Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
1
"LIQUID COMPOSITION FOR INHALATION FOR ELECTRONIC
CIGARETTES"
DESCRIPTION
Application field of the invention
The present invention relates to a liquid composition for
inhalation for electronic cigarettes.
Background art
The use of electronic cigarettes, so-called "vaping", is
now a widespread practice all over the world as an at
least partial substitute for smoking cigarettes. In fact,
it is known that cigarette smoke causes serious damage to
health, not so much because of nicotine, which is also a
highly toxic substance, but because of the combustion by-
products, such as polycyclic aromatic hydrocarbons, tar,
and carbon monoxide, often having a marked carcinogenic
effect.
There are two types of alternative smoking on the market.
A first type consists of systems which include heating
tobacco at a controlled temperature (generally not higher
than 350 C), so as to avoid the harmful effects of high-
temperature combustion. The second type is given by so-
called "electronic cigarettes" which vaporize a liquid
also comprising, in addition to a base adapted to give a
sufficiently dense body to the vapor released, a
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
2
controlled amount of nicotine and various types of
flavorings.
The first type, with heated tobacco, is more similar to
traditional smoking, but despite the lower combustion
temperatures some toxic substances contained in the
tobacco in addition to nicotine are still released. A
typical example is nitrosamines.
Electronic cigarettes are safer since they do not release
such toxic or carcinogenic substances, apart from a
controlled amount of nicotine, which can be added to the
composition in order to give the desired effect of
stimulating the nicotinic receptors to the smoker. The
possibility of flavoring the composition in various
manners is a further attraction.
However, even electronic cigarettes are not without
toxicity. In fact, the basic composition mostly consists
of a mixture of propylene glycol and glycerol which
impart, especially the former, a toxicity on respiratory
tract cells.
Therefore, the problem of being able to further lower the
toxicity of a composition for inhalation by electronic
cigarette so as to make the prolonged consumption thereof
much safer is still felt.
The electronic cigarettes currently on the market are born
from a Chinese inventor with the aim of providing smokers
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
3
with an alternative tool characterized by less toxicity
while maintaining a high efficacy in the administration
of nicotine. 15 years after its worldwide diffusion, it
can be considered that if the first characteristic was
largely centered, albeit with the limits set out above,
the second was definitely lacking. According to the Public
Health of England and the Royal College of Physicians, e-
cigarettes on the market are 95% less dangerous than
conventional cigarettes. However, if on the one hand there
is a growing scientific literature supporting the ability
of the electronic cigarette to offer a valid tool in the
fight against smoking, currently only a minority of
smokers have given up the habit of smoking. This
limitation of the effectiveness of the electronic
cigarette as a tool for smoking cessation finds several
causes, including the incorrect perception of danger in
consumers, the sensory experience that is not entirely
satisfying and above all the nicotine release profile. The
traditional cigarette has an exceptional ability to
deliver nicotine to the nicotinic receptors in terms of
quantity and speed. On the contrary, the pharmacological
devices currently on the market for the controlled release
of nicotine have performances that are not comparable to
traditional cigarettes. Being able to increase the rate
of nicotine release and delivery to the central nervous
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
4
system via e-cigarettes can therefore be a considerable
tool in helping smokers transition to less harmful
products.
Cigarette smoke is a colloidal dispersion composed of
solid elements, liquids and airborne gases. A conventional
cigarette contains on average 8-10 mg of nicotine and
about 10-20% of this is absorbed by the smoker. The high
pH of the processed tobacco blends allows to deprotonate
a high amount of nicotine, which is released in the form
of gas during combustion. The combination of these
elements (high concentration, free form, gaseous state)
generates a mix of ideal conditions for a rapid and
efficient nicotine uptake profile.
The formulations for electronic cigarettes are normally
composed of a mixture of propylene glycol, vegetable
glycerin and nicotine. Unlike cigarette smoke, the aerosol
produced by these electronic devices is characterized by
the presence of droplets (drops of liquid). Nicotine is
present in the form of free nicotine (free base) or its
salt. When present in free form, nicotine tends to exit
the droplets, in the form of gas or vapor. This mixture
tends to deposit nicotine in airborne form on the
oropharyngeal mucous membranes and in the upper airways
and the trapped one of the droplets at the alveolar level.
The particle size is a decisive element in modulating the
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
nicotine deposition efficiency as particles that are too
large tend to deposit on the mucous membranes of the
respiratory tree (decreasing the speed and efficiency of
absorption) while too small particles sequester the
nicotine present, as they tend to be exhaled with the
breath. The particle size distribution depends in turn on
a number of aspects including the characteristics of the
device and the components of the mixture.
An ideal device will be able to produce an aerosol
characterized by particles of the right size and an
optimal flow of particles to deposit the right fraction
of nicotine at the oropharyngeal and lung level, where the
first site is important for correct sensory perception and
the second is important for high absorption.
The formulation of the consumable liquid component will
have to be optimized to maximize the bioavailability of
nicotine. Some of the factors affecting this parameter
include the polarity of the particles, the size of the
particles, the shape of the nicotine (free or complexed),
the excipients and the pH of the solution.
Summary of the invention
The aforesaid technical problem is substantially solved
by a composition comprising the technical features set out
in one or more of the appended claims, the definitions of
which form an integral part of the present description for
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
6
the purpose of sufficiency of description.
Therefore, the present invention relates to a composition
for inhalation by electronic cigarette comprising the
following components:
a) water 25-40% by weight
b) 1,3-propanediol 30-50% by weight
c) glycerol 20-30% by weight
d) a preservative 0.1-5% by weight
e) optionally, nicotine 0.2-6% by weight
f) optionally, a flavouring 0-10% by weight
g) optionally, a cyclodextrin 0.1-5% by weight.
The invention further relates to a kit comprising one or
more doses of the composition of the invention and one or
more doses of flavorings.
Further features and advantages of the present invention
will become more apparent from the indicative and thus
non-limiting description of preferred, but not exclusive
embodiments of the invention.
Detailed description of the invention
The present invention relates to a base composition for
inhalation by electronic cigarette which does not contain
propylene glycol and comprising the following components:
a) water 25-40% by weight
b) 1,3-propanediol 30-50% by weight
c) glycerol 20-30% by weight
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
7
d) a preservative 0.1-5% by weight
e) optionally, nicotine 0.2-6% by weight
f) optionally, a flavouring 0-10% by weight
g) optionally, at least
a cyclodextrin 0.1-5% by weight.
The water is preferably purified water FU. Its main
function is to modulate the polarity of the aerosol
particles, break down the toxicity of the mixture and
increase the bioavailability of nicotine.
The 1,3-propanediol (component b)) acts as a viscosifying
agent, increases the share of deprotonated nicotine by
increasing the pH of the solution, bind the water
particles by modifying the properties of the mixture both
biologically and in the tank, and convey the aromas with
high efficiency.
Glycerol (component c)) is preferably vegetable glycerol,
whose main function is to modulate the body of the aerosol,
defining its hygroscopicity and osmolarity.
The preservative (component d)) is preferably sodium
benzoate.
Cyclodextrins (component g)) have the function of
enhancing aromas and modulating the perception and
bioavailability of nicotine.
The flavorings (component f)) can be of any type normally
used for electronic cigarettes, such as fruit, tobacco,
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
8
mentholated flavors, or mixtures thereof. The flavorings
can be added to a base composition which does not contain
them directly by the smoker.
The greater amount of water compared to the compositions
for conventional electronic cigarettes allows to decrease
the toxicity of the composition.
The substitution of propylene glycol (used in conventional
compositions) with 1,3-propanediol also produces a
substantial decrease in the toxicity of the composition.
Furthermore, the high amount of water, by modulating the
polarity of the aerosol particles, increases the
bioavailability of nicotine, making the product extremely
effective from the point of view of pharmacokinetics, but
in itself an excessive increase in water can lead to
malfunctions and losses of liquid from the device. These
possible disadvantages are counterbalanced by the
presence, in appropriate quantities, of 1,3-propanediol,
which by forming hydrogen bonds with water causes a change
in the surface tension and a different capillarity
behavior.
In preferred embodiments, the basic composition for
inhalation via e-cigarette that does not contain propylene
glycol comprises:
a) water 29-33% by weight
b) 1,3-propanediol 38-43% by weight
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
9
c) glycerol 22-28% by weight
d) a preservative 0.1-5% by weight
e) optionally, nicotine 0.2-6% by weight
f) optionally, a flavouring 0-10% by weight
g) optionally, at least
a cyclodextrin 0.1-5% by weight.
EXPERIMENTAL PART
In order to study the potential skin irritation of the
compositions of the invention, a sample of the composition
was applied as such to reconstructed human epidermis
(RHE), the cell viability of which was then evaluated by
MTT test.
The reconstructed human epidermis consists of normal human
keratinocytes grown on an inert polycarbonate filter at
the air-liquid interface in a chemically well-defined
growth medium.
The chemical base of the test is the reduction of MTT, a
yellow substance in solution, to form purple formazan
crystals. Such a reduction process mainly occurs in the
mitochondria and is highly dependent on the activity of
the mitochondrial enzyme succinate dehydrogenase. As a
result of these metabolic processes, purple formazan
crystals appear within some hours, which can be dissolved
in isopropanol. The absorbance of the solubilized crystals
can be measured at the wavelength 540 nm and is
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
proportional to the number of living cells in a very wide
linear range.
The reduction of the cell viability of the tissues treated
with the test sample with respect to the negative control
is used to predict the potential for skin irritation.
For this purpose, 3 RHE tissues were treated with the
tested product and 3 were treated with 5% sodium dodecyl
sulfate (SDS) (positive control). 3 untreated RHE tissues
(kept in D-PBS during the incubation period) were used as
a negative control. The tested sample is considered
irritating to the skin if the cell viability of the tissues
upon the treatment is .50%.
The test was performed following the guidelines of UNI EN
ISO 10993-10:2013.
Pre-incubation
The RHE tissues were left in growth medium for at least 2
hours (37 C, 5% 002) before treatment.
Treatment
The RHE tissues were treated for 15 minutes with 30 pl of
substance according to the following pattern:
- Negative control DPBS
- Positive control 5% SDS
- Tested sample.
Each experiment was conducted in triplicate.
Washes
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
11
The RHE tissues were repeatedly washed with DPBS, in order
to eliminate all traces of the substances used for the
treatments.
Post-incubation
The RHE tissues were transferred to the growth medium for
42 2 hours (37 C, 5% 002).
MTT Test
The RHE tissues were treated with MTT (1 mg/ml) for 3
hours 5 minutes (37 C, 5% 002) and then the formazan
crystals were extracted in isopropanol for 2 hours 5
minutes at room temperature. The optical density reading
was performed at 540 nm.
The composition of the invention containing PURIFIED WATER
F.U. 30.8%, 1,3-PROPANEDIOL (PDO) 41%, VEGETAL GLYCEROL
28%, GRANULAR SODIUM BENZOATE EP-E 211 0.2% (mg, powder),
was tested in the aforesaid MTT test, resulting in a
treated tissue vitality percentage of about 100%.
Therefore, the base composition of the present invention
does not exhibit the cytotoxicity which is typical of
compositions for electronic cigarettes based on propylene
glycol, thus making the practice of "vaping" much safer.
Panel test with users
To assess whether our liquid is more effective than the
current electronic cigarette in delivering nicotine, a
test was conducted with regular users. The tests were
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
12
designed involving 16 "dual users", ie traditional smokers
who also use electronic cigarettes. Since the choice of
nicotine concentration is a very subjective parameter, the
volunteers were asked to compare the performance of their
traditional cigarette with their traditional electronic
cigarette and with the composition according to the
invention, balancing the nicotine concentration between
our liquid and that present in the traditional electronic
cigarette.
The composition according to the invention is the same as
the previous example.
The conventional composition contains an amount of
nicotine ranging from 4 to 12 mg/ml with a preference for
the concentration of 8 mg/ml.
The data are shown in the following table I.
Table I - Results of test on regular users
PERCEIVED INTENSITY
(1=LITTLE intensE; 8=VERY intensE
1 2 3 4 5 6 7 8 Average
cigarette 4 3 9 7,3
Conventional e- 4 9 2 1 5,8***
cigarette composition
e-cigarette composition 1 12 3 6,9 ns
of invention 000
CA 03211812 2023-08-24
WO 2022/185117 PCT/IB2021/062189
13
THROAT SHOT
(1=little strong; 8=very strong)
cigarette 2 1 8 5 7,2
Conventional e- 8 7 1 6,45**
cigarette composition
e-cigarette composition 1 2 5 7 1 6,2**
of invention NS
NICOTINE PERCEPTION SPEED
(1=very slow; 8=very fast)
cigarette 1 9 6 7,45
Conventional e- 10 3 2 1 5,3***
cigarette composition
e-cigarette composition 2 3 4 7 7,1 ns
of invention 000
LEVEL OF SATISFACTION
(1=little satisfying; 8=very satisfying)
cigarette 1 6 9 7,6
Conventional e- 4 7 3 2 5,9***
cigarette composition
e-cigarette composition 2 3 8 3 6,8**
of invention 000
Nicotinic 4 6 8 9 12
contents
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
14
analyzed
(mg)
No. samples 2 1 5 2 1
Cigarette vs Conventional e-cigarette composition or cigarette vs e-
cigarette composition of invention
the difference is statistically significative
the difference is statistically significative
*p<0,05 the difference is statistically significative
ns the two products are equivalent.
Conventional e-cigarette composition vs e-cigarette composition of
invention
000p -u-,
001 the difference is statistically significative
p<0,01 the difference is statistically significative
p<0,05 the difference is statistically significative
NS the two products are equivalent.
The intensity of nicotine is statistically perceived in
the same way in the cigarette and in the composition
according to the invention and significantly less in
conventional compositions.
The throat shot is perceived significantly less both in
the conventional composition and in the composition of the
invention than in the cigarette. Conventional composition
and composition of the invention do not show significant
differences.
The rate of perception of nicotine is statistically
CA 03211812 2023-08-24
WO 2022/185117
PCT/IB2021/062189
perceived in the same way in the cigarette and in the
composition of the invention and significantly less in the
conventional composition.
The level of satisfaction is significantly higher in the
cigarette than in the other two products, but the
composition of the invention is significantly better than
the conventional composition.
From the above data it therefore appears that the
composition of the invention is not only less toxic than
conventional compositions for electronic cigarettes, but
allows for better availability of nicotine, thus
approaching the sensory and general satisfaction
performance of a traditional cigarette.
***
It is apparent that only a few particular embodiments of
the present invention have been described, and those
skilled in the art will be able to make all the necessary
changes thereto for the adaptation to particular
applications, without departing from the scope of
protection of the present invention.
