Note: Descriptions are shown in the official language in which they were submitted.
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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.
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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;
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(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
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(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
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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
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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
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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
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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
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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.
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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:
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[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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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(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.
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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
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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
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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)
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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
6
L-menthol
2.3 7 87.8 1 3 acetic 1.2
4
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
0_ (cfu/mL) , decrease in cfu ,
(cfu/mL) decrease in cfu
N) .
0
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
4
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
11711
.0 :gc
0 Organism Control 14 days
28 days Pass/Fail E4-
0
==i,
ID Control Count Test Count % Increase/ Test Count
% Increase/ =
iir
ISr.
x cfuimL decrease in cfu cfu/mL
decrease in cfu aN
0
'cak
0 Pseudomonas 1.4 x10 0 100% decrease 0
100% decrease Pass 4*,
CD
R* aeru inosa
0
0_
N) Staphylococcus 2.0 x 106 0 100% decrease 0
100% decrease Pass
0
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.
4
a
#
.8:
..,,,,
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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.
28
