one embodiment,
(i) water in an amount of at least 85 wt. % based on the aerosolizable formulation;
(ii) nicotine. In this aspect, when the aerosolizable formulation includes one or more cyclodextrins, the aerosolizable formulation may be free of flavorings that may be encapsulated by the one or more cyclodextrins.

In one embodiment,
(i) water in an amount of at least 95 wt. % based on the aerosolizable formulation;
(ii) nicotine.

In one embodiment, there is provided a method for generating an aerosol, comprising:
A method is provided, comprising aerosolizing an aerosolizable formulation comprising: (i) water in an amount of at least 85 wt. % based on the aerosolizable formulation; and (ii) nicotine or one or more flavorings. In this aspect, if the aerosolizable formulation comprises one or more cyclodextrins, the aerosolizable formulation may be free of flavorings that can be encapsulated by the one or more cyclodextrins.

In one embodiment, there is provided a method for generating an aerosol, comprising:
A method is provided that includes aerosolizing an aerosolizable formulation that includes: (i) water in an amount of at least 95 wt. % based on the aerosolizable formulation; and (ii) nicotine.

In one embodiment, a contained aerosolizable formulation is provided that includes: (a) a container; and (b) (i) water in an amount of at least 85 wt. % based on the aerosolizable formulation; and (ii) an aerosolizable formulation that includes nicotine. In this embodiment, when the aerosolizable formulation includes one or more cyclodextrins, the aerosolizable formulation may not include a flavoring that can be encapsulated by the one or more cyclodextrins.

In one embodiment,
(a) a container;
(b)
A contained aerosolizable formulation is provided that includes: (i) water in an amount of at least 95 wt. %, based on the aerosolizable formulation; and (ii) an aerosolizable formulation that includes nicotine.

In one aspect, an electronic aerosol delivery system is provided that includes: (a) an aerosolization device for aerosolizing a formulation for inhalation by a user of the electronic aerosol delivery system; (b) a power source including a cell or battery for powering the aerosolization device; and (c) an aerosolizable formulation that includes (i) water in an amount of at least 85 wt. % based on the aerosolizable formulation, and (ii) nicotine or one or more flavorings. In this aspect, if the aerosolizable formulation includes one or more cyclodextrins, the aerosolizable formulation may be free of flavorings that may be encapsulated by the one or more cyclodextrins.

In one embodiment, an electronic aerosol delivery system is provided, comprising:
(a) an aerosolization device for aerosolizing a formulation for inhalation by a user of an electronic aerosol delivery system;
(b) a power source comprising a cell or battery for powering the aerosolization device;
(c)
An electronic aerosol delivery system is provided that comprises: (i) water in an amount of at least 95 wt. %, based on the aerosolizable formulation; and (ii) an aerosolizable formulation that includes nicotine.

Detailed Description

As discussed herein, there is provided an aerosolizable formulation comprising: (i) water in an amount of at least 85 wt. % based on the aerosolizable formulation; and (ii) nicotine. A method for generating an aerosol comprising:
Further provided is a method comprising the step of aerosolizing an aerosolizable formulation comprising: (i) water in an amount of at least 85 wt. %, based on the aerosolizable formulation; and (ii) nicotine or one or more flavorings.

The inventors have found that aerosolizable formulations can contain very high contents of water and provide advantageous systems that can be used to deliver nicotine and/or flavors.

The inventors have surprisingly found that a very high water content provides a sensory perception to the user that is desirably closer to the nicotine "hit" and/or flavor release provided by tobacco-based cigarettes. This desirable nicotine "hit" and/or flavor release is in contrast to "traditional" e-liquids based on glycerol and propylene glycol, which users sometimes avoid due to perceived differences with respect to the nicotine "hit" and/or flavor release provided by tobacco-based cigarettes.

The inventors have also discovered that it is possible to provide an aqueous system in which an aerosolized formulation is generated at low temperature from an aerosolizable formulation. This is in contrast to "conventional" e-cigarettes that use heaters that are typically applied to glycerol and propylene glycol based liquids to generate an aerosolized formulation. The provision of such a system and avoidance of heating can address the prior art issues of toxin generation. More specifically, the inventors have discovered an aqueous system that provides the desired nicotine "hit" and/or flavor release by selecting a very high water content, but avoids the need to use heaters associated with conventional liquids based on glycerol and propylene glycol. In the inventive system, the number of components present can be reduced, leading to a reduced chance of degradation product/toxin generation. In particular, the use of water allows for the replacement of some or all of the glycerol, propylene glycol, 1,3-propanediol and mixtures thereof that are typically used in e-cigarettes.

For ease of reference, these and further aspects of the present invention are discussed herein under appropriate section headings. However, the teachings of each section are not necessarily limited to each particular section.

Water As discussed herein, the aerosolizable formulation comprises water in an amount of at least 85 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 87 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 89 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 91 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 93 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 95 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 97 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99 wt. % based on the aerosolizable formulation. %. In one embodiment, water is present in an amount of at least 99.1 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.2 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.3 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.4 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.5 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.6 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.7 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.8 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of at least 99.9 wt. % based on the aerosolizable formulation.

In one embodiment, water is present in an amount of 85-99.9 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of 99-99.9 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of 92-99.9 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of 94-99.9 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of 95-99.9 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of 96-99.9 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of 97-99.9 wt. % based on the aerosolizable formulation. In one embodiment, water is present in an amount of 98-99.9 wt. % based on the aerosolizable formulation. %. In one embodiment, water is present in an amount of 99-99.9 wt. % based on the aerosolizable formulation.

As discussed herein, the use of water allows for the replacement of some or all of the glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof typically used in e-cigarettes. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 10 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 8 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 5 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 2 wt. % or less based on the aerosolizable formulation. % or less combined amount of glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 0.5 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 0.2 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 0.1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof in a combined amount of 0.01 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation does not comprise glycerol, propylene glycol, 1,3-propanediol, and mixtures thereof.

In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 10 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 8 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 5 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 2 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 0.5 wt. % or less based on the aerosolizable formulation. % or less combined amount of glycerol, propylene glycol, and mixtures thereof. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 0.2 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 0.1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol, propylene glycol, and mixtures thereof in a combined amount of 0.01 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation does not include glycerol, propylene glycol, and mixtures thereof.

In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 10 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 8 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 5 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 2 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 0.5 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 0.2 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 0.1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises glycerol in an amount of 0.01 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation does not comprise glycerol.

In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 10 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 8 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 5 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 2 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 0.5 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 0.2 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 0.1 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation comprises propylene glycol in an amount of 0.01 wt. % or less based on the aerosolizable formulation. In one embodiment, the aerosolizable formulation does not comprise propylene glycol.

Acid In one embodiment, the aerosolizable formulation further comprises an acid. The acid may be any suitable acid. In one embodiment, the acid is an organic acid. In one embodiment, the acid is a carboxylic acid. In one embodiment, the acid is an organic carboxylic acid.

In one embodiment, the acid is selected from the group consisting of acetic acid, lactic acid, formic acid, citric acid, benzoic acid, pyruvic acid, levulinic acid, succinic acid, tartaric acid, sorbic acid, propionic acid, phenylacetic acid, and mixtures thereof. In one embodiment, the acid is selected from the group consisting of citric acid, benzoic acid, levulinic acid, lactic acid, sorbic acid, and mixtures thereof. In one embodiment, the acid is selected from the group consisting of citric acid, benzoic acid, levulinic acid, and mixtures thereof. In one embodiment, the acid is at least citric acid. In one embodiment, the acid consists of citric acid.

In one embodiment, the acid is selected from acids having a pKa of 2 to 5. In one embodiment, the acid is a weak acid. In one embodiment, the acid is a weak organic acid.

The acid may be present in any suitable amount. In one embodiment, the acid is present in an amount of 6 wt% or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-6 wt% based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-6 wt% based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-6 wt% based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-6 wt% based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-5 wt% based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-5 wt% based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-5 wt% based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-5 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 4 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-4 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-4 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-4 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-4 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 3 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-3 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-3 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-3 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-3 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 2 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 1 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.1-1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.6 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-0.6 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-0.6 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-0.6 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-0.6 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.1-0.6 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.5 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-0.5 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-0.5 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-0.5 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-0.5 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.2 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-0.2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-0.2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-0.2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08-0.2 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.1 wt % or less based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.01-0.1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.02-0.1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.05-0.1 wt % based on the aerosolizable formulation. In one embodiment, the acid is present in an amount of 0.08 to 0.1 wt % based on the aerosolizable formulation.

In one embodiment, the acid has a water solubility of at least 2 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 5 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 10 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 20 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 50 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 100 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 200 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 300 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 400 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 500 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 600 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 700 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 800 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 900 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 1000 g/L at 20° C. In one embodiment, the acid has a water solubility of at least 1100 g/L at 20° C.

The amount of acid and the solubility of the acid may be selected such that a given amount of the acid dissolves in water. In one embodiment, at least 20% of the acid dissolves in water at 20° C. In one embodiment, at least 20% of the acid dissolves in water at 25° C. In one embodiment, at least 20% of the acid dissolves in water at 30° C. In one embodiment, at least 35% of the acid dissolves in water at 20° C. In one embodiment, at least 40% of the acid dissolves in water at 20° C. In one embodiment, at least 45% of the acid dissolves in water at 20° C. In one embodiment, at least 50% of the acid dissolves in water at 20° C. In one embodiment, at least 55% of the acid dissolves in water at 20° C.

In embodiments of the invention in which nicotine is present, the molar ratio of acid to nicotine may be selected as desired. In one embodiment, the molar ratio of acid to nicotine is 5:1 to 1:5. In one embodiment, the molar ratio of acid to nicotine is 4:1 to 1:4. In one embodiment, the molar ratio of acid to nicotine is 3:1 to 1:3. In one embodiment, the molar ratio of acid to nicotine is 2:1 to 1:2. In one embodiment, the molar ratio of acid to nicotine is 1.5:1 to 1:1.5. In one embodiment, the molar ratio of acid to nicotine is 1.2:1 to 1:1.2. In one embodiment, the molar ratio of acid to nicotine is 5:1 to 1:1. In one embodiment, the molar ratio of acid to nicotine is 4:1 to 1:1. In one embodiment, the molar ratio of acid to nicotine is 3:1 to 1:1. In one embodiment, the molar ratio of acid to nicotine is 2:1 to 1:1. In one embodiment, the molar ratio of acid to nicotine is 1.5:1 to 1:1. In one embodiment, the molar ratio of acid to nicotine is 1.2:1 to 1:1.

In one embodiment, the total content of acids present in the formulation is 5 molar equivalents or less based on nicotine. In one embodiment, the total content of acids present in the formulation is 4 molar equivalents or less based on nicotine. In one embodiment, the total content of acids present in the formulation is 3 molar equivalents or less based on nicotine. In one embodiment, the total content of acids present in the formulation is 2 molar equivalents or less based on nicotine. In one embodiment, the total content of acids present in the formulation is 1 molar equivalent or less based on nicotine.

In one embodiment, the total content of acids present in the formulation is 0.01 molar equivalents or more based on nicotine. In one embodiment, the total content of acids present in the formulation is 0.05 molar equivalents or more based on nicotine. In one embodiment, the total content of acids present in the formulation is 0.1 molar equivalents or more based on nicotine. In one embodiment, the total content of acids present in the formulation is 0.2 molar equivalents or more based on nicotine. In one embodiment, the total content of acids present in the formulation is 0.3 molar equivalents or more based on nicotine. In one embodiment, the total content of acids present in the formulation is 0.4 molar equivalents or more based on nicotine. In one embodiment, the total content of acids present in the formulation is 0.5 molar equivalents or more based on nicotine. In one embodiment, the total content of acids present in the formulation is 0.7 molar equivalents or more based on nicotine.

A nicotine formulation having desirable characteristics of nicotine flavor, impact, stimulation, smoothness and/or nicotine reward to the user can be provided. In one embodiment, nicotine is present in an amount of 6 wt% or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 4 wt% or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-4 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-4 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-4 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-4 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 3 wt% or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-3 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-3 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-3 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-3 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 2 wt% or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-2 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-2 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-2 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-2 wt % based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 1 wt % or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-1 wt % based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-1 wt % based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-1 wt % based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-1 wt % based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.1-1 wt % based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.6 wt % or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-0.6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-0.6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-0.6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-0.6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.1-0.6 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.5 wt% or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-0.5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-0.5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-0.5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-0.5 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.2 wt% or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-0.2 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-0.2 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-0.2 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-0.2 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.1 wt% or less based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.01-0.1 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.02-0.1 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.05-0.1 wt% based on the total weight of the aerosolizable formulation. In one embodiment, nicotine is present in an amount of 0.08-0.1 wt% based on the total weight of the aerosolizable formulation.

As will be appreciated by those of skill in the art, nicotine may exist in unprotonated, monoprotonated or diprotonated forms. The structures of each of these forms are shown below.

References herein to the protonated form refer to both monoprotonated and diprotonated nicotine. References herein to the amount of protonated form refer to the combined amount of monoprotonated and diprotonated nicotine. Additionally, when referring to a fully protonated formulation, it will be understood that there may be very small amounts of unprotonated nicotine present at any one time, e.g., less than 1% unprotonated nicotine.

In one embodiment, the formulation may include nicotine in a protonated form. In one embodiment, the formulation may include nicotine in an unprotonated form. In one embodiment, the formulation includes nicotine in an unprotonated form and nicotine in a monoprotonated form. In one embodiment, the formulation includes nicotine in an unprotonated form and nicotine in a diprotonated form. In one embodiment, the formulation includes nicotine in an unprotonated form, nicotine in a monoprotonated form and nicotine in a diprotonated form.

In one embodiment, at least 5 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 10 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 15 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 20 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 25 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 30 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 35 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 40 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 45 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 50 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 55 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 60 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 65 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 70 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 75 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 80 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 85 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 90 wt% of the nicotine present in the formulation is in protonated form. In one embodiment, at least 95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 99 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, at least 99.9 wt% of the nicotine present in the formulation is in the protonated form.

In one embodiment, 50-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 55-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 60-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 65-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 70-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 75-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 80-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 85-95 wt% of the nicotine present in the formulation is in the protonated form. In one embodiment, 90-95 wt% of the nicotine present in the formulation is in the protonated form.

The relevant amounts of nicotine present in the formulations in protonated form are specified herein. These amounts can be readily calculated by one of ordinary skill in the art. Nicotine (3-(1-methylpyrrolidin-2-yl)pyridine) is a diacid base with a pKa of 3.12 for the pyridine ring and 8.02 for the pyrrolidine ring. Nicotine can exist in protonated (mono- and di-) and unprotonated (free base) forms with different bioavailability depending on pH.

The distribution of protonated and unprotonated nicotine will change at various pH increments.

At higher pH levels the proportion of unprotonated nicotine dominates, while a decrease in pH will see an increase in the proportion of protonated nicotine (mono- or di-, depending on the pH). If the relative proportion of protonated nicotine and the total amount of nicotine in a sample are known, the absolute amount of protonated nicotine can be calculated.

The relative proportion of protonated nicotine in a formulation can be calculated by using the Henderson-Hasselbalch equation, which expresses pH as a derivative of the acid dissociation constant equation and is widely used in chemical and biological systems. Consider the following equilibrium:

The Henderson-Hasselbalch equation for this equilibrium is:

It is.

where [B] is the amount of unprotonated nicotine (i.e., the free base), [BH+] is the amount of protonated nicotine (i.e., the conjugate acid), and pKa is the reference pKa value of the pyrrolidine ring nitrogen of nicotine (pKa=8.02). The relative proportion of protonated nicotine can be derived from the alpha value of unprotonated nicotine calculated from the Henderson-Hasselbalch equation as follows:

The pKa values of the nicotine formulations were determined using the basic method described in "Spectroscopic investigations into the acid-based properties of nicotine at different temperatures", Peter M. Clayton, Carl A. Vas, Tam T. T. Bui, Alex F. Drake and Kevin McAdam, Anal. Methods, 2013, 5, 81-88.

As discussed herein, the aerosolizable formulation may include one or more fragrances or flavoring ingredients. As used herein, the terms "flavor" and "flavoring" refer to materials that can be used, where topical control permits, to create a desired taste or scent in adult consumer products. Fragrances and flavorings include extracts (e.g., licorice, hydrangea, magnolia leaf, chamomile, fenugreek, clove, menthol, mint, aniseed, cinnamon, herbs, wintergreen, cherry, berry, peach, apple, Drambuie, bourbon, scotch, whiskey, spearmint, peppermint, lavender, cardamom, celery, cascarilla, nutmeg, sandalwood, bergamot, geranium, honey essence, rose oil, vanilla, lemon oil, orange oil, cassia, caraway, cognac, jasmine, ylang ylang, linseed ... The compositions may contain other additives such as spices, spices, flavor enhancers, bitter taste receptor site blockers, sensory receptor site activators or stimulators, sugars and/or sugar substitutes (e.g. sucralose, acesulfame potassium, aspartame, saccharin, cyclamate, lactose, sucrose, glucose, fructose, sorbitol or mannitol), and other additives such as charcoal, chlorophyll, minerals, botanicals or breath fresheners. These may be of imitation, synthetic or natural origin or blends thereof. They may be in any suitable form, for example oil, liquid or powder. The one or more flavoring agents may be selected from the group consisting of (4-(para-)methoxyphenyl)-2-butanone, vanillin, gamma-undecalactone, menthone, 5-propenylguaethol, menthol, para-mentha-8-thiol-3-one, and mixtures thereof. In one embodiment, the flavoring agent is at least menthol.

When present, the one or more fragrances may be present in any suitable amount. In one embodiment, the one or more fragrances are present in a total amount of 10 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 7 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 5 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 4 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 3 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 2 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 1 wt. % or less based on the aerosolizable formulation.

In one embodiment, the one or more fragrances are present in a total amount of 0.01 to 5 wt. % based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 to 4 wt. % based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 to 3 wt. % based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 to 2 wt. % based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 to 1 wt. % based on the aerosolizable formulation. In one embodiment, the one or more fragrances are present in a total amount of 0.01 to 0.5 wt. % based on the aerosolizable formulation.

In one embodiment , when the aerosolizable formulation comprises one or more cyclodextrins, the aerosolizable formulation does not include a fragrance that can be encapsulated by the one or more cyclodextrins. In one embodiment, when the aerosolizable formulation comprises one or more cyclodextrins, the aerosolizable formulation does not include a fragrance.

As will be appreciated, the one or more cyclodextrins may be present in the aerosolizable formulation in any suitable amount or none. In one embodiment, the one or more cyclodextrins are present in a total amount of 12 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 10 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 9 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 8 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 7 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 6 wt. % or less based on the aerosolizable formulation. % or less. In one embodiment, the one or more cyclodextrins are present in a total amount of 5 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 4 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 3 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 2 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 1 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 0.1 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 0.01 wt. % or less based on the aerosolizable formulation. In one embodiment, the one or more cyclodextrins are present in a total amount of 0.001 wt. % or less based on the aerosolizable formulation.

The aerosolizable formulations of the present invention may include one or more cyclodextrins. The one or more cyclodextrins may be selected from the group consisting of unsubstituted cyclodextrins, substituted cyclodextrins, and mixtures thereof. In one embodiment, at least one cyclodextrin is an unsubstituted cyclodextrin. In one embodiment, the one or more cyclodextrins are selected from the group consisting of unsubstituted cyclodextrins. In one embodiment, at least one cyclodextrin is a substituted cyclodextrin. In one embodiment, the one or more cyclodextrins are selected from the group consisting of substituted cyclodextrins.

In one embodiment, the one or more cyclodextrins are selected from the group consisting of unsubstituted (α)-cyclodextrin, substituted (α)-cyclodextrin, unsubstituted (β)-cyclodextrin, substituted (β)-cyclodextrin, unsubstituted (γ)-cyclodextrin, substituted (γ)-cyclodextrin, and mixtures thereof. In one embodiment, the one or more cyclodextrins are selected from the group consisting of unsubstituted (β)-cyclodextrin, substituted (β)-cyclodextrin, and mixtures thereof.

In one embodiment, the one or more cyclodextrins are selected from the group consisting of unsubstituted (α)-cyclodextrin, unsubstituted (β)-cyclodextrin, unsubstituted (γ)-cyclodextrin, and mixtures thereof. In one embodiment, the one or more cyclodextrins are selected from unsubstituted (β)-cyclodextrin.

In one embodiment, the one or more cyclodextrins are selected from the group consisting of substituted (α)-cyclodextrins, substituted (β)-cyclodextrins, substituted (γ)-cyclodextrins, and mixtures thereof. In one embodiment, the one or more cyclodextrins are selected from substituted (β)-cyclodextrins. Chemical substitutions at the 2-, 3-, and 6-hydroxyl sites are contemplated, particularly substitution at the 2-position.

In one embodiment, the one or more cyclodextrins are selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, and mixtures thereof. In one embodiment, the one or more cyclodextrins are at least 2-hydroxypropyl-α-cyclodextrin. In one embodiment, the one or more cyclodextrins are at least 2-hydroxypropyl-β-cyclodextrin. In one embodiment, the one or more cyclodextrins are at least 2-hydroxypropyl-γ-cyclodextrin.

2-Hydroxypropyl derivatives of cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, have increased solubility in water when compared to base cyclodextrins, such as β-cyclodextrin.

In a further aspect, the aerosolizable formulation comprises 0.001 wt.% or less total cyclodextrin based on the aerosolizable formulation, such as 1×10 ⁻⁴ wt.% or less total cyclodextrin based on the aerosolizable formulation, such as 1×10 ⁻⁵ wt.% or less total cyclodextrin based on the aerosolizable formulation, such as 1×10 ⁻⁶ wt.% or less total cyclodextrin based on the aerosolizable formulation. Thus, in a further aspect, the present invention provides:
(1)
(i) water in an amount of at least 85 wt. % based on the aerosolizable formulation;
(ii) nicotine, wherein the cyclodextrin is present in a total amount of 0 to 0.001 wt. % based on the aerosolizable formulation.
(2) A method for generating an aerosol, comprising:
1. A method comprising the step of aerosolizing an aerosolizable formulation comprising: (i) water in an amount of at least 85 wt. % based on the aerosolizable formulation; and (ii) nicotine or one or more flavorings, wherein cyclodextrin is present in a total amount of 0-0.001 wt. % based on the aerosolizable formulation.
(3)
(a) a container;
(b)
1. A contained aerosolizable formulation comprising: (i) water in an amount of at least 85 wt. % based on the aerosolizable formulation; and (ii) an aerosolizable formulation comprising nicotine, wherein cyclodextrin is present in a total amount of 0-0.001 wt. % based on the aerosolizable formulation.
(4) An electronic aerosol delivery system, comprising:
(a) an aerosolization device for aerosolizing a formulation for inhalation by a user of an electronic aerosol delivery system;
(b) a power source comprising a cell or battery for powering the aerosolization device;
(c)
1. An electronic aerosol delivery system comprising: (i) water in an amount of at least 85 wt. % based on the aerosolizable formulation; and (ii) an aerosolizable formulation comprising nicotine or one or more flavorings, wherein cyclodextrin is present in a total amount of 0-0.001 wt. % based on the aerosolizable formulation.

As discussed herein, in one aspect, a method for generating an aerosol comprises:
A method is provided, comprising the step of aerosolizing an aerosolizable formulation comprising: (i) water in an amount of at least 85 wt. %, based on the aerosolizable formulation; and (ii) nicotine or one or more flavorings.

In a further aspect, there is provided a method for generating an aerosol, comprising the steps of:
A method is provided that includes the step of aerosolizing an aerosolizable formulation that includes: (i) water in an amount of at least 95 wt. % based on the aerosolizable formulation; and (ii) nicotine.

In the method, the aerosol may be generated by a method performed at a temperature below 60°C. In the method, the aerosol may be generated by a method performed at a temperature below 50°C. In the method, the aerosol may be generated by a method performed at a temperature below 40°C. In the method, the aerosol may be generated by a method performed at a temperature below 30°C. In the method, the aerosol may be generated by a method performed at a temperature below 25°C. In the method, the aerosol may be generated by a method that does not involve heating.

In the method, the aerosol may be generated by applying ultrasonic energy to the aerosolizable formulation.

In one embodiment, the aerosol of the aerosolized formulation has a D50 of 2-6 μm. References herein to particle size distribution, D50, D10 or D90 are taken from British and European Pharmacopoeia, 2.9.31 Particle Size Analysis By Laser Light Diffraction (BRITISH PHARMACOPOEIA COMMISSION. (2014), British Pharmacopoeia. London, England: Stationery Office and COUNCIL OF EUROPE. (2013). European Pharmacopoeia. Strasbourg, France: Council of The terms D50, Dv50 and Dx50 are interchangeable. The terms D10, Dv10 and Dx10 are interchangeable. The terms D90, Dv90 and Dx90 are interchangeable.

In one embodiment, the aerosol has a D50 of 2.5-6 μm. In one embodiment, the aerosol has a D50 of 3-6 μm. In one embodiment, the aerosol has a D50 of 3.5-6 μm. In one embodiment, the aerosol has a D50 of 4-6 μm. In one embodiment, the aerosol has a D50 of 4.5-6 μm. In one embodiment, the aerosol has a D50 of 5-6 μm. In one embodiment, the aerosol has a D50 of 2.5-5.5 μm. In one embodiment, the aerosol has a D50 of 3-5.5 μm. In one embodiment, the aerosol has a D50 of 3.5-5.5 μm. In one embodiment, the aerosol has a D50 of 4-5.5 μm. In one embodiment, the aerosol has a D50 of 4.5-5.5 μm. In one embodiment, the aerosol has a D50 of 5 to 5.5 μm.

In one embodiment, the aerosol has a D10 of at least 0.5 μm. In one embodiment, the aerosol has a D10 of at least 1 μm. In one embodiment, the aerosol has a D10 of at least 2 μm.

In one embodiment, the aerosol has a D90 of 15 μm or less. In one embodiment, the aerosol has a D90 of 12 μm or less. In one embodiment, the aerosol has a D90 of 10 μm or less.

In one embodiment, D50 is measured after excluding particles having a particle size less than 1 μm. In one embodiment, D10 is measured after excluding particles having a particle size less than 1 μm. In one embodiment, D90 is measured after excluding particles having a particle size less than 1 μm.

The formulation may be contained or delivered by any means. In one aspect, the present invention provides a contained aerosolizable formulation comprising (a) one or more containers and (b) an aerosolizable formulation as defined herein. The container may be any suitable container, e.g., for enabling storage or delivery of the formulation. In one aspect, the container is configured to engage with an electronic aerosol delivery system. The container may be configured to be in fluid communication with an electronic aerosol delivery system such that the formulation can be delivered to the electronic aerosol delivery system. As mentioned above, the present disclosure relates to a container that can be used in an electronic aerosol delivery system, such as an e-cigarette. Throughout the following description, the term "e-cigarette" is used, which term can be used interchangeably with electronic aerosol delivery system.

As discussed herein, the container of the present invention is typically provided for delivery of an aerosolizable formulation to or within an e-cigarette. The aerosolizable formulation may be retained within the e-cigarette or may be sold as a separate container for subsequent use with or within the e-cigarette. As will be appreciated by those skilled in the art, the e-cigarette may include a unit known as a removable cartomizer, which typically includes a reservoir of the aerosolizable formulation, an aerosolization device such as a wick material, and a heating element for vaporizing the aerosolizable formulation. In some e-cigarettes, the cartomizer is part of an integrally molded device and is not removable. In one aspect, the container is the cartomizer or is part of the cartomizer. In one aspect, the container is not the cartomizer or is not part of the cartomizer, but is a container such as a tank, which can be used to deliver a nicotine formulation to or within the e-cigarette.

In one aspect, the container is part of an e-cigarette. Thus, in a further aspect, the present invention provides an electronic aerosol delivery system comprising an aerosolizable formulation as defined herein, an aerosolization device for aerosolizing the formulation for inhalation by a user of the electronic aerosol delivery system, and a power source comprising a cell or battery for powering the aerosolization device.

The methods of the present invention may include additional steps either before the recited steps, after the recited steps, or between one or more of the recited steps.

The invention will now be described in more detail, by way of example only, with reference to the accompanying drawings in which:

1 is a graph showing the change in p _s K _a2 with nicotine concentration.

The invention will now be described with reference to the following non-limiting examples.

Example 1
A series of tests were conducted using a commercially available vibrating mesh nebulizer device: A "control" device was loaded with a formulation containing 90.0% (w/w) water, 8.8% (w/w) propylene glycol with flavour, and 1.2% (w/w) nicotine.

Similar devices were prepared in which 10.0% w/w glycerol was added to the formulation and the water content was reduced accordingly to 80.0% (w/w).

Similar devices were prepared in which 10.0% w/w propylene glycol was added to the formulation and the water content was adjusted accordingly to 80.0% (w/w).

Similar devices were prepared in which glycerol 5.0% w/w and propylene glycol 5.0% (w/w) were added to the formulation and the water content adjusted accordingly to 80.0% (w/w).

Similar devices were prepared in which 20.0% w/w glycerol was added to the formulation and the water content was reduced accordingly to 70.0% (w/w).

Similar devices were prepared in which 20.0% w/w propylene glycol was added to the formulation and the water content was adjusted accordingly to 70.0% (w/w).

Similar devices were prepared in which 10.0% w/w glycerol and 10.0% propylene glycol were added to the formulation and the water content was adjusted accordingly to 70.0% (w/w).

Each of these devices was given to eight subjects, including e-cigarette users, who were asked to puff on each device five times in a continuous monadic manner. To aid in feedback on the water, glycerol, and propylene glycol compositions, each subject was asked to choose a preferred flavor of their choice.

Eight panelists preferred the formulation that did not contain propylene glycol or glycerol at concentrations greater than 10.0% (w/w); five panelists preferred the control device formulation; and three panelists preferred the formulation that contained 10% glycerol.

Example 2
Three amaretto flavored and three non-flavored formulations were blindly evaluated by up to nine panelists, experienced vapers with different nicotine tolerances. During the sensory evaluation, panelists ranked several sensory attributes, such as throat irritation and chest impact, from low (1) to high (9). Panelists were also asked to indicate their favorite formulation of the tested formulations. A series of tests were performed using a commercially available vibrating mesh nebulizer device.

The devices were loaded with a formulation containing the following:
Formulation 1 - Water 82% (w/w), 2-hydroxypropyl-β-cyclodextrin 9.4% (w/w), glycerol 8% (w/w) and nicotine 0.6% (w/w).
Formulation 2 - Water 85% (w/w), 2-hydroxypropyl-β-cyclodextrin 9.4% (w/w), glycerol 5% (w/w) and nicotine 0.6% (w/w).
Formulation 3 - Water 87% (w/w), 2-hydroxypropyl-β-cyclodextrin 9.4% (w/w), glycerol 3% (w/w) and nicotine 0.6% (w/w).
Formulation 4 - Water 82% (w/w), Propylene glycol with amaretto flavour 2.0% (w/w), Glycerol 9.8% (w/w), Ethanol 5% (w/w), Nicotine 0.6% (w/w) and Citric Acid 0.6% (w/w).
Formulation 5 - Water 85% (w/w), Propylene glycol with amaretto flavour 2.0% (w/w), Glycerol 6.8% (w/w), Ethanol 5% (w/w), Nicotine 0.6% (w/w) and Citric Acid 0.6% (w/w).
Formulation 6 - Water 87% (w/w), Propylene glycol with amaretto flavour 2.0% (w/w), Glycerol 4.8% (w/w), Ethanol 5% (w/w), Nicotine 0.6% (w/w) and Citric Acid 0.6% (w/w).

A summary of the formulations tested is given in the table below.

Five out of seven monitors preferred the unflavored formulation with a water content of 85% (w/w), one out of seven monitors preferred the unflavored formulation with a water content of 87% (w/w), while only one monitor preferred the unflavored formulation with a water content of 82% (w/w).

Eight out of nine panelists preferred the amaretto-flavored formulations with water contents of 85% and 87% (w/w), while only one panelist preferred the amaretto-flavored formulation with a water content of 82% (w/w).

Various modifications and variations of the present invention will become apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the present invention has been described in connection with certain preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the chemical or related fields are intended to be within the scope of the following claims.

Claims (20)

(i) water in an amount of 85 wt. % based on the aerosolizable formulation;
(ii) nicotine,
(iii) one or more cyclodextrins ; and
(iv) an acid;
wherein the one or more cyclodextrins are present in an amount of 0.001 to 12 wt. % based on the aerosolizable formulation, and the molar ratio of acid to nicotine is 5:1 to 1:1 . The aerosolizable formulation of claim 1, wherein the nicotine is present in an amount of 0.01 to 1 wt. % based on the aerosolizable formulation. The aerosolizable formulation of claim 2, wherein the nicotine is present in an amount of 0.01 to 0.6 wt. % based on the aerosolizable formulation. 2. The aerosolizable formulation of claim 1, wherein the acid is selected from the group consisting of acetic acid, lactic acid, formic acid, citric acid, benzoic acid, pyruvic acid, levulinic acid, succinic acid, tartaric acid, sorbic acid, propionic acid, phenylacetic acid, and mixtures thereof . 5. The aerosolizable formulation of claim 4 , wherein the acid is selected from the group consisting of citric acid, benzoic acid, levulinic acid, sorbic acid, lactic acid, and mixtures thereof. 6. The aerosolizable formulation of claim 4 or 5 , wherein the acid is at least citric acid. The aerosolizable formulation of any one of claims 1 to 6 , further comprising one or more fragrances. 8. The aerosolizable formulation of claim 7, wherein the one or more flavorings are selected from the group consisting of (4-(para-)methoxyphenyl)-2-butanone, vanillin, γ-undecalactone, menthone, 5-propenylguaethol, menthol, para-mentha-8-thiol- 3 -one, and mixtures thereof. 9. The aerosolizable formulation of claim 8 , wherein the flavoring is at least menthol. 10. The aerosolizable formulation of claim 7 , wherein the one or more flavorings are present in a total amount of 0.01 to 2 wt. % based on the aerosolizable formulation. 10. The aerosolizable formulation of claim 7 , wherein the one or more flavorings are present in a total amount of 0.01 to 1 wt. % based on the aerosolizable formulation. 1. A method for generating an aerosol, comprising:
(i) water in an amount of 85 wt. % based on the aerosolizable formulation;
(ii) nicotine ,
(iii) one or more cyclodextrins , and
(iv) Acid
wherein the one or more cyclodextrins are present in an amount of 0.001-12 wt. % based on the aerosolizable formulation, and a molar ratio of acid to nicotine is 5:1-1:1. A method for generating an aerosol, comprising the step of aerosolizing an aerosolizable formulation according to any one of claims 2 to 11. 14. The method of claim 12 or 13 , wherein the aerosol is generated by a method carried out at a temperature below 50°C. The method of any one of claims 12 to 14 , wherein the aerosol is generated by applying ultrasonic energy to an aerosolizable formulation. (a) a container;
(b)
(i) water in an amount of 85 wt. % based on the aerosolizable formulation;
(ii) nicotine ,
(iii) one or more cyclodextrins , and
(iv) Acid
wherein the one or more cyclodextrins are present in an amount of 0.001 to 12 wt. % based on the aerosolizable formulation, and a molar ratio of acid to nicotine is 5:1 to 1:1. (a) a container;
(b) an aerosolizable formulation according to any one of claims 2 to 11;
16. A contained aerosolizable formulation comprising: 18. The contained aerosolizable formulation of claim 16 or 17 , wherein the container is configured to engage an electronic aerosol delivery system. 1. An electronic aerosol delivery system comprising:
(a) an aerosolization device for aerosolizing a formulation for inhalation by a user of said electronic aerosol delivery system;
(b) a power source comprising a cell or battery for powering the aerosolization device; and
(c)
(i) water in an amount of 85 wt. % based on the aerosolizable formulation;
(ii) nicotine ,
(iii) one or more cyclodextrins , and
(iv) Acid
wherein the one or more cyclodextrins are present in an amount of 0.001 to 12 wt. % based on the aerosolizable formulation, and a molar ratio of acid to nicotine is between 5:1 and 1:1. 1. An electronic aerosol delivery system comprising:
(a) an aerosolization device for aerosolizing a formulation for inhalation by a user of said electronic aerosol delivery system;
(b) a power source comprising a cell or battery for powering the aerosolization device; and
(c) an aerosolizable formulation according to any one of claims 2 to 11;
An electronic aerosol delivery system comprising:

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