CA3118005C

CA3118005C - Aerosolisable formulation

Info

Publication number: CA3118005C
Application number: CA3118005A
Authority: CA
Inventors: Ross CABOT
Original assignee: Nicoventures Trading Ltd
Current assignee: Nicoventures Trading Ltd
Priority date: 2018-11-01
Filing date: 2019-10-31
Publication date: 2024-03-26
Anticipated expiration: 2039-10-31
Also published as: WO2020089633A1; US20230270154A1; AU2019371078B2; CN113260261A; CA3118005A1; KR20210074307A; UA127838C2; BR112021008570A2; JP2023120357A; IL282617A; GB201817867D0; EP3873241A1; AU2019371078A1; JP2022506073A; MX2021005164A

Abstract

There is provided an aerosolisable formulation comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation; (ii) nicotine; and (iii) an acid which is at least partially water soluble; wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

Description

AEROSOLISABLE FORMULATION
FIELD OF THE INVENTION
The present disclosure relates to an aerosolisable formulation, a method of forming the same, a container containing the same, a device containing the same and processes and uses of the same.
BACKGROUND TO THE INVENTION
Electronic aerosol provision systems such as e-cigarettes generally contain a reservoir of liquid which is to be vaporised, typically containing nicotine. When a user inhales on the device, a heater is activated to vaporise a small amount of liquid, which is therefore inhaled by the user.
The use of e-cigarettes in the UK has grown rapidly, and it has been estimated that there are now over a million people using them in the UK.
One challenge faced in providing such systems is to provide from the aerosol provision device an aerosol to be inhaled which provides consumers with an acceptable experience.
Some consumers may prefer an e-cigarette that generates an aerosol that closely 'mimics' smoke inhaled from a tobacco product such as a cigarette. Aerosols from e-cigarettes and smoke from tobacco products such as cigarettes provides to the user a complex chain of flavour in the mouth, nicotine absorption in the mouth and throat, followed by nicotine .. absorption in the lungs. These various aspects are described by users in terms of flavour, intensity/quality, impact, irritation/smoothness and nicotine reward. Nicotine contributes to a number of these factors, and is strongly associated with factors such as impact, irritation and smoothness; these are readily perceived by consumers, and e-cigarettes may offer too much or too little of these parameters for consumers, depending upon individual preferences.
Nicotine reward is particularly complex as it results from both the amount of and speed with which nicotine is absorbed from the lining of the mouth, this is typically nicotine in the vapour phase, and from the amount and speed nicotine that is absorbed from the lungs, this is typically nicotine in the particulate phase of the aerosol which is inhaled.
Each of these factors, and their balance, can strongly contribute to consumer acceptability of an e-.. cigarette. Providing means to optimise the overall vaping experience is therefore desirable to e-cigarette manufacturers.

A further challenge facing such systems is the continued demand for harm reduction. Harm from cigarette and e-cigarette devices primarily comes from toxicants.
Therefore, there is a desire to reduce the components present in the system which may form toxicants.
SUMMARY OF THE INVENTION
In one aspect there is provided an aerosolisable formulation comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
In one aspect there is provided a process for forming an aerosol, the process comprising aerosolising an aerosolisable formulation comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
In one aspect there is provided a contained aerosolisable formulation comprising (a) a container; and (b) an aerosolisable formulation, comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form;
and wherein the formulation has a pH of from 4 to 6.
In one aspect there is provided an electronic aerosol provision system comprising:
(a) an aerosoliser for aerosolising formulation for inhalation by a user of the electronic aerosol provision system;
(b) a power supply comprising a cell or battery for supplying power to the aerosoliser (c) an aerosolisable formulation , comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;

2

3 (ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form;
and wherein the formulation has a pH of from 4 to 6.
In one aspect there is provided a process for improving the sensory properties of an aerosolised nicotine formulation, the process comprising the steps of (a) providing an aerosolisable material comprising (i) water in an amount of at least 20 wt%
based on the aerosolisable material and (ii) nicotine;
(b) incorporating into the aerosolisable material an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
In one aspect there is provided a process for improving the storage stability of an aerosolised nicotine formulation, the process comprising the steps of (a) providing an aerosolisable material comprising (i) water in an amount of at least 20 wt%
based on the aerosolisable material and (ii) nicotine;
(b) incorporating into the aerosolisable material an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
In one aspect there is provided use of one or more acids for improving sensory properties of an aerosolised nicotine formulation, wherein the nicotine formulation comprises (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form;
and wherein the formulation has a pH of from 4 to 6.
In one aspect there is provided use of one or more acids for improving storage stability of an aerosolised nicotine formulation, wherein the nicotine formulation comprises (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
DETAILED DESCRIPTION
As discussed herein in one aspect there is provided an aerosolisable formulation comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
We have found that an advantageous system may be provided which contains water and in which an acid which is at least partially dissolved. In particular the inclusion of the an acid such that at least 5 wt% of the nicotine present in the formulation is in protonated form and such that the formulation has a pH of from 4 to 6 both protonates the nicotine and inhibits microbial growth in the water containing system. In such a system, the number of components present may be reduced leading to less chance of forming breakdown products/toxicants. In particular, the use of water allows for the replacement of some or all of the glycerol, propylene glycol, 1,3-propane diol and mixtures thereof typically used in e-cigarettes. Furthermore, the use of an acid as a multi-functional component also allows for a reduction in the number of components in the formulation.
As is understood by one skilled in the art, nicotine may exist in unprotonated form, monoprotonated form or diprotonated form. The structures of each of these forms are given below.
H H H
N ,,,,N
1 \ 1 H/ r,1_, \
.-0. .3 1 Fi" \CH3 CH3 i\l+
N
N
I
H
Unprotonated nicotine monoprotonated nicotine di protonated nicotine Reference in the specification to protonated form means both monoprotonated nicotine and diprotonated nicotine. Reference in the specification to amounts in the protonated form

4 means the combined amount of monoprotonated nicotine and diprotonated nicotine.
Furthermore, when reference is made to a fully protonated formulation it will be understood that at any one time there may be very minor amounts of unprotonated nicotine present, e.g.
less than 1% unprotonated.
For ease of reference, these and further aspects of the present invention are now discussed under appropriate section headings. However, the teachings under each section are not necessarily limited to each particular section.
Water As discussed herein the aerosolisable formulation comprises water in an amount of at least wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 25 wt.% based on the aerosolisable formulation. In one aspect water is present in 15 an amount of at least 30 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 35 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 40 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 45 wt.%
based on the aerosolisable formulation. In one aspect water is present in an amount of at least 50 wt.%
20 based on the aerosolisable formulation. In one aspect water is present in an amount of at least 55 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 60 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 65 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 70 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 75 wt.%
based on the aerosolisable formulation. In one aspect water is present in an amount of at least 80 wt.%
based on the aerosolisable formulation. In one aspect water is present in an amount of at least 85 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 90 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 95 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of at least 99 wt.% based on the aerosolisable formulation.
In one aspect water is present in an amount of from 20 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 25 to 99 wt.%
based on the aerosolisable formulation. In one aspect water is present in an amount of from 30 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an

5 amount of from 35 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 40 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 45 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 50 to 99 wt.%
based on the aerosolisable formulation. In one aspect water is present in an amount of from 55 to 99 wt.%
based on the aerosolisable formulation. In one aspect water is present in an amount of from 60 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 65 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 70 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 75 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 80 to 99 wt.%
based on the aerosolisable formulation. In one aspect water is present in an amount of from 85 to 99 wt %
based on the aerosolisable formulation. In one aspect water is present in an amount of from 90 to 99 wt.% based on the aerosolisable formulation. In one aspect water is present in an amount of from 95 to 99 wt.% based on the aerosolisable formulation.
As discussed herein the use of water allows for the replacement of some or all of the glycerol, propylene glycol, 1,3-propane diol and mixtures thereof typically used in e-cigarettes. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 10 wt.%
based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 8 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 5 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 2 wt.%
based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 1 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 0.5 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 0.2 wt.%
based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 0.1 wt.% based on the aerosolisable formulation. In one aspect the

6 aerosolisable formulation contains glycerol, propylene glycol, 1,3-propane diol and mixtures thereof in a combined amount of no greater than 0.01 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains no glycerol, propylene glycol, 1,3-propane diol and mixtures thereof.
In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 10 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 8 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 5 wt.%
based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 2 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 1 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 0.5 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 0.2 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 0.1 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol, propylene glycol, and mixtures thereof in a combined amount of no greater than 0.01 wt.%
based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains no glycerol, propylene glycol, and mixtures thereof.
In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 10 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 8 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 5 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 2 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 1 wt.% based on the aerosolisable formulation.
In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 0.5 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation

7 contains glycerol in an amount of no greater than 0.2 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 0.1 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains glycerol in an amount of no greater than 0.01 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains no glycerol.
In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 10 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 8 wt.%
based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 5 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 2 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 1 wt.%
based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 0.5 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 0.2 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 0.1 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains propylene glycol in an amount of no greater than 0.01 wt.% based on the aerosolisable formulation. In one aspect the aerosolisable formulation contains no propylene glycol.
Nicotine The formulation comprises nicotine in protonated form. The formulation may comprise nicotine in unprotonated form. In one aspect the formulation comprises nicotine in unprotonated form and nicotine in monoprotonated form. In one aspect the formulation comprises nicotine in unprotonated form and nicotine in diprotonated form. In one aspect the formulation comprises nicotine in unprotonated form, nicotine in monoprotonated form and nicotine in diprotonated form.
The one or more acids protonate at least 5% of the nicotine. In one aspect, at least 10 wt%
of the nicotine present in the formulation is in protonated form. In one aspect, at least 15 wt% of the nicotine present in the formulation is in protonated form. In one aspect, at least

8 20 wt% of the nicotine present in the formulation is in protonated form. In one aspect, at least 25 wt% of the nicotine present in the formulation is in protonated form.
In one aspect, at least 30 wt% of the nicotine present in the formulation is in protonated form. In one aspect, at least 35 wt% of the nicotine present in the formulation is in protonated form. In one aspect, at least 40 wt% of the nicotine present in the formulation is in protonated form.
In one aspect, at least 45 wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 50wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 55wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 60wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 65wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 70wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 75wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 80wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 85wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 90wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 95wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 99wt% of the nicotine present in the formulation is in protonated form. In one aspect at least 99.9wt% of the nicotine present in the formulation is in protonated form.
In one aspect from 5 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 10 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 15 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 20 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 25 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 30 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 35 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 40 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 45 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 50 to 95 wt%
of the nicotine present in the formulation is in protonated form. In one aspect from 55 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 60 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 65 to 95 wt% of the nicotine present in the formulation is in protonated form.
In one aspect from 70 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 75 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 80 to 95 wt% of the nicotine present in the formulation is in protonated form.

9 In one aspect from 85 to 95 wt% of the nicotine present in the formulation is in protonated form. In one aspect from 90 to 95 wt% of the nicotine present in the formulation is in protonated form.
The relevant amounts of nicotine which are present in the formulation in protonated form are specified herein. These amounts may be readily calculated by one skilled in the art. Nicotine, 3-(1-methylpyrrolidin-2-y1) pyridine, is a diprotic base with pKa of 3.12 for the pyridine ring and 8.02 for the pyrrolidine ring It can exist in pH-dependent protonated (mono- and di-) and non-protonated (free base) forms which have different bioavailability.
H,C1,0 illifrc_Houten The distribution of protonated and non-protonated nicotine will vary at various pH
increments.
r--") H+ 14+ rTh `"1,4 --NH+ r-- = -y NH+
)Lõ
1-1*
The fraction of non-protonated nicotine will be predominant at high pH levels whilst a decrease in the pH will see an increase of the fraction of protonated nicotine (mono- or di-depending on the pH). If the relative fraction of protonated nicotine and the total amount of nicotine in the sample are known, the absolute amount of protonated nicotine can be calculated.
The relative fraction of protonated nicotine in formulation can be calculated by using the Henderson-Hasselbalch equation, which describes the pH as a derivation of the acid dissociation constant equation, and it is extensively employed in chemical and biological systems. Consider the following equilibrium:
B + H > BH+
The Henderson-Hasselbalch equation for this equilibrium is:

[B]
pH yr- pKa 4-[131.1 +1 Where [B] is the amount of non-protonated nicotine (i.e. free base), [BHA] the amount of protonated nicotine (i.e. conjugate acid) and pKa is the reference pKa value for the pyrrolidine ring nitrogen of nicotine (pKa=8.02). The relative fraction of protonated nicotine can be derived from the alpha value of the non-protonated nicotine calculated from the Henderson-Hasselbalch equation as:
[B]
[RH -F1 Voprotonated nicotine ¨ 100 tf [B] *100}
EBB
Determination of pKa values of nicotine formulations was carried out using the basic approach described in "Spectroscopic investigations into the acid¨base 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.
The one or more acids provide a formulation having a pH of from 4 to 6. In one aspect the one or more acids provide a formulation having a pH of from 4.5 to 6. In one aspect the one or more acids provide a formulation having a pH of from 4 to 5.5. In one aspect the one or more acids provide a formulation having a pH of from 4.5 to 5.5. In one aspect the one or more acids provide a formulation having a pH of from 4.5 to 5. In one aspect the one or more acids provide a formulation having a pH of from 5 to 6. In one aspect the one or more acids provide a formulation having a pH of from 5 to 5.5. In one aspect the one or more acids provide a formulation having a pH of from 5.5 to 6.
Nicotine formulations may be provided having desirable properties of flavour, impact, irritation, smoothness and/or nicotine reward for the user. In one aspect nicotine is present in an amount of no greater than 6 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 6 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 6 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 6 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 6 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of no greater than 4 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 4 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 4 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 4 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 4 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of no greater than 3 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 3 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 3 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 3 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 3 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of no greater than 2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of no greater than 1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.1 to 1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of no greater than 0.5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 0.5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 0.5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 0.5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 0.5 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of no greater than 0.2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 0.2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 0.2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 0.2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 0.2 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of no greater than 0.1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.01 to 0.1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.02 to 0.1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.05 to 0.1 wt% based on the total weight of the aerosolisable formulation. In one aspect nicotine is present in an amount of from 0.08 to 0.1 wt% based on the total weight of the aerosolisable formulation.
Acid As discussed herein the aerosolisable formulation contains an acid which is at least partially .. water soluble. By the term "at least partially water soluble" it is meant the acid has a solubility in water of at least 2g/L at 20 C. In one aspect the acid has a solubility in water of at least 5g/L at 20 C. In one aspect the acid has a solubility in water of at least 10g/L at 20 C. In one aspect the acid has a solubility in water of at least 20g/L at 20 C. In one aspect the acid has a solubility in water of at least 50g/L at 20 C. In one aspect the acid has a solubility in water of at least 100g/L at 20 C. In one aspect the acid has a solubility in water of at least 200g/L at 20 C. In one aspect the acid has a solubility in water of at least 300g/L
at 20 C. In one aspect the acid has a solubility in water of at least 400g/L
at 20 C. In one aspect the acid has a solubility in water of at least 500g/L at 20 C. In one aspect the acid has a solubility in water of at least 600g/L at 20 C. In one aspect the acid has a solubility in water of at least 700g/L at 20 C. In one aspect the acid has a solubility in water of at least 800g/L at 20 C. In one aspect the acid has a solubility in water of at least 900g/L at 20 C.
In one aspect the acid has a solubility in water of at least 1000g/L at 20 C.
In one aspect the acid has a solubility in water of at least 1100g/L at 20 C.
The acid may be any suitable acid provided of course the acid at least 5 wt%
of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
In one aspect the acid is an organic acid. In one aspect the acid is a carboxylic acid. In one aspect the acid is an organic carboxylic acid. In one aspect the acid has a bitter or sour taste. In one aspect the acid has a bitter taste. In one aspect the acid has a sour taste.
In one aspect the acid is selected from the group consisting of citric acid, maleic acid, malic acid, lactic acid, levulinic acid, benzoic acid, sorbic acid, acetic acid and mixtures thereof. In one aspect the acid is selected from the group consisting of citric acid, maleic acid, lactic acid, levulinic acid, benzoic acid, and mixtures thereof. In one aspect the acid is selected from the group consisting of citric acid, benzoic acid, sorbic acid, acetic acid and mixtures thereof. In one aspect the acid is selected from the group consisting of benzoic acid, sorbic acid, acetic acid and mixtures thereof. In one aspect the acid is at least sorbic acid. In one aspect the acid consists of sorbic acid. In one aspect the acid is at least acetic acid. In one aspect the acid consists of acetic acid. In one aspect the acid is at least benzoic acid. In one aspect the acid consists of benzoic acid. In one aspect the acid is at least citric acid. In one aspect the acid consists of citric acid.
In one aspect the acid is selected from acids having a pka of from 2 to 5. In one aspect the acid is a weak acid. In one aspect the acid is a weak organic acid.
The molar ratio of acid to nicotine may be selected as desired. In one aspect the molar ratio of acid to nicotine is from 5:1 to 1:5. In one aspect the molar ratio of acid to nicotine is from 4:1 to 1:4. In one aspect the molar ratio of acid to nicotine is from 3:1 to 1:3. In one aspect the molar ratio of acid to nicotine is from 2:1 to 1:2. In one aspect the molar ratio of acid to nicotine is from 1.5:1 to 1:1.5. In one aspect the molar ratio of acid to nicotine is from 1.2:1 to 1:1.2. In one aspect the molar ratio of acid to nicotine is from 5:1 to 1:1.
In one aspect the molar ratio of acid to nicotine is from 4:1 to 1:1. In one aspect the molar ratio of acid to nicotine is from 3:1 to 1:1. In one aspect the molar ratio of acid to nicotine is from 2:1 to 1:1.
In one aspect the molar ratio of acid to nicotine is from 1.5:1 to 1:1. In one aspect the molar ratio of acid to nicotine is from 1.2:1 to 1:1.
In one aspect the total content of acid present in the formulation is no greater than 5 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no greater than 4 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no greater than 3 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no greater than 2 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no greater than 1 mole equivalents based on the nicotine.
In one aspect the total content of acid present in the formulation is no less than 0.01 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no less than 0.05 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no less than 0.1 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no less than 0.2 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no less than 0.3 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no less than 0.4 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no less than 0.5 mole equivalents based on the nicotine. In one aspect the total content of acid present in the formulation is no less than 0.7 mole equivalents based on the nicotine.
The acid may be present in any suitable amount. In one aspect the acid is present in an amount of no greater than 6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 6 wt% based on the aerosolisable formulation.
In one aspect the acid is present in an amount of from 0.02 to 6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.02 to 5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 4 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 4 wt% based on the aerosolisable formulation.
In one aspect the acid is present in an amount of from 0.02 to 4 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 4 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 4 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 3 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 3 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.02 to 3 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 3 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 3 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.02 to 2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.02 to 1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.1 to 1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 0.6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 0.6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.02 to 0.6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 0.6 wt% based on the aerosolisable formulation.
In one aspect the acid is present in an amount of from 0.08 to 0.6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.1 to 0.6 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 0.5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 0.5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.02 to 0.5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 0.5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 0.5 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 0.2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 0.2 wt% based on the aerosolisable formulation.
In one aspect the acid is present in an amount of from 0.02 to 0.2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 0.2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 0.2 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of no greater than 0.1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.01 to 0.1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.02 to 0.1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.05 to 0.1 wt% based on the aerosolisable formulation. In one aspect the acid is present in an amount of from 0.08 to 0.1 wt% based on the aerosolisable formulation.
The amount of acid and the solubility of the acid may be selected such that a given amount of the acid will dissolve in the water. In one aspect at 20 C at least 20% of the acid dissolves in the water. In one aspect at 25 C at least 20% of the acid dissolves in the water.
In one aspect at 30 C at least 20% of the acid dissolves in the water. In one aspect at 20 C
at least 35% of the acid dissolves in the water. In one aspect at 20 C at least 40% of the acid dissolves in the water. In one aspect at 20 C at least 45% of the acid dissolves in the water. In one aspect at 20 C at least 50% of the acid dissolves in the water.
In one aspect at 20 C at least 55% of the acid dissolves in the water. In one aspect at 20 C at least 60%
of the acid dissolves in the water. In one aspect at 20 C at least 65% of the acid dissolves in the water. In one aspect at 20 C at least 70% of the acid dissolves in the water. In one aspect at 20 C at least 75% of the acid dissolves in the water. In one aspect at 20 C at least 80% of the acid dissolves in the water.
Formulation In one aspect the aerosolisable formulation further comprises one or more flavours or flavouring components. As used herein, the terms "flavour" and "flavourant"
refer to materials which, where local regulations permit, may be used to create a desired taste or aroma in a product for adult consumers. They may include extracts (e.g.
liquorice, hydrangea, Japanese white bark magnolia leaf, chamomile, fenugreek, clove, menthol, Japanese mint, aniseed, cinnamon, herb, 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, sage, fennel, piment, ginger, anise, coriander, coffee, or a mint oil from any species of the genus Mentha), flavour enhancers, bitterness receptor site blockers, sensorial receptor site activators or stimulators, sugars and/or sugar substitutes (e.g., sucralose, acesulfame potassium, aspartame, saccharine, cyclamates, lactose, sucrose, glucose, fructose, sorbitol, or mannitol), and other additives such as charcoal, chlorophyll, minerals, botanicals, or breath freshening agents.
They may be imitation, synthetic or natural ingredients or blends thereof.
They may be in any suitable form, for example, oil, liquid, or powder. The one or more flavours may be selected from the group consisting of (4-(para-)methoxypheny1)-2-butanone, vanillin, y-undecalactone, menthone, 5-propenyl guaethol, menthol, para-mentha-8-thioI-3-one and mixtures thereof. In one aspect the flavour is at least menthol.
If present, the one or more flavours may be present in any suitable amount. In one aspect the one or more flavours are present in a total amount of no greater than 10 wt.% based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of no greater than 7 wt.% based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of no greater than 5 wt.%
based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of no greater than 4 wt.% based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of no greater than 3 wt.%
based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of no greater than 2wt.% based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of no greater than 1wt. /0 based on the aerosolisable formulation.
In one aspect the one or more flavours are present in a total amount of from 0.01 to 5wt. /0 based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of from 0.01 to 4wt.% based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of from 0.01 to 3wt. /0 based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of from 0.01 to 2wt.% based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of from 0.01 to 1wt.% based on the aerosolisable formulation. In one aspect the one or more flavours are present in a total amount of from 0.01 to 0.5wt.% based on the aerosolisable formulation.
As discussed above, in the present system the number of components present may be reduced leading to less chance of forming breakdown products/toxicants. Thus in one aspect there is provided an aerosolisable formulation as described herein consisting of (i) water; (ii) nicotine; (iii) the acid; and (iv) optionally one or more flavours. In one aspect there is provided an aerosolisable formulation as described herein consisting of (i) water; (ii) nicotine;
(iii) the acid; and (iv) one or more flavours. In one aspect there is provided an aerosolisable formulation as described herein consisting of (i) water; (ii) nicotine; and (iii) the acid.

One or more cyclodextrins may or may not be present in any suitable amount in the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 12 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 10 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 9 wt.% based on the aerosolisable formulation.
In one aspect the one or more cyclodextrins are present in a total amount of no greater than 8 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 7 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 6 wt.%
based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 5 wt.% based on the aerosolisable formulation.
In one aspect the one or more cyclodextrins are present in a total amount of no greater than 4 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 3 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 2 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 1 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 0.1 wt.% based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 0.01 wt.%
based on the aerosolisable formulation. In one aspect the one or more cyclodextrins are present in a total amount of no greater than 0.001 wt.% based on the aerosolisable formulation.
The one or more cyclodextrins may be selected from the group consisting of unsubstituted cyclodextrins, substituted cyclodextrins and mixtures thereof. In one aspect at least one cyclodextrin is an unsubstituted cyclodextrin. In one aspect the one or more cyclodextrins are selected from the group consisting of unsubstituted cyclodextrins. In one aspect at least one cyclodextrin is a substituted cyclodextrin. In one aspect the one or more cyclodextrins are selected from the group consisting of substituted cyclodextrins.
In one aspect the one or more cyclodextrins are selected from the group consisting of unsubstituted (a)-cyclodextrin, substituted (a)-cyclodextrin, unsubstituted (f3)-cyclodextrin, substituted (13)-cyclodextrin, unsubstituted (y)-cyclodextrin, substituted (y)-cyclodextrin, and mixtures thereof. In one aspect the one or more cyclodextrins are selected from the group consisting of unsubstituted (3)-cyclodextrin, substituted (13)-cyclodextrin, and mixtures thereof.
In one aspect the one or more cyclodextrins are selected from the group consisting of unsubstituted (a)-cyclodextrin, unsubstituted (3)-cyclodextrin, unsubstituted (y)-cyclodextrin, and mixtures thereof. In one aspect the one or more cyclodextrins is selected from unsubstituted (3)-cyclodextrin.
In one aspect the one or more cyclodextrins are selected from the group consisting of substituted (a)-cyclodextrin, substituted (3)-cyclodextrin, substituted (y)-cyclodextrin, and mixtures thereof. In one aspect the one or more cyclodextrins is selected from substituted (3)-cyclodextrins. Chemical substitutions at the 2-, 3-, and 6-hydroxyl sites are envisaged, and in particular substitution at the 2-position.
In one aspect the one or more cyclodextrins are selected from the group consisting of 2-hydroxy- propyl-a-cyclodextrin, 2- hydroxy- propy1-3-cyclodextrin, 2-hydroxy-propyl-y-cyclodextrin and mixtures thereof. In one aspect the one or more cyclodextrins is at least 2-hydroxy-propyl-a-cyclodextrin. In one aspect the one or more cyclodextrins is at least 2-hydroxy-propy1-3-cyclodextrin. In one aspect the one or more cyclodextrins is at least 2-hydroxy-propyl-y-cyclodextrin.
2-hydroxy-propyl derivatives of cyclodextrins, such as 2-hydroxy-propyl-p-cyclodextrin have increased solubility in water when compared to base cyclodextrins such as f3-cyclodextrin.
In one aspect the aerosolisable formulation is in liquid form. In one aspect the aerosolisable formulation is not in liquid form. In one aspect if the aerosolisable formulation is in the form of a gel or paste.
In one aspect if the aerosolisable formulation contains one or more cyclodextrins, then the aerosolisable formulation contains no flavours that can be encapsulated by the one or more cyclodextrins.
Process As discussed herein, in one aspect there is provided a process for forming an aerosol, the process comprising aerosolising an aerosolisable formulation comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.
In the process the aerosol may be formed by a process performed at a temperature below 60 C.In the process the aerosol may be formed by a process performed at a temperature below 50 C. In the process the aerosol may be formed by a process performed at a temperature below 40 C. In the process the aerosol may be formed by a process performed at a temperature below 30 C. In the process the aerosol may be formed by a process performed at a temperature below 25 C. In the process the aerosol may be formed by a process which does not involve heating.
In the process the aerosol may be formed by applying ultrasonic energy to the aerosolisable formulation.
In one aspect the aerosol of the aerosolised formulation has a D50 of from 2 to 6pm.
References in the present specification to particle size distribution, D50, D10 or D90 refer to values measured in accordance with British and European Pharmacopoeia, 2.9.31 Particle Size Analysis By Laser Light Diffraction (see BRITISH PHARMACOPOEIA
COMMISSION.
(2014), British Pharmacopoeia. London, England: Stationery Office and COUNCIL
OF
EUROPE. (2013). European Pharmacopoeia. Strasbourg, France: Council of Europe). 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 aspect the aerosol has a D50 of from 2.5 to 6pm. In one aspect the aerosol has a D50 of from 3 to 6pm. In one aspect the aerosol has a D50 of from 3.5 to 6pm.
In one aspect the aerosol has a D50 of from 4 to 6pm. In one aspect the aerosol has a D50 of from 4.5 to 6pm. In one aspect the aerosol has a D50 of from 5 to 6pm. In one aspect the aerosol has a D50 of from 2.5 to 5.5pm. In one aspect the aerosol has a D50 of from 3 to 5.5pm. In one aspect the aerosol has a D50 of from 3.5 to 5.5pm. In one aspect the aerosol has a D50 of from 4 to 5.5pm. In one aspect the aerosol has a D50 of from 4.5 to 5.5pm. In one aspect the aerosol has a D50 of from 5 to 5.5pm.
In one aspect the aerosol has a D10 of at least 0.5pm. In one aspect the aerosol has a D10 of at least 1pm. In one aspect the aerosol has a D10 of at least 2pm.

In one aspect the aerosol has a D90 of no greater than 15pm. In one aspect the aerosol has a D90 of no greater than 12pm. In one aspect the aerosol has a D90 of no greater than 10pm.
In one aspect D50 is measured after exclusion of particles having a particle size of less than 1pm. In one aspect D10 is measured after exclusion of particles having a particle size of less than 1pm. In one aspect D90 is measured after exclusion of particles having a particle size of less than 1pm.
We have identified a water-based system which, by careful selection of the particle size distribution of the aerosol, delivers water droplets containing the active agent into desirable areas of the lungs, such as the deep lung. We have identified that in water-based aerosols, the droplets have a tendency to evaporate and decrease in size when inhaled by the user.
Therefore the specific selection of particle size described herein addresses the reduction of size through evaporation and still delivers the active agent into the desired area of the lungs.
These problems and the choice made in the present invention is in contrast to the prior liquids based on glycerol and propylene glycol in which the liquid droplets tend to adhere to moisture within the lungs and thereby increase in size when inhaled.
The formulation may be contained or delivered by any means. In one aspect the present invention provides a contained aerosolisable formulation comprising (a) one or more containers; and (b) an aerosolisable formulation as defined herein. The container may be any suitable container, for example to allow for the storage or delivery of the formulation. In one aspect the container is configured for engagement with an electronic aerosol provision system. The container may be configured to become fluidly in communication with an electronic aerosol provision system so that formulation may be delivered to the electronic aerosol provision system. As described above, the present disclosure relates to container which may be used in an electronic aerosol provision system, such as an e-cigarette.
Throughout the following description the term "e-cigarette" is used; however, this term may be used interchangeably with electronic aerosol provision system.
As discussed herein, the container of the present invention is typically provided for the delivery of aerosolisable formulation to or within an e-cigarette. The aerosolisable formulation may be held within an e-cigarette or may be sold as a separate container for subsequent use with or in an e-cigarette. As understood by one skilled in the art, e-cigarettes may contain a unit known as a detachable cartomiser which typically comprises a reservoir of aerosolisable formulation, and an aerosoliser such as a wick material and a heating element for vaporising the aerosolisable formulation. In some e-cigarettes, the cartomiser is part of a single-piece device and is not detachable. In one aspect the container is a cartomiser or is part of a cartomiser. In one aspect the container is not a cartomiser or part of a cartomiser and is a container, such as a tank, which may be used to deliver nicotine formulation to or within an e-cigarette.
In one aspect the container is part of an e-cigarette. Therefore in a further aspect the present invention provides an electronic aerosol provision system comprising: an aerosolisable formulation as defined herein; an aerosoliser for aerosolising formulation for inhalation by a user of the electronic aerosol provision system; and a power supply comprising a cell or battery for supplying power to the aerosoliser.
In addition to the aerosolisable formulation of the present invention and to systems such as containers and electronic aerosol provision systems containing the same, the present invention provides a process for improving the sensory properties of an aerosolised nicotine.
In a further aspect the present invention provides a process for improving the storage stability of an aerosolised nicotine formulation.
Reference to an improvement in the sensory properties of a vaporised nicotine solution refer may include an improvement in the smoothness of the vaporised nicotine solution as perceived by a user.
The process of the present invention may comprises additional steps either before the steps listed, after the steps listed or between one or more of the steps listed.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will now be described in further detail by way of example only with reference to the accompanying figure in which:-Figure 1 shows a graph illustrating variation of p5K32 with nicotine concentration The invention will now be described with reference to the following non-limiting examples.
Examples Example 1 A series of tests were conducted using a formulation containing 90.0% (w/w) water, 9.0% 2-hydroxy-propyl-p-cyclodextrin, 0.9% I-menthol, and 0.1% nicotine. With no additional components, the pH of this formulation is approximately 8. With pH treatment using certain acids, preservative effects will be observed in the pH range of 4 ¨ 6.
In this example, the viable micro-organisms are fungal: Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus brasiliensis, Candida albicans and Escherichia coli, .. The Council of Europe (2011) (European Pharmacopoeia. Strasbourg, France:
Council of Europe) has published standards relating to the efficacy of antimicrobial preservation as a relevant test methodology for oral preparations. Acceptance criteria for Fungi is expressed as a log reduction in the number of viable-micro-organisms after 14 days against the value obtained for the inoculum (control sample ¨ e.g. <0 days).
Acceptance criteria for the efficacy of antimicrobial preservation may be based on those published in the literature for similar aerosol products (European Pharmacopoeia 2011).
Suitable statistical models are also recommended but not mandatory to contextualise any resulting data. An example includes Analysis of Variance (ANOVA) and at a suitable confidence interval ¨ e.g. 95%.
Example 2 Formulations with different acids at a range of pHs (4 to 6) were tested for 14 and 28 days at 20 C for microbial growth. The acids tested were benzoic acid, sorbic acid and acetic acid.
The following tests were carried out Sample preparation A 1 in 10 dilution was prepared using Neutraliser as a diluent. Further dilutions were performed to create 1/100 and 1/1000 dilutions.
Determining the initial bioburden of the test product A 1/10, 1/100 & 1/1000 dilution of the test sample in Neutraliser was prepared. The sample was pour plated and incubated. For the product, the initial bioburden was determined.
Method Suitability Testing for Total Aerobic Microbial Count (TAMC) and Total Yeasts and Mould Count (TYMC) 1% Nicotine Solution in de-ionised water Each dilution of test product in diluent (Neutraliser), the test product and a positive control (diluent without product) were inoculated with test microorganisms. The test microorganisms were Aspergifius brasiliensis, Candida albicans, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.
The method tested duplicate plates of test product and positive controls (diluent without product) inoculated with test organisms. Duplicate plates of test product in diluent (Neutraliser) were also included. All samples were incubated.
The following samples were tested Sample Flavour, Water, Nicotine, 2-hydroxy-propyl- Acid Acid, pH
w/w % w/w % w/w % ii-cyclodextrin, w/w %
w/w /0 2.1 0.9 89.9 0.1 9 benzoic 0.1 6 L-menthol 2.2 0.9 89.5 0.1 9 sorbic 0.5 L-menthol 2.3 7 87.8 1 3 acetic 1.2 Apple BAT: P10018254; 81883115- DYC: P115645PCT
ci ID
FIP
.4 X TIVffil,CrOPTUMOrncou fere aS f0.09W5 (D
Z.:
K) C
:g O :=, a, Er Sample 2.1 I.-menthol =
=ISr.
x aN
o 'cak 0 Organism Control 14 days 28 days Pass/Fail 4*, CD
R* Control Count Test Count % Increase/ Test Count % Increase/

0_ (cfu/mL) , decrease in cfu , (cfu/mL) decrease in cfu N) .

ry Pseudomonas 1.2*.108 9.5 x 102 99.9% decrease 5.2 x 102 99.9% decrease Pass f? aeru inosa Staphylococcus 1.4 x 106 0 100% decrease 0 100% decrease Pass Fo' aureus Escherichia coli 7.1 x 105 0 100% decrease 0 100% decrease Pass Candida albicans 2.1 x 105 0 100% decrease 0 100% decrease Pass Aspergillus 3.2 x 105 9.1 x 10 71.5% decrease 7.2 x 104 78% decrease Pass _ brasiliensis , Sample 2,2 L-menthol Organism Control 14 days 28 days Pass/Fail Control Count Test Count % Increase/ Test Count % Increase/
(cfu/mL) decrease in cfu (cfu/mL) decrease in cfu Pseudomonas 12 i0 0 100% decrease 0 100% decrease Pass aeru inosa Staphylococcus 1.4 x 106 0 100% decrease 0 100% decrease Pass aureus Escherichia coli 7.1 x 105 0 100% decrease 0 100% decrease Pass a Candida albicans 2.1 x 106 0 100% decrease 0 100% decrease Pass =:
Aspergillus 3_2 x 10 0 100% decrease 0 100% decrease Pass :#
brasiliensis #
'I
õet BAT: P10018254; 81883115- DYC: P115645PCT
ci 0, Sarni;le 2.3 ti*
ar ...4 X
CD

.0 :gc 0 Organism Control 14 days 28 days Pass/Fail E4-==i, ID Control Count Test Count % Increase/ Test Count % Increase/ =
iir ISr.
x cfuimL decrease in cfu cfu/mL
decrease in cfu aN

'cak 0 Pseudomonas 1.4 x10 0 100% decrease 0 100% decrease Pass 4*, CD
R* aeru inosa 0_ N) Staphylococcus 2.0 x 106 0 100% decrease 0 100% decrease Pass ry aureus f?
Escherichia coil 2.0 x 106 0 100% decrease 0 100% decrease Pass '8 Candida albicans 1.7 x 106 0 100% decrease 0 100% decrease Pass Aspergillus 4.9 x 105 0 100% decrease 0 100% decrease Pass brasiliensis Each of samples 2:1*2 2 and2Zwere found to significantly inhibit microbial growth. In respect of the majority of samples tested a 100%
INI 5 decrease in was observed.

a #
.8:
..,,,, Various modifications and variations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention.
Although the invention has been described in connection with specific 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 which are obvious to those skilled in chemistry or related fields are intended to be within the scope of the following claims.

Claims

1. An aerosolisable formulation comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine;
(iii) an acid which is at least partially water soluble present in an amount of from 0.08 to 6 wt%
based on the aerosolisable formulation; and (iv) one or more cyclodextrins;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

2. The aerosolisable formulation according to claim 1 wherein the water is present in an amount of at least 40 wt.% based on the aerosolisable formulation.

3. The aerosolisable formulation according to claim 1 or 2 wherein the water is present in an amount of at least 60 wt.% based on the aerosolisable formulation.

4 The aerosolisable formulation according to any one of claims 1 to 3 wherein the water is present in an amount of at least 80 wt.% based on the aerosolisable formulation.

The aerosolisable formulation according to any one of claims 1 to 4 wherein the water is present in an amount of at least 90 wt.% based on the aerosolisable formulation.

6 The aerosolisable formulation according to any one of claims 1 to 5 wherein the nicotine is present in an amount of no greater than 0.2wt.% based on the aerosolisable formulation.

7. The aerosolisable formulation according to claim 6 wherein the nicotine is present in an amount of from 0.01 to 0.1wt.% based on the aerosolisable formulation.

8. The aerosolisable formulation according to any one of claims 1 to 7 wherein the acid has a solubility in water of at least 100 g/100 mL at 20 C.

9. The aerosolisable formulation according to any one of claims 1 to 8 wherein at least 20 wt% of the nicotine present in the formulation is in protonated form.

Date Recue/Date Received 2023-06-19

10. The aerosolisable formulation according to any one of claims 1 to 8 wherein at least 30 wt% of the nicotine present in the formulation is in protonated form.

11. The aerosolisable formulation according to any one of claims 1 to 10 wherein the molar ratio of acid to nicotine is from 3:1 to 1:3.

12. The aerosolisable formulation according to any one of claims 1 to 11 wherein the molar ratio of acid to nicotine is from 2:1 to 1:2.

13. The aerosolisable formulation according to any one of claims 1 to 12 wherein the molar ratio of acid to nicotine is from 1.2:1 to 1:1.2.

14. The aerosolisable formulation according to any one of claims 1 to 10 wherein the acid is a carboxylic acid.

15. The aerosolisable formulation according to any one of claims 1 to 10 wherein the acid is selected from the group consisting of citric acid, maleic acid, lactic acid, levulinic acid, benzoic acid, sorbic acid, acetic acid and mixtures thereof.

16. The aerosolisable formulation according to any one of claims 1 to 15 wherein the acid is at least citric acid.

17. The aerosolisable formulation according to any one of claims 1 to 16 further comprising one or more flavours.

18. The aerosolisable formulation according to claim 17 wherein the one or more flavours are selected from the group consisting of (4-(para-)methoxyphenyl)-2-butanone, vanillin, y-undecalactone, menthone, 5-propenyl guaethol, menthol, para-mentha-8-thiol-3-one and mixtures thereof.

19. The aerosolisable formulation according to claim 18 wherein the flavour is at least menthol.

Date Recue/Date Received 2023-06-19

20. The aerosol isable formulation according to any one of claims 17 to 19 wherein the one or more flavours are present in a total amount of from 0.01 to lwt.% based on the aerosolisable formulation.

21. The aerosolisable formulation according to any one of claims 1 to 16 consisting essentially of (i) water;
(ii) nicotine;
(iii) the acid; and (iv) one or more cyclodextrins.

22. The aerosolisable formulation according to any one of claims 1 to 20 consisting essentially of (i) water;
(ii) nicotine;
(iii) the acid;
(iv) one or more flavours; and (v) one or more cyclodextrins.

23. A process for forming an aerosol, the process comprising aerosolising an aerosolisable formulation comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine;
(iii) an acid which is at least partially water soluble present in an amount of from 0.08 to 6 wt%
based on the aerosolisable formulation; and (iv) one or more cyclodextrins;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

24. The process according to claim 23 wherein the aerosolisable formulation is an aerosolisable formulation as defined in any one of claims 2 to 22.

25. The process according to claim 23 or 24 wherein the aerosol is formed by a process performed at a temperature below 50 C.

Date Recue/Date Received 2023-06-19

26. The process according to any one of claims 23 to 25 wherein the aerosol is formed by applying ultrasonic energy to the aerosolisable formulation.

27. A contained aerosolisable formulation comprising (a) a container; and (b) an aerosolisable formulation, comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble present in an amount of from 0.08 to 6 wt% based on the aerosolisable formulation; and (iv) one or more cyclodextrins wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

28. The contained aerosolisable formulation according to claim 27 wherein the aerosolisable formulation is the aerosolisable formulation as defined in any one of claims 2 to 20.

29. The contained aerosolisable formulation according to claim 27 or 28 wherein the container is configured for engagement with an electronic aerosol provision system.

30. An electronic aerosol provision system comprising:
(a) an aerosoliser for aerosolising formulation for inhalation by a user of the electronic aerosol provision system;
(b) a power supply comprising a cell or battery for supplying power to the aerosoliser (c) an aerosolisable formulation , comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine; and (iii) an acid which is at least partially water soluble present in an amount of from 0.08 to 6 wt% based on the aerosolisable formulation; and (iv) one or more cyclodextrins;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

Date Recue/Date Received 2023-06-19

31. The electronic aerosol provision system according to claim 30 wherein the aerosolisable formulation is the aerosolisable formulation as defined in any one of claims 2 to 20.

32. A process for improving the sensory properties of an aerosolised nicotine formulation, the process comprising the steps of (a) providing an aerosolisable material comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable material and (ii) nicotine;
(b) incorporating into the aerosolisable material an acid which is at least partially water soluble in an amount of from 0.08 to 6 wt% based on the aerosolisable material and one or more cyclodextrins;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

33. A process for improving the storage stability of an aerosolised nicotine formulation, the process comprising the steps of (a) providing an aerosolisable material comprising (i) water in an amount of at least 20 wt.% based on the aerosolisable material and (ii) nicotine;
(b) incorporating into the aerosolisable material an acid which is at least partially water soluble in an amount of from 0.08 to 6 wt% based on the aerosolisable material and one or more cyclodextrins;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

34. Use of one or more acids for improving sensory properties of an aerosolised nicotine formulation, wherein the nicotine formulation comprises (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine;
(iii) an acid which is at least partially water soluble present in an amount of from 0.08 to 6 wt% based on the formulation; and (iv) one or more cyclodextrins; and wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

35. Use of one or more acids for improving storage stability of an aerosolised nicotine Date Recue/Date Received 2023-06-19 formulation, wherein the nicotine formulation comprises (i) water in an amount of at least 20 wt.% based on the aerosolisable formulation;
(ii) nicotine;
(iii) an acid which is at least partially water soluble present in an amount of from 0.08 to 6 wt% based on the formulation; and (iv) one or more cyclodextrins;
wherein at least 5 wt% of the nicotine present in the formulation is in protonated form; and wherein the formulation has a pH of from 4 to 6.

Date Recue/Date Received 2023-06-19