Note: Descriptions are shown in the official language in which they were submitted.
1
CANNABINOID CHEWING GUM WITH IMPROVED RELEASE OF CANNABINOIDS
FIELD OF THE INVENTION
The invention relates to the field of cannabinoids and alleviation or
treatment of a
condition with one or more cannabinoids. In particular, the invention relates
to
chewing gum as a vehicle for mucosal delivery of one or more cannabinoids.
BACKGROUND OF THE INVENTION
Cannabinoids are known for their health improving properties and have been
used
with respect to various medical purposes in the past. Among these medical
purposes,
cannabinoids have in particular been used for alleviating or treating
different kinds of
pain and counteracting side effects in relation to cancer treatment, such as
nausea.
Traditionally, chewing gum has been described in the prior art as a vehicle
for
delivery of cannabinoids for alleviation or treatment of medical conditions,
such as
medical conditions associated with pain. While focus has generally been
directed to
clinical studies supporting various effects of cannabinoids to the human body,
only
limited attention is given in the prior art to improving such chewing gum
formulations for the purpose of improving release af cannabinoids without
addition
of components that may interact with sensorics properties of the gum.
Since chewing gum is a complex matrix of various types of components which all
interact with each other, providing the chewing gum with specified properties,
it
appears that there is a need in the prior art for improved chewing gum
platforms that
offer a beneficial release of cannabinoids.
WO 2009/120080 discloses the use of chewing gum as a medical carrier and
release
vehicle of cannabinoids. The chewing gum disclosed herein may facilitate
prolonged
release of cannabinoids compared to other types of administering methods.
However,
various problems and challenges are associated with the chewing gum disclosed,
partly based on the specific properties of cannabinoids. While certain
specific
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conventional gum bases are used in formulating the chewing gum disclosed, the
gum
bases appear to have drawbacks for use in combination with cannabinoids.
In general, less attention is addressed in the prior art to the impact of the
gum base
and components in the gum base for the release properties of cannabinoids.
Also, less
attention is given on the impact of the gum base and components in the gum
base for
the sensorics properties of chewing gum with cannabinoids. Here, important
sensorics properties include initial chew, texture, flavor perception,
sweetness
perception and off-notes associated with cannabinoids. These properties are
both
relevant from a convenience perspective in chewing gum, but certainly also in
order
to support an appropriate delivery of cannabinoids from chewing gum and avoid
adverse side effects of cannabinoids.
Hence, there is a need in the prior art for improved chewing gum formulations
that
solve the above-referenced challenges and problems of the prior art. In
particular,
there is a need in the prior art for new gum base formulations for use in
chewing gum
that support appropriate delivery of cannabinoids combined with beneficial
sensorics
properties.
SUMMARY OF THE INVENTION
Accordingly, there is provided a chewing gum for mucosal delivery of
cannabinoids,
the chewing gum being formulated as an extruded chewing gum comprising water-
soluble chewing gum ingredients mixed into water-insoluble gum base, wherein
the
gum base comprising one or more natural resins in an amount of 10-40% by
weight
of the gum base, one or more elastomers in an amount of 3-30% by weight of the
gum base, and one or more elastomer plasticizers in an amount of 8-50% by
weight
of the gum base, and wherein the chewing gum comprises one or more
cannabinoids,
and wherein the release rate of the one or more cannabinoids is at least 10%
by
weight of the one or more cannabinoids within the first 5 minutes upon oral
administration.
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There is further provided a chewing gum for improved release of cannabinoids,
the chewing
gum being formulated as an extruded chewing gum comprising water-soluble
chewing gum
ingredients mixed into water-insoluble gum base, the gum base comprising one
or more
natural resins in an amount of 10-40% by weight of the gum base, one or more
elastomers in
an amount of 3-30% by weight of the gum base, and one or more elastomer
plasticizers in an
amount of 8-50% by weight of the gum base, wherein the chewing gum comprises
one or
more cannabinoids, and wherein the release rate of the one or more
cannabinoids at a
frequency of 60 chews per minute is at least 10% by weight of the one or more
cannabinoids
within the first 5 minutes upon oral administration.
Date Recue/Date Received 2021-02-02
3
The present invention may solve various problems of the prior art and aims at
establishing a chewing gum that combines beneficial delivery properties of
cannabinoids combined with advantageous sensorics properties.
One of the aims of the present invention is to provide a chewing gum
formulation
that both offers a relatively rapid release of cannabinoids and at the same
time
possesses beneficial or superior sensorics properties. Furthermore, it is
contemplated
that the present invention may be directed to improvements of the chewing gum
vehicle for the purpose of improving release of cannabinoids without addition
of
components that may interact with sensorics properties of the gum.
With respect to release properties, the present invention may offer an
improved
release profile of cannabinoids compared to conventional gum base. In
particular, the
specific gum base formulation of the present invention may serve to provide
improved release characteristics of cannabinoids compared to conventional gum
base
applied in combination with cannabinoids.
In the present context, an improved release profile may refer to a higher
release of
cannabinoids which is particularly seen as an advantage since it has
traditionally
been a challenge with release of cannabinoids from chewing gum. In order to
obtain
beneficial health effects both in terms of systemic delivery of cannabinoids
as well as
local delivery of cannabinoids, it is required that a certain content of
cannabinoids
are released over time. Hence, rapid release of cannabinoids may be an
advantage of
the present invention.
In addition, the present invention may serve to provide controlled release of
cannabinoids such that the chewing gum is tailored to deliver an effective
content of
cannabinoids over time and at the same time avoid adverse effects of
cannabinoids,
such as off-notes. Accordingly, the chewing gum of the present invention may
at the
same time offer a relatively sustained release of cannabinoids.
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The special combination of the present invention with one or more natural
resins in a
certain amount combined with one or more elastomer plasticizers in a certain
amount
is particularly advantageous for release characteristics of cannabinoids. It
was
unexpected to the present inventors that the combination according to the
invention
would contribute to improved release characteristics of cannabinoids.
Importantly,
the elastomer plasticizer in the present context serves to plasticize the
elastomers
present in the gum base. The elastomer plasticizers are not to be considered
elastomers by themselves in the present context. The elastomeric properties
are
provided by the elastomers of the invention, and the elastomer plasticizers
are
present to plasticize the elastomers in order to obtain the beneficial release
characteristics of the present invention.
A very important aspect of the present invention is the provision of
beneficial
sensorics properties. Here, important sensorics properties include initial
chew,
texture, flavor perception, sweetness perception and off-notes associated with
cannabinoids. These properties are both relevant from a convenience
perspective in
chewing gum, but certainly also in order to support an appropriate delivery of
cannabinoids from chewing gum, such as an improved release profile, and avoid
adverse side effects of cannabinoids.
The present inventors have shown very surprising results with the specific
combination of features of the present invention in terms of these sensorics
properties. It was an unexpected result that the invention could both
contribute to an
improved release profile, such as rapid release of cannabinoids, and at the
same time
provide very beneficial sensorics properties which in terms may also support
an
appropriate delivery of cannabinoids from chewing gum and avoid adverse side
effects of cannabinoids.
The taste masking challenge is more profound when a higher release of
cannabinoids
are delivered by such chewing gum. If off-notes are the predominant sensation
during administration, convenience may be affected and even more critically,
the
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delivery of cannabinoids may also be affected. Saliva production may be
suppressed,
and the delivery vehicle may not be handled correctly.
One of the sensorics properties that are particularly advantageous is the
initial chew.
Both in order to secure a desired release of cannabinoids and to improve the
sensation by a consumer, it is critical that the initial chew is improved.
Also, the
texture of the chewing gum during chewing is critical for the release of
cannabinoids
and the experience as well as convenience during chewing. These properties may
be
improved by the present invention which was not expected by the inventors of
the
present invention.
The present gum base may also offer improved taste masking in the sense that
the
gap between the release of the cannabinoid and the taste masking ingredients
may be
overall reduced.
Another important result of the specific combination of cannabinoids and gum
base
composition is that a reduced content of cannabinoids will reduce the
requirements
for taste masking, or alternatively make the taste masking more efficient.
This is
important given the fact that when applied as a medical delivery platform,
many
patients may have difficulties in sensing the taste of cannabinoid.
It should also be noted that this unexpected effect is very attractive in
relation to
medicated chewing gum in the present context as a large group of the patients
who
may benefit from the inventive chewing gum will be very vulnerable to off-
notes.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is at least 15% by weight of the one or more cannabinoids within the first 5
minutes
upon oral administration.
In certain embodiments of the invention, the release rate is preferably above
15%
within the first 5 minutes after chewing is initiated.
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According to the invention, an extruded chewing gum is provided, comprising
water-
soluble chewing gum ingredients mixed into water-insoluble gum base.
Traditionally, such types of chewing gum has been problematic with
cannabinoids
due to the fact that release of cannabinoids tends to be low. This is
particularly
relevant when no release improving agents are added to the extruded chewing
gum,
which agents may affect the sensorics properties of the extruded chewing gum.
Also,
when agents such a microcrystalline cellulose are added in pre-blends, the
sensorics
properties may be affected.
Since extruded chewing gum is a complex matrix of various types of components
which all interact with each other, providing the chewing gum with specified
properties, it appears that there is a need in the prior art for improved
extruded
chewing gum platforms that offer a beneficial release of cannabinoids without
compromising sensorics properties.
A release rate of more than 15% is considered a relatively rapid release of
cannabinoids for extruded chewing gum, while at the same time maintaining
beneficial sensorics properties.
In some embodiments, the present invention may solve various problems of the
prior
art and aims at establishing a chewing gum that combines beneficial delivery
properties of cannabinoids combined with advantageous sensorics properties,
such as
initial chew, texture, flavor perception, sweetness perception and off-notes
associated
with cannabinoids. These properties are both relevant from a convenience
perspective in chewing gum, but certainly also in order to support an
appropriate
delivery of cannabinoids from chewing gum and avoid adverse side effects of
cannabinoids.
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In an embodiment of the invention, the release rate of the one or more
cannabinoids
is at least 20% by weight of the one or more cannabinoids within the first 5
minutes
upon oral administration.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is at least 25% by weight of the one or more cannabinoids within the first 5
minutes
upon oral administration.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is at most 50% by weight of the one or more cannabinoids within the first 5
minutes
upon oral administration.
In certain embodiments of the invention, the release rate may be relatively
high. This
may in particular be the case when cannabinoids are both located in the
extruded
chewing gum and at the same time in an outer hard coating of the extruded
chewing
gum. In certain embodiments, this may be the case when cannabinoids are only
located in an outer hard coating of the extruded chewing gum.
By locating the cannabinoids in both the extruded chewing gum and in a
coating,
controlled release of cannabinoids may be possible. Such "bi-phasic" release
may be
an advantage if for instance the desire is a rapid release from the coating
and a more
sustained release from the extruded chewing gum over time. In this way, a
patient in
need thereof may profit from an initial dose of cannabinoids and a more
sustained
dose of cannabinoids. Combined this may provide a dosage regimen that benefits
certain medical treatments.
In some embodiments, the present invention may solve various problems of the
prior
art and aims at establishing a chewing gum that combines beneficial delivery
properties of cannabinoids combined with advantageous sensorics properties,
such as
initial chew, texture, flavor perception, sweetness perception and off-notes
associated
with cannabinoids. These properties are both relevant from a convenience
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perspective in chewing gum, but certainly also in order to support an
appropriate
delivery of cannabinoids from chewing gum and avoid adverse side effects of
cannabinoids.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is between 10-50% by weight of the one or more cannabinoids within the first 5
minutes upon oral administration.
In certain embodiments of the invention, the release rate may be with the
range of
10-50% by weight of the one or more cannabinoids within the first 5 minutes
upon
oral administration. A content of more than 50% may be critical in some
embodiments. This may in particular be relevant when a controlled release is
desired.
In some circumstances, it is beneficial that the release rate is not too high
due to
adverse effects, such as off-note problems for a patient under medical
treatment with
cannabinoids. At the same time, the release rate is at a level where a
substantial
content of cannabinoids is delivered.
Still, the cannabinoids may both be located in the extruded chewing gum and at
the
same time in an outer hard coating of the extruded chewing gum. In certain
embodiments, this may be the case when cannabinoids are only located in an
outer
hard coating of the extruded chewing gum.
In some embodiments, the present invention may solve various problems of the
prior
art and aims at establishing a chewing gum that combines beneficial delivery
properties of cannabinoids combined with advantageous sensorics properties,
such as
initial chew, texture, flavor perception, sweetness perception and off-notes
associated
with cannabinoids. These properties are both relevant from a convenience
perspective in chewing gum, but certainly also in order to support an
appropriate
delivery of cannabinoids from chewing gum and avoid adverse side effects of
cannabinoids.
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In an embodiment of the invention, the release rate of the one or more
cannabinoids
is at most 30% by weight of the one or more cannabinoids within the first 5
minutes
upon oral administration.
In some circumstances, it is beneficial that the release rate is not too high
due to
adverse effects, such as off-note problems for a patient under medical
treatment with
cannabinoids. Still, the cannabinoids may both be located in the extruded
chewing
gum and at the same time in an outer hard coating of the extruded chewing gum.
In
certain embodiments, this may be the case when cannabinoids are only located
in an
outer hard coating of the extruded chewing gum.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is between 10-30% by weight of the one or more cannabinoids within the first 5
minutes upon oral administration.
In certain embodiments of the invention, a preferred release rate may be with
the
range of 10-30% by weight of the one or more cannabinoids within the first 5
minutes upon oral administration. A content of more than 30% is considered to
be at
an advantageous level.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is partly controlled by means of the composition of the water-insoluble gum
base.
The special combination of gum base components of the present invention with
one
or more natural resins in a certain amount combined with one or more elastomer
plasticizers in a certain amount is particularly advantageous for release
characteristics of cannabinoids. It was unexpected to the present inventors
that the
combination according to the invention would contribute to improved release
characteristics of cannabinoids. Importantly, the elastomer plasticizer in the
present
context serves to plasticize the elastomers present in the gum base. The
elastomer
plasticizers are not to be considered elastomers by themselves in the present
context.
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The elastomeric properties are provided by the elastomers of the invention,
and the
elastomer plasticizers are present to plasticize the elastomers in order to
obtain the
beneficial release characteristics of the present invention.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is partly controlled by means of the amount of the one or more natural resins.
The natural resins provide beneficial properties to the present invention. In
particular
the combination of natural resins and elastomer plasticizers provides
beneficial
properties to the gum base and followingly to the chewing gum formulation in
general, both in terms of release properties of cannabinoids and sensorics
properties.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is partly controlled by means of the amount of the one or more elastomer
plasticizers.
The elastomer plasticizers provide beneficial properties to the present
invention. In
particular the combination of natural resins and elastomer plasticizers
provides
beneficial properties to the gum base and followingly to the chewing gum
formulation in general, both in terms of release properties of cannabinoids
and
sensorics properties.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is partly controlled by means of the water-soluble chewing gum ingredients.
The water-soluble ingredients provide beneficial properties to the present
invention.
In particular, when water-soluble chewing gum ingredients are combined with
natural resins and elastomer plasticizers of the present invention, beneficial
properties to the gum base applies, both in terms of release properties of
cannabinoids and sensorics properties.
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In an embodiment of the invention, the release rate of the one or more
cannabinoids
are partly controlled by means of the location of the one or more cannabinoids
in the
chewing gum.
In an embodiment of the invention, the one or more cannabinoids are comprised
in
an outer coating of the extruded chewing gum.
In certain embodiments of the invention, cannabinoids are located in an outer
hard
coating of the extruded chewing gum, such as an outer hard coating of the
extruded
chewing gum. In certain embodiments, cannabinoids are only located in the
coating
and not in the extruded chewing gum matrix.
By locating the cannabinoids in an outer coating, more rapid release of
cannabinoids
may be possible. In this way, a patient in need thereof may profit from an
initial high
dose of cannabinoids in a dosage regimen that benefits certain medical
treatments.
In an embodiment of the invention, the one or more cannabinoids are comprised
in
the extruded chewing gum.
In certain embodiments of the invention, cannabinoids are located in the
extruded
chewing gum. In certain embodiments, cannabinoids are only located in the
extruded
chewing gum and not in a coating of the extruded chewing gum matrix.
By locating the cannabinoids in the extruded chewing gum, a more sustained
release
of cannabinoids may be possible. In this way, a patient in need thereof may
profit
from an initial high dose of cannabinoids in a dosage regimen that benefits
certain
medical treatments.
In an embodiment of the invention, the one or more cannabinoids are both
comprised
in the extruded chewing gum and an outer coating of the extruded chewing gum.
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In certain embodiments of the invention, the release rate may be relatively
high. This
may in particular be the case when cannabinoids are both located in the
extruded
chewing gum and at the same time in an outer hard coating of the extruded
chewing
gum. In certain embodiments, this may be the case when cannabinoids are only
located in an outer hard coating of the extruded chewing gum.
By locating the cannabinoids in both the extruded chewing gum and in a
coating,
controlled release of cannabinoids may be possible. Such "bi-phasic" release
may be
an advantage if for instance the desire is a rapid release from the coating
and a more
sustained release from the extruded chewing gum over time. In this way, a
patient in
need thereof may profit from an initial dose of cannabinoids and a more
sustained
dose of cannabinoids. Combined this may provide a dosage regimen that benefits
certain medical treatments.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is partly controlled by means of further release enhancing ingredients.
In an embodiment of the invention, the one or more cannabinoids are comprised
in
the water-soluble chewing gum ingredients mixed into water-insoluble gum base.
In an embodiment of the invention, the one or more cannabinoids are
homogeneously
distributed in the water-insoluble gum base.
By distributing the one or more cannabinoids homogeneously in the water-
insoluble
gum base, it may be secured that maximal effect is achieved with respect to
release
of the cannabinoids. Furthermore, it would not have been expected that
cannabinoids
in close association with the water-insoluble gum base would release to the
degree as
seen by the inventors of the present invention.
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Traditionally, water-insoluble gum base is seen as a matrix that does not
offer a high
degree of release of cannabinoids. In particular, with respect to
cannabinoids, it is a
surprise that improved release may be seen.
In an embodiment of the invention, the one or more cannabinoids are mixed into
the
water-insoluble gum base in unbound form.
A particular advantage is seen when the cannabinoids are present in unbound
form.
In general, the cannabinoids are present in unbound form. By "unbound form" is
meant that the cannabinoids are not bound to any carrier material that limits
free
transfer and release of the cannabinoids in the chewing gum formulation. An
example of "bound form" is if the cannabinoids are part of a plant material
and the
cannabinoids are not extracted and separated from the plant material. Other
examples
may be a pre-blend of microcrystalline cellulose which was seen by the
inventors to
limit free transfer of cannabinoids in the chewing gum formulation. Also, in
some
embodiments, other pre-blends with water-insoluble carrier is to be avoided
due to
both problems with sensation appearance and release of cannabinoids.
The advantage of having the cannabinoids in free form may also be improved
sensorics characteristics. For instance, plant material may compromise the
chewing
gum matrix and for instance microcrystalline cellulose may impact the texture
of the
chewing gum and the complex matrix of chewing gum in general.
In an embodiment of the invention, at least 10% by weight of the one or more
cannabinoids are present in unbound form.
Within the limits of the present invention, a certain content of cannabinoids
may be
present in bound form as long as a certain amount will also be present in
unbound
form.
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In an embodiment of the invention, at least 90% by weight of the one or more
cannabinoids are present in unbound form.
The advantage of having the cannabinoids in free form may also be improved
sensorics characteristics. For instance, plant material may compromise the
chewing
gum matrix and for instance microcrystalline cellulose may impact the texture
of the
chewing gum and the complex matrix of chewing gum in general.
In an embodiment of the invention, the one or more elastomer plasticizers are
present
in an amount of 15-35% by weight of the gum base.
A particularly preferred range of elastomer plasticizers, such as polyvinyl
acetate
elastomer plasticizers, is 15-35% by weight of the gum base. Here, very
advantageous results were achieved with respect to release of cannabinoids and
sensorics characteristics, such as initial chew, texture, flavor perception,
sweetness
and off-notes. That the preferred range would be on a level such high was a
surprise
to the inventors. Also, it was not expected that such high amount of elastomer
plasticizers, such as polyvinyl acetate elastomer plasticizers, would have a
combined
effect of improved sensorics properties.
In other embodiments of the invention, the one or more elastomer plasticizers,
such
as polyvinyl acetate elastomer plasticizers, are present in an amount of 17-
33% by
weight of the gum base. In other embodiments of the invention, the one or more
elastomer plasticizers, such as polyvinyl acetate elastomer plasticizers, are
present in
an amount of 20-35% by weight of the gum base. In other embodiments of the
invention, the one or more elastomer plasticizers, such as polyvinyl acetate
elastomer
plasticizers, are present in an amount of 20-30% by weight of the gum base. In
other
embodiments of the invention, the one or more elastomer plasticizers, such as
polyvinyl acetate elastomer plasticizers, are present in an amount of 15-40%
by
weight of the gum base. In other embodiments of the invention, the one or more
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elastomer plasticizers, such as polyvinyl acetate elastomer plasticizers, are
present in
an amount of 20-40% by weight of the gum base.
In an embodiment of the invention, the gum base comprises less than 50% by
weight
of gum base polymers.
In order to achieve the effects of the invention, it may in some embodiments
be
preferred that the content of polymers is relatively low. This ensures for
instance that
the release of cannabinoids may be improved and that the sensorics properties
of the
chewing gum may be improved. In particular, when vinyl laurate-vinyl acetate
copolymer are applied, it appears critical that the content of gum base
polymers
should be below 50% by weight of the gum base. It appears that this polymer
may
compromise the chewing gum formulation in the present context.
In an embodiment of the invention, the gum base does not comprise vinyl
laurate-
vinyl acetate copolymer.
To the surprise of the inventors, it was seen that vinyl laurate-vinyl acetate
copolymer may compromise the release of cannabinoids and the sensorics
characteristics of the chewing gum. Hence, it is preferred that this copolymer
is not
present in the gum base.
In certain other embodiments, the gum base polymers comprise less than 20% by
weight of vinyl laurate-vinyl acetate copolymer. In certain other embodiments,
the
gum base polymers comprise less than 15% by weight of vinyl laurate-vinyl
acetate
copolymer. In certain other embodiments, the gum base polymers comprise less
than
10% by weight of vinyl laurate-vinyl acetate copolymer. In certain other
embodiments, the gum base polymers comprise less than 5% by weight of vinyl
laurate-vinyl acetate copolymer.
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In some embodiments of the invention, if polyvinyl acetate elastomers are
present in
the gum base formulation, the gum base polymers comprise less than 20% by
weight
of vinyl laurate-vinyl acetate copolymer, such as less than 10%, such as less
than 5%.
In the present context, polyvinyl acetate elastomers are not the same as
polyvinyl
acetate elastomer plasticizers. Basically, polyvinyl acetate elastomers
provides
elastomeric properties to the chewing gum, whereas polyvinyl acetate elastomer
plasticizers work to plasticize the elastomers present in the gum base.
In an embodiment of the invention, the one or more natural resins are present
in an
amount of 15-35% by weight of the gum base.
The natural resins provides beneficial properties to the present invention. In
particular the combination of natural resins and elastomer plasticizers
provides
beneficial properties to the gum base and followingly to the chewing gum
formulation in general, both in terms of release properties of cannabinoids
and
sensorics properties.
A particularly advantageous range of natural resins is 15-35% by weight of the
gum
base. This range of natural resin was seen to give an improved release profile
and
best sensorics properties. While natural resins of 10-40% by weight of gum
base is
also within the scope of the invention, the best results were seen with 15-35%
by
weight of the gum base.
In other embodiments of the invention, the one or more natural resins are
present in
an amount of 17-33% by weight of the gum base. In other embodiments of the
invention, the one or more natural resins are present in an amount of 20-35%
by
weight of the gum base. In other embodiments of the invention, the one or more
natural resins are present in an amount of 20-30% by weight of the gum base.
In
other embodiments of the invention, the one or more natural resins are present
in an
amount of 15-40% by weight of the gum base. In other embodiments of the
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invention, the one or more natural resins are present in an amount of 20-40%
by
weight of the gum base.
In an embodiment of the invention, the one or more natural resins are selected
from
the group consisting of polyterpene resins, resins based on gum rosin, wood
rosin or
tall oil resin.
In an embodiment of the invention, the one or more elastomers are selected
from the
group consisting of styrene-butadiene copolymers, polyisobutylene, isobutylene-
isoprene copolymers, polyethylene, polyurethane or any combination thereof.
In an embodiment of the invention, the one or more elastomers are present in
an
amount of 3-20 % by weight, such as in an amount of 3-15 % by weight, such as
in
an amount of 5-10 % by weight.
In an embodiment of the invention, the chewing gum comprises water-soluble
chewing gum ingredients in an amount of 40-70% by weight of the chewing gum.
It is particularly preferred that the water-soluble chewing gum ingredients
are present
in an amount of 40-70% by weight of the chewing gum. This range of water-
soluble
chewing gum ingredients have shown particularly beneficial results. The
inventors of
the present invention did not expect that an improved release would be
possible
within this range of water-soluble chewing gum ingredients. As the water-
soluble
chewing gum ingredients are mixed into the gum base during the manufacturing
process, it was expected the water-soluble ingredients did not provide enough
porosity of the chewing gum to facilitate an improved release. In addition,
due to the
specific properties of cannabinoids, it was a surprise to discover that the
release rate
of cannabinoids was improved with water-soluble chewing gum ingredients.
Importantly, the sensorics characteristics were thought to be compromised when
the
water-soluble chewing gum ingredients are present in an amount of 40-70% by
CA 3031519 2019-01-25
18
weight of the chewing gum. However, contrary to expectations, the sensorics
properties were improved in combination with an improved release of
cannabinoids.
In particular, the texture of the chewing gum was improved. It was expected
that the
texture would be worse with this amount of water-soluble ingredients in the
chewing
gum.
In an embodiment of the invention, the water-soluble chewing gum ingredients
comprise at least one sugar alcohol.
Best results were seen when the water-soluble chewing gum ingredients
comprised at
least one sugar alcohol. Both with respect to release properties and sensorics
properties, the chewing gum was improved when at least one sugar alcohol was
present in the formulation.
In an embodiment of the invention, the water-soluble chewing gum ingredients
comprise at least one saccharose.
In an embodiment of the invention, the one or more cannabinoids are mixed into
the
water-insoluble gum base as part of a pre-mixture with water-soluble chewing
gum
ingredients.
This aspect of the invention was particularly surprising since it was not
expected that
the time of adding sugar alcohols would have in impact of the properties of
the
finished chewing gum. However, both the release rate and sensorics properties
were
improved by adding the sugar alcohol in the manufacturing process after more
than
half the mixing time. This was highly significant.
In the present context, a premixture is mainly used to allocate the one or
more
cannabinoids properly to the manufacturing process and secure that the
uniformity is
not compromised and that the cannabinoids are distributed properly into the
mixture.
Preferably, the cannabinoids are provided in a premixture with one or more
sugar
CA 3031519 2019-01-25
19
alcohols. It was a surprise to the inventors that a premixture was important
to have
the cannabinoids distributed properly in the manufacturing process and to end
up
with a product where the uniformity was consistent.
In an embodiment of the invention, the one or more cannabinoids are not part
of a
pre-mixture with microcrystalline cellulose.
In certain embodiments of the invention, the cannabinoids are not part of a
pre-
mixture with microcrystalline cellulose. It was seen that both release rate of
cannabinoids and sensorics properties were to some degree compromised by using
microcrystalline cellulose in premixture. Without being bound by theory, it is
expected that cannabinoids are bound to a higher degree to microcrystalline
cellulose
than preferred.
In some embodiments, less than 50% of the cannabinoids are part of a pre-
mixture
with microcrystalline cellulose. In some embodiments, less than 20% of the
cannabinoids are part of a pre-mixture with microcrystalline cellulose. In
some
embodiments, less than 10% of the cannabinoids are part of a pre-mixture with
microcrystalline cellulose.
In an embodiment of the invention, the one or more cannabinoids are present in
an
amount of 0.1 to 200 mg. In some other embodiments of the invention, the one
or
more cannabinoids are present in an amount of 0.1 to 100 mg. In some other
embodiments of the invention, the one or more cannabinoids are present in an
amount of 0.1 to 50 mg. In an embodiment of the invention said chewing gum
comprises said cannabinoids in an amount of 0.1-30 mg, such as 1-20 mg, such
as 5-
15 mg.
In an embodiment of the invention, the one or more cannabinoids comprise
cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), salts and
derivatives thereof. In an embodiment of the invention the one or more
cannabinoids
CA 3031519 2019-01-25
20
comprises CBD, salts and derivatives thereof, including analogues and
homologues.
In an embodiment of the invention said one or more cannabinoids comprises
cannabidiol (CBD). In an embodiment of the invention said one or more
cannabinoids is CBD.
In an embodiment of the invention, the one or more cannabinoids comprise
tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),
tetrahydrocannabivarin (THCV), salts and derivatives thereof. In an embodiment
of
the invention said one or more cannabinoids comprises tetrahydrocannabinol
(THC).
Preferably THC is intended to mean (¨)-trans-d9-tetrahydrocannabinol, i.e.
(6aR,10aR)-delta-9-tetrahydrocannabinol). In an embodiment of the invention
said
one or more cannabinoids is THC.
In an embodiment of the invention, the one or more cannabinoids comprise
cannabigerol (CBG), salts and derivatives thereof.
In an embodiment of the invention, the one or more cannabinoids comprise at
least
two cannabinoids. In an embodiment of the invention said one or more
cannabinoids
comprises a combination of several cannabinoids, such as THC and CBD. In an
embodiment of the invention said one or more cannabinoids is a combination of
THC
and CBD.
In an embodiment of the invention the chewing gum comprises gum base in an
amount of 30-75 % by weight of the chewing gum before any optionally applied
coating, such as 35-70% by weight of the chewing gum or 40-65% by weight of
the
chewing gum or 45-60% by weight of the chewing gum.
In an embodiment of the invention the chewing gum comprises wax. In an
embodiment of the invention the chewing gum comprises fat.
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21
In an embodiment of the invention the chewing gum comprises flavor in an
amount
between 0.01 and 10% by weight of the chewing gum such as in an amount between
0.01 and 5% by weight of the chewing gum.
According to an advantageous embodiment of the invention, the chewing gum may
be foimulated with flavors, e.g. flavors including acids, which may be more
acceptable for seriously ill patients, such as patients receiving
chemotherapy.
In an embodiment of the invention the chewing gum comprises high intensity
sweetener.
In an embodiment of the invention the chewing gum is manufactured in a two-
step
process, the first step including the process of providing gum base in a first
mixing
process and a further step including the process of mixing gum base with
further
chewing gum components in a further mixing process. In an embodiment of the
invention the chewing gum is manufactured in a one step process by means of an
extruder. This is referred to as extruded chewing gum.
In an embodiment of the invention, the one or more cannabinoids are present in
solid
form. In an embodiment of the invention, the one or more cannabinoids are
present
in liquid or semi-liquid form. In an embodiment of the invention, the one or
more
cannabinoids are present in granules.
In an embodiment of the invention, the one or more cannabinoids are present in
a
pre-mixture with one or more sugar alcohols or saccharose.
In the present context, a pre-mixture is mainly used to allocate the one or
more
cannabinoids properly to the manufacturing process and secure that the
uniformity is
not compromised and that the cannabinoids are distributed properly into the
mixture.
Preferably, the cannabinoids are provided in a premixture with one or more
sugar
alcohols. It was a surprise to the inventors that a premixture was important
to have
CA 3031519 2019-01-25
22
the cannabinoids distributed properly in the manufacturing process and to end
up
with a product where the uniformity was consistent.
In an embodiment of the invention, the chewing gum comprises further release
enhancing ingredients.
In an embodiment of the invention, the one or more cannabinoids form part of a
complex with cyclodextrin. This complex may enhance the release of
cannabinoids
according to the present invention.
In an embodiment of the invention, the one or more cannabinoids comprise at
least
one phytocannabinoid that forms part of an extract. In some embodiments of the
invention, it was seen that cannabinoids as part of an extract may enhance the
release
of cannabinoids. It was also seen that the lower concentration applied in the
extract,
the higher release.
In an embodiment of the invention, the chewing gum further comprising
terpenes.
such as at least one terpene that forms part of an extract.
In an embodiment of the invention, the one or more cannabinoids comprise at
least
one isolated cannabinoid.
In an embodiment of the invention, the one or more cannabinoids comprise at
least
one water-soluble cannabinoid. Water-soluble cannabinoids may enhance the
release
according to the present invention.
In an embodiment of the invention, the chewing gum comprises one or more
emulsifiers.
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23
In an embodiment of the invention the chewing gum comprises emulsifiers in an
amount of 0.1% to 25% by weight of said chewing gum, such as 1 ¨ 10% by weight
of said chewing gum, such as 2 ¨ 8% by weight of said chewing gum.
In an embodiment of the invention the emulsifiers are selected from the group
of
acetylated monoglycerides, mono- and/or di-glycerides of fatty acids such as
glycerol
monostearate, acetem, lecithin and any combination thereof.
In an embodiment of the invention, the chewing gum comprises one or more
solubilizers.
In an embodiment of the invention, the chewing gum comprises a self-
emulsifying
agent.
In an embodiment of the invention, the chewing gum comprises a polymer carrier
for
the one or more cannabinoids.
In an embodiment of the invention, the chewing gum comprises a lipid carrier
for the
one or more cannabinoids.
In an embodiment of the invention, the chewing gum comprises enzyme
inhibitors.
In an embodiment of the invention, the chewing gum comprises one or more
antioxidants.
In an embodiment of the invention, the one or more cannabinoids have a
systemic
effect.
In an embodiment of the invention, the one or more cannabinoids have a local
effect.
CA 3031519 2019-01-25
=
24
In an embodiment of the invention, the one or more cannabinoids are comprised
in
an outer coating of the chewing gum.
In certain embodiments of the invention, the cannabinoids are present in the
coating
of the chewing gum. This is particularly preferred when an enhanced release of
cannabinoids are preferred. Also, if controlled release of cannabinoids is
preferred, it
is an advantage to allocate cannabinoids in the coating. It was not expected
by the
inventors of the present invention that it was possible to use a coating to
deliver
cannabinoids. By combining cannabinoids in the coating and in the chewing gum,
controlled release of cannabinoids may be provided. In the present context,
cannabinoids may both be allocated in the coating, in the chewing gum or in
both
places.
In an embodiment of the invention, the one or more cannabinoids are comprised
in
an outer soft coating of the chewing gum. In certain embodiments, this coating
is a
film coating.
In another aspect of the invention, the chewing gum of the present invention
may be
used for the treatment or alleviation of a medical condition.
In certain embodiments of the invention, the chewing gum of the present
invention
may be used for the treatment or alleviation of pain, epilepsy, cancer,
nausea,
inflammation, congenital disorders, neurological disorders, oral infections,
dental
pain, sleep apnea, psychiatric disorders, gastrointestinal disorders,
inflammatory
bowel disease, appetite loss, diabetes and fibromyalgia.
In the present context, the chewing gum of the invention may be applied for
the
medical indications as single indications from the list of indications. The
invention
may also be applied for other medical indications and indications that are not
medical
for instance local conditions in the mouth, such as bacterial infections or
gingivitis,
CA 3031519 2019-01-25
= =
that may be treated or alleviated with the formulation of the present
invention. The
list is not exhaustive and other indications are part of the present
invention.
In another aspect of the invention, a package is provided comprising a chewing
gum
5 according to the invention, the package comprising a material acting as a
barrier for
the one or more cannabinoids and oxygen, preferably a copolymer of
acrylonitrile
and methyl acrylate.
In certain embodiments of the invention, the package comprising a chewing gum
10 according to the invention, wherein the package includes a liquid or a
semisolid for
the provision of a preventive environment therein.
In certain embodiments of the invention, the package comprising a chewing gum
according to the invention, wherein the package is a blister package.
In another aspect of the invention, there is provided a method of producing
extruded
chewing gum for increased release of one or more cannabinoids, the method
comprising the steps of:
i) providing water-insoluble gum base, water-soluble chewing gum ingredients
and
one or more cannabinoids,
ii) mixing a first amount of water-soluble chewing gum ingredients into the
water-
insoluble gum base under elevated temperature to obtain a mixture of gum base
and
water-soluble chewing gum ingredients,
iii) mixing a second amount of water-soluble chewing gum ingredients into the
mixture after a period of time,
iv) dosing the one or more cannabinoids to the mixture after a period of time,
and
CA 3031519 2019-01-25
26
v) extruding the final composition to obtain a chewing gum.
In certain embodiments of the method, the gum base comprising one or more
natural
resins in an amount of 10-40% by weight of the gum base, one or more
elastomers in
an amount of 3-30% by weight of the gum base, and one or more elastomer
plasticizers in an amount of 8-50% by weight of the gum base.
In certain embodiments of the method, the one or more elastomer plasticizers
comprise one or more polyvinyl acetate elastomer plasticizers, and the one or
more
polyvinyl acetate elastomer plasticizers are present in an amount of 8-50% by
weight
of the gum base.
In certain embodiments of the method, the first amount of water-soluble
chewing
gum ingredients comprise one or more sugar alcohols.
In certain embodiments of the method, the second amount of water-soluble
chewing
gum ingredients comprise one or more sugar alcohols.
In certain embodiments of the method, the one or more cannabinoids are mixed
into
the mixture at about the same time as mixing the second amount of water-
soluble
chewing gum ingredients into the mixture.
In certain embodiments of the method, the one or more cannabinoids are mixed
into
the mixture after a period of time of more than half the total mixing time.
In certain embodiments of the method, the one or more cannabinoids are mixed
into
the mixture as Close as possible to the end of mixing while at the same time
securing
that the one or more cannabinoids are homogeneously distributed in the water-
insoluble gum base comprising the one or more polyvinyl acetate elastomer
plasticizers.
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In certain embodiments of the method, the one or more cannabinoids are
included in
a pre-mixture prior to mixing, the pre-mixture comprising one or more sugar
alcohols.
In certain embodiments of the method, the method comprises a step v) of adding
an
outer coating to the chewing gum.
In certain embodiments of the method, the one or more cannabinoids are
comprised
in the outer coating of the chewing gum.
In certain embodiments of the method, high intensity sweeteners are mixed into
the
water-insoluble gum base.
In certain embodiments of the method, flavors are mixed into the water-
insoluble
gum base.
In certain embodiments of the method and product, the water-insoluble gum base
is a
natural gum base comprising natural ingredients, such as chicle.
In certain embodiments of the method, the chewing gum is formulated according
to
any of the product embodiments of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in more details with respect to certain
aspects
and embodiments of the invention. These aspects and embodiments are intended
to
be understood in connection with the rest of the description, including the
Summary
of the Invention and Examples of the invention.
The verb "to comprise" as is used in this description and in the claims and
its
conjugations are used in its non-limiting sense to mean that items following
the word
are included, but items not specifically mentioned are not excluded. In
addition,
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28
reference to an element by the indefinite article "a" or "an" does not exclude
the
possibility that more than one of the elements are present, unless the context
clearly
requires that there is one and only one of the elements. The indefinite
article "a" or
"an" thus usually means "at least one". Additionally, the words "a" and "an"
when
used in the present document in concert with the word comprising or containing
denote "one or more."
By the terms "gum base" and "gum base matrix" is meant the mainly water-
insoluble
ingredients and hydrophobic gum base ingredients that are mixed together,
typically
before the bulk portion of the chewing gum is added. The "gum base" may
contain
gum base polymers and plasticizers, waxes, emulsifiers, fats and/or fillers.
The gum
base may thus designate the typical water-insoluble chewing gum components,
which may be manufactured in a first step and subsequently mixed with the
mainly
water soluble portion in a second step. The term gum base may, evidently, also
refer
to the relevant gum base components that may be fed into an extruder and
forming
part of the final chewing gum when mixed with the chewing gum components in
the
extruder.
The term "bulk portion" or "water-soluble ingredients" intends to mean the
mainly
water-soluble and hydrophilic chewing gum ingredients that may be mixed into
the
gum base matrix, either in a separate process or in a one-step process by
means of an
extruder.
The term "weight of the chewing gum" or similar wording meaning the same is
defined in the present context as weight of the chewing gum, not including the
weight of an outer coating, such as a hard coating, soft coating, and the
like.
By the phrase "texture" is meant a qualitative measure of the viscoelastic
properties
of the chewing gum and of the overall mouth-feel experienced by the user
during the
chewing process. Thus, the term "texture" encompasses measurable quantities
such
CA 3031519 2019-01-25
29
as hardness and elasticity as well as more subjective parameters related to
the chew-
feel experienced by a user.
The term "in vivo chewing" intends to mean that the chewing gum system is
chewed
by a human subject in an experimental setup of trained test persons according
to
statistically principles and that either the saliva of the human subject is
subject to
measurements or the chewed chewing gum is subject to measurements, the
experimental setup being performed at a chewing frequency of 60 chews per
minute.
The term "in vivo release" or "in vivo testing of release" or similar wording
intends
to mean that the chewing gum is tested according to Example 24.
The term "in vitro release" or "in vitro testing of release" or similar
wording intends
to mean that the chewing gum is tested according to Example 25, in particular
according to Dissolution Test for Chewing Gums, General Monograph 2.9.25. In
European Pharmacopoeia, 5th ed.
The term "release" in the present context is intended to mean under "in vivo"
or "in
vitro" conditions. In particular, the "release rate" during a certain period
of time is
intended to mean the amount in percentage of cannabinoids that is released
during
the period at a chewing frequency of 60 chews per minute.
The term "sustained release" or "extended release" is herein intended to mean
prolonged release over time. The term "rapid release" or "quick release" or
"high
release" is herein intended to mean a higher content released for a given
period of
time. The term "controlled release" is intended to mean a release of a
substance from
a gum by the aid of active chewing of the gum in the oral cavity of the
subject,
whereby the active chewing is controlling the amount of substance released.
The term "delivery to the oral mucosa" or similar wording intends to mean that
the
chewing gum is tested according to Example 27.
CA 3031519 2019-01-25
30
A "self-emulsifying agent" is an agent which will form an emulsion when
presented
with an alternate phase with a minimum energy requirement. In contrast, an
emulsifying agent, as opposed to a self-emulsifying agent, is one requiring
additional
energy to form an emulsion.
The term "natural resin", as used herein, means resinous compounds being
either
polyterpene derived from terpenes of natural origin or resinous compounds
derived
from gum rosin, wood rosin or tall-oil rosin.
The gum base is the masticatory substance of the chewing gum, which imparts
the
chew characteristics to the final product. The gum base typically defines the
release
profile and plays a significant role in the gum product. The gum base portion
is
retained in the mouth throughout the chew. The water-soluble portion
disappears
over a period of time during chewing.
According to embodiments of the invention, a preferred amount of gum base
matrix
in the final chewing gum is 30 -75 % by weight of the chewing gum before any
optionally applied coating, such as 35-70% by weight of the chewing gum or 40-
65%
by weight of the chewing gum or 45-60% by weight of the chewing gum.
Elastomers provide the rubbery, elastomeric and bouncing nature to the gum,
which
varies depending on this ingredient's chemical structure and how it may be
compounded with other ingredients. Elastomers suitable for use in the gum base
and
gum of the present invention may include natural or synthetic types. Polyvinyl
acetate elastomer plasticizers are not considered elastomers according to the
invention.
Elastomers may be selected from the group consisting of styrene-butadiene
copolymers, polyisobutylene, isobutylene-isoprene copolymers, polyethylene,
CA 3031519 2019-01-25
31
polyurethane or any combination thereof. Preferred elastomers are styrene-
butadiene
copolymers (SBR), polyisobutylene and isobutylene-isoprene copolymers (BR).
Butadiene-styrene type elastomers, or SBR as they may be called, typically are
copolymers of from about 20:80 to 60:40 styrenes:butadiene monomers. The ratio
of
these monomers affects the elasticity of the SBR as evaluated by mooney
viscosity.
As the styrene:butadiene ratio decreases, the mooney viscosity decreases.
The structure of SBR typically consists of straight chain 1,3-butadiene
copolymerized with phenylethylene (styrene). The average molecular weight of
SBR
is <600.000 g/mole.
Isobutylene-isoprene type elastomers, or butyl as they may be called, have
molar
percent levels of isoprene ranging from 0.2 to 4Ø Similar to SBR, as the
isoprene:isobutylene ratio decreases, so does the elasticity, measured by
mooney
viscosity.
The structure of butyl rubber typically consists of branched 2-methyl-1,3-
butadiene
(isoprene) copolymerized with branched 2-methylpropene (isobutylene). The
average
molecular weight of SBR is in the range from 150.000 g/mole to 1.000.000
g/mole.
Polyisobutylene, or PIB as they may be called, type elastomers are polymers of
2-
methylpropeneThe low molecular weight elastomers provide soft chew
characteristics to the gum base and still provide the elastic qualities as do
the other
elastomers. Average molecular weights may range from about 30,000 to 120,000
g/mole and the penetration may range from about 4 millimeters to 20
millimeters.
The higher the penetration, the softer the PIB. Similar to the SBR and butyl,
the high
molecular weight elastomers provide elasticity the gum. Average molecular
weight
may range from 120.000 to 1.000.000 g/mole.
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Polybutene range in average molecular weight from about 5.000 g/mole to about
30.000 g/mole.
Useful natural elastomers include natural rubber such as smoked or liquid
latex and
guayule, natural gums such as jelutong, lechi caspi, perillo, sorva,
massaranduba
balata, massaranduba chocolate, nispero, rosidinha, chicle, gutta percha,
gutta kataiu,
niger gutta, tunu, chilte, chiquibul, gutta hang kang. Natural elastomers may
also be
applied in aspects of the present invention.
Elastomer plasticizers vary the firmness of the gum base. Their specificity on
elastomer inter-molecular chain breaking (plasticizing) along with their
varying
softening points cause varying degrees of finished gum firmness and
compatibility
when used in base. Polyvinyl acetate elastomers plasticizers are examples of
elastomer plasticizers of the present invention.
In some embodiments of the invention, the weight-average molecular weight (Mw)
of the one or more polyvinyl acetate elastomer plasticizers is from 5,000 to
40,000.
In some embodiments of the invention, the weight-average molecular weight (Mw)
of the one or more polyvinyl acetate elastomer plasticizers is from 6,000 to
35,000.
In some embodiments of the invention, the weight-average molecular weight (Mw)
of the one or more polyvinyl acetate elastomer plasticizers is from 7,000 to
30,000.
In some embodiments of the invention, the weight-average molecular weight (Mw)
of the one or more polyvinyl acetate elastomer plasticizers is from 8,000 to
25,000.
In some embodiments of the invention, the weight-average molecular weight (Mw)
of the one or more polyvinyl acetate elastomer plasticizers is from 10,000 to
20,000.
In some embodiments of the invention, the viscosity of the one or more
polyvinyl
acetate elastomer plasticizers is from 1.0 to 3.0 mPa*s as measured according
to
ASTM D445-06 (10 wt. % in ethyl acetate), such as from 1.0 to 2.5 mPa*s.
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In some embodiments of the invention, the K value of the one or more polyvinyl
acetate elastomer plasticizers is from 15 to 33 as measured according to DIN
53726
(1 wt. % in acetone), such as from 18 to 30.
Generally, the term "polyvinyl acetate elastomer plasticizer" is intended to
mean
polyvinyl acetate having a weight-average molecular weight (Mw) of less than
about
40,000.
Generally, the term "polyvinyl acetate elastomer" is intended to mean
polyvinyl
acetate having a weight-average molecular weight (Mw) of more than about
40,000.
In certain embodiments of the invention, the gum base comprises less than 10%
by
weight of polyvinyl acetate elastomer. In certain embodiments of the
invention, the
gum base comprises less than 5% by weight of polyvinyl acetate elastomer. In
certain embodiments of the invention, the gum base comprises 2 to 6% by weight
of
polyvinyl acetate elastomer. In certain embodiments of the invention, the gum
base
comprises 3 to 5% by weight of polyvinyl acetate elastomer. In certain
embodiments
of the invention, the gum base is substantially free of polyvinyl acetate
elastomer
In certain embodiments of the invention, the gum base comprises 15-35% by
weight
of the one or more polyvinyl acetate elastomer plasticizers and less than 10%
by
weight of polyvinyl acetate elastomer. In certain embodiments of the
invention, the
gum base comprises 15-35% by weight of the one or more polyvinyl acetate
elastomer plasticizers and less than 5% by weight of polyvinyl acetate
elastomer. In
certain embodiments of the invention, the gum base comprises 15-35% by weight
of
the one or more polyvinyl acetate elastomer plasticizers and 2 to 6% by weight
of
polyvinyl acetate elastomer.
Natural resins may be selected from ester gums including as examples glycerol
esters
of partially hydrogenated rosins, glycerol esters of polymerized rosins,
glycerol es-
ters of partially dimerized rosins, glycerol esters of tally oil rosins,
pentaerythritol
CA 3031519 2019-01-25
34
esters of partially hydrogenated rosins, methyl esters of rosins, partially
hydrogenated methyl esters of rosins, pentaerythritol esters of rosins,
synthetic resins
such as terpene resins derived from alpha-pinene, beta-pinene, and/or d-
limonene,
and natural terpene resins.
In an embodiment of the invention, the chewing gum comprises further chewing
gum
ingredients selected from the group consisting of flavors, dry-binders, tab
leting aids,
anti-caking agents, emulsifiers, antioxidants, enhancers, absorption
enhancers, high
intensity sweeteners, softeners, colors, active ingredients, water-soluble
indigestible
polysaccharides, water-insoluble polysaccharides or any combination thereof.
According to embodiments of the invention, the emulsifiers may be selected
from the
group consisting of sucrose ester of fatty acids (such as sucrose mono
stearate),
polyethylene glycol esters or ethers (PEG) (such as caprylocaproyl macrogo1-8
glycerides and lauroyl macrogo1-32-glycerides), mono- and diglyceride of fatty
acids
(such as glycerol monostearate, glycerol monolaurate, glyceryl behenate
ester),
acetic acid esters of mono- and diglycerides of fatty acids (Acetem),
polyoxyethylene
alkyl ethers, diacetyl tartaric ester of monoglycerides, lactylated
monoglycerides,
glycerophospholipids (such as lecithin), poloxamer (non-ionic block copolymer
of
ethylene oxide and propylene oxide), cyclodextrins, fatty acid esters of
sorbitol (such
as sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate,
polysorbates).
Self-emulsifying emulsifiers may be phospholipids (Lecithin), Polysorbates
(polysorbate 80).
SEDDS (self-emulsifying drug delivery system) may consist of hard or soft
capsules
filled with a liquid or a gel that consists of self-emulsifiers, one or more
cannabinoids, oil (to dissolve the cannabinoids) and a surfactant. SEDDS may
comprise of a blend or mixture of self-emulsifiers, one or more cannabinoids,
oil (to
dissolve the cannabinoids) and a surfactant. SEDDS may comprise granules
comprising self-emulsifiers, one or more cannabinoids, oil (to dissolve the
cannabinoids) and a surfactant. Upon contact with gastric fluid, the SEDDS
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spontaneously emulsify due to the presence of surfactants. Many surfactants,
however, are lipid based and interact with lipases in the GIT (gastro
intestinal tract).
This can lead to a reduced capability of the lipid-based surfactants to
emulsify the
one or more cannabinoids as well as the oil carrier, both reducing
bioavailability.
According to embodiments of the invention, flavors may be selected from the
group
consisting of coconut, coffee, chocolate, vanilla, grape fruit, orange, lime,
menthol,
liquorice, caramel aroma, honey aroma, peanut, walnut, cashew, hazelnut,
almonds,
pineapple, strawberry, raspberry, tropical fruits, cherries, cinnamon,
peppermint,
wintergreen, spearmint, eucalyptus, and mint, fruit essence such as from
apple, pear,
peach, strawberry, apricot, raspberry, cherry, pineapple, and plum essence.
The
essential oils include peppermint, spearmint, menthol, eucalyptus, clove oil,
bay oil,
anise, thyme, cedar leaf oil, nutmeg, and oils of the fruits mentioned above.
Petroleum waxes aid in the curing of the finished gum made from the gum base
as
well as improve shelf life and texture. Wax crystal size influences the
release of
flavor. Those waxes high in iso-alkanes have a smaller crystal size than those
waxes
high in normal-alkanes, especially those with normal-alkanes of carbon numbers
less
than 30. The smaller crystal size allows slower release of flavor since there
is more
hindrance of the flavor's escape from this wax versus a wax having larger
crystal
sizes.
Petroleum wax (refined paraffin and microcrystalline wax) and paraffin wax are
composed of mainly straight-chained normal-alkanes and branched iso-alkanes.
The
ratio of normal-alkanes to iso-alkanes varies.
Antioxidants prolong shelf life and storage of gum base, finished gum or their
respective components including fats and flavor oils.
Antioxidants suitable for use in gum base include butylated hydroxyanisole
(BHA),
butylated hydroxytoluene (BHT), betacarotenes, tocopherols, acidulants such as
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Vitamin C (ascorbic acid or corresponding salts (ascorbates)), propyl gallate,
catechins, other synthetic and natural types or mixtures thereof.
Further chewing gum ingredients, which may be included in the chewing gum
according to the present invention, include surfactants and/or solubilizers.
As
examples of types of surfactants to be used as solubilizers in a chewing gum
composition according to the invention, reference is made to H.P. Fiedler,
Lexikon
der Hilfstoffe fur Pharmacie, Kosmetik und Angrenzende Gebiete, pages 63-64
(1981) and the lists of approved food emulsifiers of the individual countries.
Anionic, cationic, arnphoteric or non-ionic solubilizers can be used. Suitable
solubilizers include lecithin, polyoxyethylene stearate, polyoxyethylene
sorbitan fatty
acid esters, fatty acid salts, mono and diacetyl tartaric acid esters of mono
and
diglycerides of edible fatty acids, citric acid esters of mono and
diglycerides of
edible fatty acids, saccharose esters of fatty acids, polyglycerol esters of
fatty acids,
polyglycerol esters of interesterified castor oil acid (E476), sodium
stearoyllatylate,
sodium lauryl sulfate and sorbitan esters of fatty acids and polyoxyethylated
hydrogenated castor oil (e.g. the product sold under the trade name
CREMOPHOR),
block copolymers of ethylene oxide and propylene oxide (e.g. products sold
under
trade names PLURONIC and POLOXAMER), polyoxyethylene fatty alcohol ethers,
polyoxyethylene sorbitan fatty acid esters, sorbitan esters of fatty acids and
polyoxyethylene steraric acid esters.
Particularly suitable solubilizers are polyoxyethylene stearates, such as for
instance
polyoxyethylene(8)stearate and polyoxyethylene(40)stearate, the
polyoxyethylene
sorbitan fatty acid esters sold under the trade name TWEEN, for instance TWEEN
20 (monolaurate), TWEEN 80 (monooleate), TWEEN 40 (monopalmitate), TWEEN
60 (monostearate) or TWEEN 65 (tristearate), mono and diacetyl tartaric acid
esters
of mono and diglycerides of edible fatty acids, citric acid esters of mono and
diglycerides of edible fatty acids, sodium stearoyllatylate, sodium lauryl
sulfate,
polyoxyethylated hydrogenated castor oil, blockcopolymers of ethylene oxide
and
propyleneoxide and polyoxyethylene fatty alcohol ether. The solubilizer may
either
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be a single compound or a combination of several compounds. In the presence of
an
active ingredient, such as the included one or more cannabinoids, the chewing
gum
may preferably also comprise a carrier known in the arts of chewing gum and
active
ingredients. Poloxamer F68 is a further highly suitable solubilizer.
High intensity artificial sweetening agents can also be used according to
preferred
embodiments of the invention. Preferred high intensity sweeteners include, but
are
not limited to sucralose, aspartame, salts of acesulfame, alitame, neotame,
saccharin
and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones,
thaumatin,
monellin, monk fruit extract, advantame, stevioside and the like, alone or in
combination.
In order to provide longer lasting sweetness and flavor perception, it may be
desirable to encapsulate or otherwise control the release of at least a
portion of the
artificial sweeteners.
Techniques such as wet granulation, wax granulation, spray drying, spray
chilling,
fluid bed coating, conservation, encapsulation in yeast cells and fiber
extrusion may
be used to achieve desired release characteristics. Encapsulation of
sweetening
agents can also be provided using another chewing gum component such as a
resinous compound.
Usage level of the high-intensity sweetener will vary considerably and will
depend
on factors such as potency of the sweetener, rate of release, desired
sweetness of the
product, level and type of flavor used and cost considerations. Thus, the
active level
of artificial sweetener may vary from about 0.001 to about 8% by weight
(preferably
from about 0.02 to about 8% by weight). When carriers used for encapsulation
are
included, the usage level of the encapsulated high-intensity sweetener will be
proportionately higher.
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A chewing gum and/or gum base may, if desired, include one or more
fillers/texturizers including as examples, magnesium- and calcium carbonate,
sodium
sulphate, ground limestone, silicate compounds such as magnesium- and aluminum
silicate, kaolin and clay, aluminum oxide, silicium oxide, talc, titanium
oxide,
mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and
combinations thereof. According to an embodiment of the invention, one
preferred
fillcr/texturizer is calcium carbonate.
A number of chewing gum components well known within the art may be applied
within the scope of the present invention. Such components comprise but are
not
limited to waxes, fats, softeners, fillers, bulk sweeteners, flavors,
antioxidants,
emulsifiers, coloring agents, binding agents and acidulants.
In an embodiment of the invention, water-soluble ingredients comprise at least
one
sugar alcohol. The at least one sugar alcohol may be selected from the group
consisting of xylitol, sorbitol, mannitol, maltitol, isomaltitol, isomalt,
erythritol,
lactitol, maltodextrin, hydrogenated starch hydrolysates, and combinations
thereof.
A specific example of one category of polyol sweeteners include sugars, in
particular
a sugar selected from the group consisting of dextrose, sucrose, maltose,
fructose,
lactose, and combinations thereof.
A method of manufacturing extruded chewing gum may be as follows:
Gum bases are typically prepared by adding an amount of the elastomer,
elastomer
plasticizer and filler to a heated (100 C.-120 C.) sigma blade mixer with a
front to
rear speed ratio of from about 1.2:1 to about 2:1, the higher ratio typically
being used
for gum base which requires more rigorous compounding of its elastomers.
The initial amounts of ingredients comprising the initial mass may be
determined by
the working capacity of the mixing kettle in order to attain a proper
consistency and
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by the degree of compounding desired to break down the elastomer and increase
chain branching. The higher the level of filler at the start or selection of a
filler
having a certain particle size distribution, the higher the degree of
compounding and
thus more of the elastomeric chain crosslinking are broken, causing more
branching
of the elastomer thus lower viscosity gum bases and thus softer final gum base
and
gum made from such a gum base. The longer the time of compounding, the use of
lower molecular weight or softening point gum base ingredients, the lower the
viscosity and firmness of the final gum base.
Compounding typically begins to be effective once the ingredients have massed
together. Anywhere from 15 minutes to 90 minutes may be the length of
compounding time.
Preferably, the time of compounding is from 20 minutes to about 60 minutes.
The
amount of added elastomer plasticizer depends on the level of elastomer and
filler
present. If too much elastomer plasticizer is added, the initial mass becomes
over
plasticized and not homogeneous.
After the initial ingredients have massed homogeneously and compounded for the
time desired, the balance of the gum base ingredients are added in a
sequential
manner until a completely homogeneous molten mass is attained. Typically, any
remainder of elastomer, elastomer plasticizer and filler, are added within 60
minutes
after the initial compounding time. The filler and the elastomer plasticizer
would
typically be individually weighed and added in portions during this time. The
optional waxes, softeners and antioxidants are typically added after the
elastomer and
elastomer plasticizers and during the next 60 minutes. Then the mass is
allowed to
become homogeneous before dumping.
Typical gum base processing times may vary from about one to about three
hours,
preferably from about 1V2 to 21/2 hours, depending on the formulation. The
final mass
temperature when dumped may be between 70 C. and 130 C. and preferably
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between 100 C. and 120 C. The completed molten mass is emptied from the
mixing kettle into coated or lined pans, extruded or cast into any desirable
shape and
allowed to cool and solidify. Those skilled in the art will recognize that
many
variations of the above described procedure may be followed.
The water-soluble portion of the chewing gum may comprise softeners,
sweeteners,
high intensity sweeteners, flavoring agents, acidulants, fillers,
antioxidants, and other
components that provide desired attributes. Softeners typically constitute
from about
0.5% to about 25.0% by weight of the chewing gum. The bulking agents generally
comprise from about 5% to about 90%, preferably from about 20% to about 80% of
the chewing gum. High-intensity sweeteners in gum typically may range from
about
0.01 to 0.50 weight percent. A flavoring agent may be present in the chewing
gum in
an amount within the range of from about 0.1 to about 15.0 weight percent of
the
gum.
In general, chewing gum may be manufactured by sequentially adding the various
chewing gum ingredients to a commercially available mixer known in the art
where
the finished gum base is already present. After the initial ingredients have
been
thoroughly mixed, the gum mass is discharged from the mixer and shaped into
the
desired form such as by rolling into sheets and cutting into sticks, extruded
into
chunks or casting into pellets.
Generally, the ingredients may be mixed by first melting the gum base and
adding it
to the running mixer. Colors, active agents and/or emulsifiers may also be
added at
this time. A softener such as glycerin may also be added at this time, along
with
syrup and a portion of the bulking agent/sweetener. Further portions of the
bulking
agent/sweetener may then be added to the mixer. A flavoring agent is typically
added
with the final portion of the bulking agent/sweetener. A high-intensity
sweetener is
preferably added after the final portion of bulking agent and flavor have been
added.
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The entire mixing procedure typically takes from thirty to forty minutes, but
longer
mixing times may sometimes be required. Those skilled in the art will
recognize that
many variations of the above described procedure may be followed.
In accordance with the invention, the chewing gum may comprise about 0.1 to
about
75% by weight of an outer coating applied onto the chewing gum centre. Thus,
suitable coating types include hard coatings, film coatings and soft coatings
of any
composition including those currently used in coating of chewing gum.
One presently preferred outer coating type is a hard coating, which term is
used in
the conventional meaning of that term including sugar coatings and sugar-free
(or
sugarless) coatings and combinations thereof. The object of hard coating is to
obtain
a sweet, crunchy layer, which is appreciated by the consumer and it may
moreover
protect the gum centres for various reasons. In a typical process of providing
the
chewing gum centres with a protective sugar coating, the gum centres are
successively treated in suitable coating equipment with aqueous solutions of
crystallisable sugar such as sucrose or dextrose, which, depending on the
stage of
coating reached, may contain other functional ingredients, e.g. fillers,
binding agents,
colours, etc. In the present context, the sugar coating may contain further
functional
or active compounds including flavour compounds and/or active compounds.
In a typical hard coating process as it will be described in detail in the
following, a
suspension containing crystallisable sugar and/or polyol is applied onto the
gum
centres and the water it contains is evaporated off by blowing with air. This
cycle
must be repeated several times, typically 3 to 80 times, in order to reach the
swelling
required. The term "swelling" refers to the increase in weight or thickness of
the
products, as considered at the end of the coating operation by comparison with
the
beginning, and in relation to the final weight or thickness of the coated
products. In
accordance with the present invention, the coating layer constitutes about 0.1
to
about 75% by weight of the finished chewing gum element, such as about 10 to
about 60% by weight, including about 15 to about SO% by weight.
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In further useful embodiments, the outer coating of the chewing gum element of
the
invention is an element that is subjected to a film coating process and which
therefore comprises one or more film-forming polymeric agents and optionally
one
or more auxiliary compounds, e.g. plasticizers, pigments and opacifiers. A
film
coating is a thin polymer-based coating applied to a chewing gum centre of any
of
the above forms. The thickness of such a coating is usually between 20 and 100
jtm.
Generally, the film coating is obtained by passing the chewing gum centres
through a
spray zone with atomized droplets of the coating materials in a suitable
aqueous or
organic solvent vehicle, after which the material adhering to the gum centres
is dried
before the next portion of coating is received. This cycle is repeated until
the coating
is complete.
In the present context, suitable film-coating polymers include edible
cellulose
derivatives such as cellulose ethers including methylcellulose (MC),
hydroxyethyl
cellulose (HEC), hydroxypropyl cellulose (HPC) and hydroxypropyl
methylcellulose
(HPMC). Other useful film-coating agents are acrylic polymers and copolymers,
e.g.
methylacrylate aminoester copolymer or mixtures of cellulose derivatives and
acrylic
polymers. A particular group of film-coating polymers, also referred to as
functional
polymers are polymers that, in addition to its film-forming characteristics,
confer a
modified release performance with respect to active components of the chewing
gum
formulation. Such release modifying polymers include methylacrylate ester
copolymers, ethylcellulose (EC) and enteric polymers designed to resist the
acidic
stomach environment. The latter group of polymers include: cellulose acetate
phtalate (CAP), polyvinyl acetate phtalate (PVAP), shellac, metacrylic acid
copolymers, cellulose acetate trimellitate (CAT) and HPMC. It will be
appreciated
that the outer film coating according to the present invention may comprise
any
combination of the above film-coating polymers.
According to the invention, the one or more cannabinoids may be selected from
various cannabinoids.
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"Cannabinoids" are a group of compounds including the endocannabinoids, the
phytocannabinoids and those which are neither endocannabinoids or
phytocannabinoids, hereinafter "syntho-cannabinoids".
"Endocannabinoids" are endogenous cannabinoids, which are high affinity
ligands of
CB1 and CB2 receptors.
"Phytocannabinoids" are cannabinoids that originate in nature and can be found
in
the cannabis plant. The phytocannabinoids can be present in an extract
including a
botanical drug substance, isolated, or reproduced synthetically.
"Syntho-cannabinoids" are those compounds capable of interacting with the
cannabinoid receptors (CBI and/or CB2) but are not found endogenously or in
the
cannabis plant. Examples include WIN 55212 and rimonabant.
An "isolated phytocannabinoid" is one which has been extracted from the
cannabis
plant and purified to such an extent that the additional components such as
secondary
and minor cannabinoids and the non-cannabinoid fraction have been removed.
A "synthetic cannabinoid" is one which has been produced by chemical
synthesis.
This term includes modifying an isolated phytocannabinoid, by, for example,
forming a pharmaceutically acceptable salt thereof.
A "substantially pure" cannabinoid is defined as a cannabinoid which is
present at
greater than 95% (w/w) pure. More preferably greater than 96% (w/w) through
97%
(w/w) thorough 98% (w/w) to 99% % (w/w) and greater.
A "highly purified" cannabinoid is defined as a cannabinoid that has been
extracted
from the cannabis plant and purified to the extent that other cannabinoids and
non-
cannabinoid components that are co-extracted with the cannabinoids have been
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substantially removed, such that the highly purified cannabinoid is greater
than or
equal to 95% (w/w) pure.
"Plant material" is defined as a plant or plant part (e.g. bark, wood, leaves,
stems,
roots, flowers, fruits, seeds, berries or parts thereof) as well as exudates,
and includes
material falling within the definition of "botanical raw material" in the
Guidance for
Industry Botanical Drug Products Draft Guidance, August 2000, US Department of
Health and Human Services, Food and Drug Administration Center for Drug
Evaluation and Research.
In the context of this application the terms "cannabinoid extract" or "extract
of
cannabinoids", which are used interchangeably, encompass "Botanical Drug
Substances" derived from cannabis plant material. A Botanical Drug Substance
is
defined in the Guidance for Industry Botanical Drug Products Draft Guidance,
August 2000, US Department of Health and Human Services, Food and Drug
Administration Centre for Drug Evaluation and Research as: "A drug substance
derived from one or more plants, algae, or macroscopic fungi. It is prepared
from
botanical raw materials by one or more of the following processes:
pulverisation, decoction, expression, aqueous extraction, ethanolic
extraction, or
other similar processes." A botanical drug substance does not include a highly
purified or chemically modified substance derived from natural sources. Thus,
in the
case of cannabis, "botanical drug substances" derived from cannabis plants do
not
include highly purified, Pharmacopoeial grade cannabinoids.
The term "Cannabis plant(s)" encompasses wild type Cannabis sativa and also
variants thereof, including cannabis chemovars which naturally contain
different
amounts of the individual cannabinoids, Cannabis sativa subspecies indica
including
the variants var. indica and var. kafiristanica, Cannabis indica, Cannabis
ruderalis
and also plants which are the result of genetic crosses, self-crosses or
hybrids thereof.
The term "Cannabis plant material" is to be interpreted accordingly as
encompassing
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plant material derived from one or more cannabis plants. For the avoidance of
doubt
it is hereby stated that "cannabis plant material" includes dried cannabis
biomass.
Preferably the one or more cannabinoids are selected from: cannabichromene
(CBC),
5 cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid
(CBDA),
eannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV),
cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV),
cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid
(THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCV
10 A). More preferably the one or more cannabinoid is CBD or THC. This list
is not
exhaustive and merely details the cannabinoids which are identified in the
present
application for reference.
So far, more than 120 different phytocannabinoids have been identified which
are
15 within the scope of the present invention.
Cannabinoids can be split into different groups as follows: Phytocannabinoids;
Endocannabinoids; and Synthetic cannabinoids.
20 Cannabinoid receptors can be activated by three major groups of agonist
ligands, for
the purposes of the present invention and whether or not explicitly
denominated as
such herein, lipophilic in nature and classed respectively as:
endocannabinoids
(produced endogenously by mammalian cells); phytocannabinoids (such as
cannabidiol, produced by the cannabis plant); and, synthetic cannabinoids
(such as
25 HU-210).
Phytocannabinoids can be found as either the neutral carboxylic acid form or
the
decarboxylated form depending on the method used to extract the cannabinoids.
For
example, it is known that heating the carboxylic acid form will cause most of
the
30 carboxylic acid form to decarboxylate.
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Phytocannabinoids can also occur as either the pentyl (5 carbon atoms) or
propyl (3
carbon atoms) variant. For example, the phytocannabinoid THC is known to be a
CB1 receptor agonist whereas the propyl variant THCV has been discovered to be
a
CBI receptor antagonist meaning that it has almost opposite effects.
According to the invention, examples of phytocannabinoids may be
cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD),
cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),
cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN),
cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol
(THC), tetrahydrocannabinolic acid (THCA). tetrahydrocannabivarin (THCV) and
tetrahydrocannabivarinic acid (THCV A). More preferably the one or more
cannabinoid is CBD or THC.
The formulation according to the present invention may also comprise at least
one
cannabinoid selected from those disclosed in A. Douglas Kinghorn et al.,
Phytocannabinoids, Vol. 103, Chapter 1, pages 1-30.
Examples of endocannabinoids are molecules that activate the cannabinoid
receptors
within the body Examples include 2-arachidonyl glycerol (2AG), 2-arachidonyl
glyceryl ether (2AGE), arachidonyl dopamine, and arachidonyl ethanolamide
(anandamide). Structurally related endogenous molecules have been identified
that
share similar structural features, but that display weak or no activity
towards the
cannabinoid receptors but are also termed endocannabinoids. Examples of these
endocannabinoid lipids include 2-acyl glycerols, alkyl or alkenyl glyceryl
ethers,
acyl dopamines and N-acylethanolamides that contain alternative fatty acid or
alcohol moieties, as well as other fatty acid amides containing different head
groups.
These include N-acylserines as well as many other N-acylated amino acids.
Examples of cannabinoid receptor agonists are neuromodulatory and affect short-
term memory, appetite, stress response, anxiety, immune function and
analgesia.
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47
Synthetic cannabinoids encompass a variety of distinct chemical classes: the
cannabinoids structurally related to THC, the cannabinoids not related to THC,
such
as (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles,
quinolines, and arylsulfonamides, and eicosanoids related to the
endocannabinoids.
All or any of these cannabinoids can be used in the present invention.
It is preferred that the formulation comprises one or two primary
cannabinoids,
which are preferably selected from the group consisting of, cannabidiol (CBD)
or
cannabidivarin (CBDV), tetrahydrocannabinol (THC), tetrahydrocannabivarin
(THCV), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG) and
cannabidiolic acid (CBDA) or a combination thereof. It is preferred that the
formulation comprises cannabidiol and/or tetrahydrocannabinol.
Preferably, the chewing gum of the present invention may be used for the
treatment
or alleviation of pain, epilepsy, cancer, nausea, inflammation, congenital
disorders,
neurological disorders, oral infections, dental pain, sleep apnea, psychiatric
disorders, gastrointestinal disorders, inflammatory bowel disease, appetite
loss,
diabetes and fibromyalgia.
In a further aspect of the present invention the oral cannabinoid formulation
is
suitable for use in the treatment of conditions requiring the administration
of a
neuroprotectant or anti-convulsive medication.
The oral cannabinoid formulation may be for use in the treatment of seizures.
The oral cannabinoid formulation may be for use in the treatment of Dravet
syndrome, Lennox Gastaut syndrome, myoclonic seizures, juvenile myoclonic
epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome,
infantile spasms, refractory infantile spasms, tuberous sclerosis complex,
brain
tumours, neuropathic pain, cannabis use disorder, post-traumatic stress
disorder,
anxiety, early psychosis, Alzheimer's disease, and autism.
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48
The following non-limiting examples illustrate different variations of the
present
invention. The examples are meant for indicating the inventive concept; hence
the
mentioned examples should not be understood as exhaustive for the present. In
particular, CBD is used as an exemplary compound, but may also be another
cannabinoid.
EXAMPLES
Example 1
Preparation of gum base
Twenty different water-insoluble gum bases were prepared. The gum bases were
prepared in the process as described below. In the subsequent examples, the
specific
compositions of the gum bases (GB10 to GB29) are outlined.
Elastomers and elastomer plasticizer (PVA) were mixed at 120 C together with
filler, either calcium carbonate or talc, in a mixer having horizontally
placed Z-
shaped arms for mixing. It is noted that PVA was applied as an elastomer
plasticizer
for the elastomers in the composition and not in form of an elastomer. PVA as
an
elastomer plasticizer has special properties in the present context. For some
of the
comparative examples, another comparative polymer was added together with the
elastomers and elastomer plasticizer and mixed together with the elastomer and
the
elastomer plasticizer.
Natural resins were added after about 30 minutes of mixing of the polymers.
After the polymers and the natural resin had softened in the composition,
additional
ingredients were added, such as triacetin, emulsifier, wax, antioxidants and
vegetable
fat.
After a total mixing time of about 45-60 minutes, the mixture was discharged
into a
pan and allowed to cool at room temperature.
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For some of the examples where butyl rubber (BR) was added as an elastomer,
the
mixing time was optionally extended to a total of about 90-105 minutes
depending
on the amount of optional fillers.
In all of the gum base examples, the amount of the various ingredients is
given as %
by weight of the gum base.
Example 2
Various gum base formulations
GB number GB10 GB11 GB12 GB13 GB14
PVA 25 18 30 10 40
PIB 5 10 5 10 5
BR 5 5 5 5 -
Nat.
25 20 20 35 15
resin
Calcium
17 - 17 17 17
Carbonate
Talc - 17 - - -
Triacetin - 7 - - -
Emulsifier 5 10 5 5 5
Wax
13 13 13 13 13
Veg. fat 5 - 5 5 5
Total 100 100 100 100 100
Table 1A: Gum base compositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp.,
supplied by Wacker); FIB = polyisobutylene (Oppanol B12, supplied by BASF); BR
= butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerol ester
of
hydrogenated gum rosin; Veg. fat = vegetable fat.
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.. . ,
Example 3
Various gum base formulations
GB number GB15 GB16 GB17 GB18 GB19
PVA 25 25 20 40 15
PIB 5 10 5 5 5
BR 5 5 5 5 -
Nat.
25 20 30 10 40
resin
Calcium
17 17 17 17 17
Carbonate
Talc - - - -
Triacetin - - - - -
Emulsifier 5 5 5 5 5
Wax
13 13 13 13 13
Veg. fat 5 5 5 5 5
Total 100 100 100 100 100
Table 1B: Gum base compositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp.,
5 supplied by Wacker); FIB = polyisobutylene (Oppanol B12, supplied by
BASF); BR
= butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerol ester
of
hydrogenated gum rosin; Veg. fat = vegetable fat.
Example 4
10 Various gum base formulations
GB number GB20 GB21 GB22 GB23 GB24
PVA 18 18 18 18 18
PIB 10 10 10 10 10
BR 5 5 5 5 5
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Nat.
20 20 20 20 20
resin
Calcium
-
Carbonate
Talc ' 14 16.5 13.5 17 14
Triacetin 7 7 7 7 7
Emulsifier 10 10 10 10 10
Wax
13 13 13 13 13
Veg. fat - - - - -
Acesulfame - 0.5 0.5 - -
Menthol 3 - 3 - 3
BHT - - - 0,04 0,04
Total 100 100 100 100 100
Table 1C: Gum base compositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp.,
supplied by Wacker); FIB = polyisobutylene (Oppanol B12, supplied by BASF); BR
= butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerol ester
of
hydrogenated gum rosin; Veg. fat = vegetable fat; Acesulfame K (HIS =high-
intensity
sweetener); Menthol (flavor); BHT (Butylated hydroxytoluene=antioxidant).
Example 5
Various gum base formulations
GB number GB25 GB26 GB27 GB28 GB29
PVA 25 18 30 30 20
PIB 5 10 5 3 3
BR 5 5 - 2 2
Nat.
25 20 - 20
resin
VA-VL - - 20 20 10
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Calcium
17 17 17 17
Carbonate
Talc 17
Triacetin 7 2
Emulsifier 5 10 11 11 9
Wax
13 13 12 12 12
Veg. fat 5 5 5 5
Total 100 100 100 100 100
Table 1D: Gum base compositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp.,
supplied by Wacker); PIB = polyisobutylene (Oppanol B12, supplied by BASF); BR
= butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerol ester
of
hydrogenated gum rosin; VA-VL = vinyl acetate-vinyl laurate copolymer
(Vinnapas
B 500/40 VL, supplied by Wacker); Veg. fat = vegetable fat.
Example 6
CBD extract 52%
CBD extract with a 52% content of CBD provided by CBDepot (batch number CSFF
2018/5) was preheated to around 60 C for around 0.5 to 1 hour until the
extract was
in liquid form. The extract had a content of fatty acids, glycerol, waxes,
terpenes and
flavonoids. After the preheating process, the extract was either used directly
together
with additional chewing gum ingredients, or the extract was applied in a
premix.
Example 7
CBD extract 10%
CBD extract with a 10% content of CBD provided by Medical Hemp (batch number
MH131B Gold), was preheated to around 60 C for around 0.5 to 1 hour until the
extract was in liquid form. The extract had a content of fatty acids,
glycerol, waxes,
terpenes and flavonoids. After the preheating process, the extract was either
used
directly together with additional chewing gum ingredients, or the extract was
applied
in a premix.
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Example 8
CBD isolate
CBD isolate from cannabis plant tissues (phytocannabinoid) with a 98.5%
content of
CBD provided by Medical Hemp (batch number MH18212) was dissolved in an 96%
ethanol solution. The ratio between the CBD isolate and ethanol was 1:1. Once
CBD
was dissolved in the ethanol, the CBD isolate was either used directly
together with
additional chewing gum ingredients, or the extract was applied in a premix.
Example 9
Preparation of cannabinoid sugar alcohol premix
A premix was made with CBD and sugar alcohol particles, here sorbitol. The
premix
was made in a weight ratio of 1:5 of CBD and sorbitol with either one of the
forms of
CBD outlined in Examples 6-8. CBD was added to the sugar alcohol particles and
homogenized gently.
Example 10
Preparation of cannabinoid cyclodextrin premix
CBD (extract or isolate) was added and dissolved in a 5% solution of
polysorbate 80
to obtain a 10% solution of CBD. The 10% CBD solution is slowly added and
mixed
into a solution with 10% cyclodextrin to form a CBD-cyclodextrin complex. The
water is removed, whereupon the complex was either used directly together with
additional chewing gum ingredients, or the complex was applied in a premix.
Example 11
Preparation of cannabinoid microcrystalline cellulose premix
A cannabinoid-microcrystalline cellulose (MCC) premix was made by first adding
free cannabinoid to poloxamer F68 (PF) to obtain a 10% blend of cannabinoid in
poloxamer F68. Butylated hydroxytoluene (BHT) was added (0.5%) to 50 grams of
the cannabinoid-poloxamer F68 solid mix and added to 50 grams of
microcrystalline
cellulose provided as Avicel PH 102 from FMC Biopolymer. This was then mixed
in
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a Kitchenaid mixer operated at about 30 RPM for about 30 minutes at room
temperature. This mixture was equilibrated for about 30 minutes in a sealed
container. Hereby, at 5% cannabinoid-MCC premix was obtained.
Example 12
Preparation of cannabinoid chewing gum formulation
Gum base (GB) prepared according to Example 1 and formulated according to
Examples 2-5 was mixed with filler, here either talc, calcium carbonate or
sugar
alcohol, in a 60g mixer having horizontally placed Z-shaped arms for mixing.
The
mixer was preheated to a temperature of approximately 50 C. Once the content
of
the mixer was homogeneous, chewing gum ingredients were added according to a
specified time schedule.
Example 13
Preparation of cannabinoid chewing gum formulation with specific order
Gum base (GB) prepared according to Example 1 and formulated according to
Examples 2-5 was mixed with a filler, here sugar alcohol, in a 60g mixer
having
horizontally placed Z-shaped arms for mixing. The mixer was preheated to a
temperature of approximately 50 C. Once the content of the mixer was
homogeneous, chewing gum ingredients, including water-soluble ingredient, and
cannabinoids were added according to a specified time schedule as follows:
Specified order of addition in the preparation of chewing gum
Ingredient Content in weight % Application
time in min.
Gum base (GB) 40 0
Sugar alcohol 22.8 0
Maltitol syrup 8 3
Menthol powder 3 5
Eucalyptus Powder 2 5
Acesulfame k 0.1 5
Sucralose 0.1 5
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Sugar alcohol* 5 8
CBD 52%* 1 8
Sugar alcohol 18 8
Total 100 13
Table 1E: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained Sugar alcohol* was prepared as a
premix
with CBD according to Example 9. Here, the content in weight % is calculated
as the
sugar alcohol content, excluding the CBD content in the premix. CBD 52%* was
5 prepared according to Example 6.
Example 14
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
10 formulations outlined in the examples below. The formulations were
formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of lg for each piece and a content of CBD of 5mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG100 CG101 CG102 CG103
CG104
GB10 40 - - - -
GB11 - 40 - -
GB12 - - 40 - -
,
GB13 - - - 40 -
GB14 - - - - 40
Sorbitol 45.8 45.8 45.8 45.8 45.8
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.1 0.1 0.1 0.1
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Sucralose 0.1 0.1 0.1 0.1 0.1
CBD 52%* 1 1 1 1 1
Total 100 100 100 100 100
Table 1F: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6.
Example 15
Composition of eannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of lg for each piece and a content of CBD of 5mg for
each piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG105 CG106 CG107 CG108
CG109
GB15 40 - - - -
GB16 - 40 - - -
GB17 - - 40 - -
GB18 - - - 40 -
GB19 - - - - 40
Sorbitol 45.8 45.8 45.8 45.8 45.8
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.1 0.1 0.1 0.1
Sucralose 0.1 0.1 0.1 0.1 0.1
CBD 52%* 1 1 1 1 1
Total 100 100 100 100 100
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Table 1G: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6.
Example 16
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of lg for each piece and a content of CBD of 5mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG110 CG111 CG112 CG113 CG114
GB20 40 - - - -
,
GB21
- - -
- 40
GB22 - - 40 - -
GB23 - - - 40 -
GB24 - - - - 40
Sorbitol 45.8 45.8 45.8 45.8 45.8
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.1 0.1 0.1 0.1
Sucralose 0.1 0.1 0.1 0.1 0.1
CBD 52%* 1 1 1 1 1
Total 100 100 100 100 100
Table 111: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6.
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Example 17
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of lg for each piece and a content of CBD of 5mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG115 CG116 CG117 CG118 CG119
GB25 40 - - -
GB26 - 40 - -
GB27 - 40 -
GB28 - - - 40 -
GB29 40
- -
Sorbitol 45.8 45.8 45.8 45.8 45.8
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.1 0.1 0.1 0.1
Sucralose 0.1 0.1 0.1 0.1 0.1
CBD 52%* 1 1 1 1 1
Total 100 100 100 100 100
Table II: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6.
Example 18
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
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chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of I g for each piece and a content of CBD of 5mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG120 CG121 CG122 CGI23 CG124
GBIO 40 40
GB11 - - 40 40 40
Sorbitol 30 45.8 30 35.8 45.8
Talc 15.8 - 15.8 10 -
Maltitol syrup 8 8 8 8 8
I
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.1 0.1 0.1 0.1
Sucralose 0.1 0.1 0.1 0.1 0.1
CBD 52%* 1 1 1 1 1
Total 100 100 100 100 100
Table 1J: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6.
Example 19
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of lg for each piece and a content of CBD of 5mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
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CG Number CG125 CG126 CG127 CG128 CG129
GB11 55.8 45.8 35.8 25.8 15.8
Sorbitol 30 40 50 60 70
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.1 0.1 0.1 0.1
Sucralose 0.1 0.1 0.1 0.1 0.1
CBD 52%* 1 1 1 1 1
Total 100 100 100 100 100
Table 1K: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6.
5 Example 20
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
10 pieces had a weight of lg for each piece and a content of CBD of 5mg
for each piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG130 CG131 CG132 CG133 CG134
GB10 40 40 - - -
GB11 - - 40 40 40
Sorbitol 41.8 45.8 46.3 41.8 45.8
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
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Acesulfame k 0.1 0.1 0.1 0.1 0.1
Sucralose 0.1 0.1 0.1 0.1 0.1
CBD isolate* - - - 0.5 -
CBD 10%* 5 - - 5 -
CBD 52`)/0* - - - 1 1
Total 100 100 100 100 100
Table 1L: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD isolate* was prepared according
to
Example 8. CBD 10%* was prepared according to Example 7. CBD 52%* was
prepared according to Example 6.
Example 21
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of lg for each piece and a content of CBD of 5mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG135 CG136 CG137 CG138 CG139
GB11 40 40 40 40 40
Sorbitol 45.8 45.6 45.4 45.2 45.0
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.2 0.3 0.4 0.5
Sucralose 0.1 0.2 0.3 0.4 0.5
CBD 52%* 1 1 1 1 1
Total 100 100 100 100 100
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Table 1M: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6.
Example 22
Composition of cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13 was made with the
formulations outlined in the examples below. The formulations were formed into
chewing gum pieces by extrusion (rolling and scoring). The extruded chewing
gum
pieces had a weight of lg for each piece and a content of CBD of 5mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
% by weight of the chewing gum.
CG Number CG140 CG141 CG142 CG143 CG144
GB11 40 40 40 40 40
Sorbitol 45.8 36.8 41.8 26.8 44.8
Maltitol syrup 8 8 8 8 8
Menthol powder 3 3 3 3 3
Eucalyptus Powder 2 2 2 2 2
Acesulfame k 0.1 0.1 0.1 0.1 0.1
Sucralose 0.1 0.1 0.1 0.1 0.1
CBD 52%* 1 - - - 1
CBD-MCC 5%* - 10 - -
CBD-MCC 10%* - - 5 - -
CBD-cyclodex* - - - 20 -
Self-emulsifying* - - - - 1
Total 100 100 100 100 100
Table IN: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6. CBD-MCC 5%* was prepared according to Example 11. CBD-MCC
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10%* was prepared according to Example 11 with a higher amount of CBD. CBD-
cyclodex* is CBD-cyclodextrin complex prepared according to Example 10. Self-
emulsiffing* was prepared with an emulsifier, here polysorbate.
Example 23
Coating of chewing gum
A hard coating was prepared for selected samples with the following
composition:
Hard coating
Ingredients % by weight
Number CG145 CG146
Maltitol 57 57
Water 25.4 25.9
Mannitol 11 11
gummi arabicum 4 4
titandioxid 1 1
Polysorbate 0.1 0.1
CBD 52%* 1.5
CBD isolate* 0.7
Total 100 100
Table 10: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. CBD 52%* was prepared according to
Example 6. CBD isolate* was prepared according to Example 8. The coating was
provided to samples of CG100 from Example 15.
The coating was applied as a pre-heated suspension as outlined above to lg
extruded
chewing gum with the formulation of CG100 in Example 15. except that CBD 52%
or CBD isolate was substituted with sorbitol in CG100. Hence, CBD was not
present
in the extruded gum, but only in the coating. A total of 5 mg CBD was present
in the
coated tablet. The suspension was applied in 3 subsequent steps according to
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conventional coating techniques to a total of 0.45 g coating to the 1g
extruded gum.
This corresponds to a ratio of extruded gum to coating on 70:30.
Example 24
In vivo testing of release
A sample was chewed with a chewing frequency of 60 chews pr. minute for 3 or 5
minutes in a test panel of 8 test persons. The test person was a healthy
person
appointed on an objective basis according to specified requirements. After 3
or 5
minutes, the content of CBD was measured in the remaining chewing gum residue.
The chewing gum was subject to triple measurements for each of the 8 test
persons,
giving a total of 24 measurements for each sample. An average of the 24
measurements was calculated and the weight % release was calculated based on
the
original content of CBD in the sample. The content of CBD was measured in the
remaining chewing gum residue. The chewing gum residue was positioned in a
flask
and weighted. Subsequently, an organic solvent was added for dissolution
purposes,
and the mixture was mixed on a laboratory shaker overnight. The organic phase
was
diluted and centrifuged. The supernatant was injected directly to an HPLC
system
and analyzed by an assay method.
Example 25
In vitro testing of release
In vitro release of CBD was established by means of a chewing machine
(Dissolution
Test for Chewing Gums, General Monograph 2.9.25. In European Pharmacopoeia.
5th ed). A chewing chamber was filled with 20 ml buffer (phosphate buffer pH
7.4).
The chewing gum sample was placed in the chamber and the chewing machine was
initiated at 20 degree Celsius with I chew per second. After 3 or 5 minutes of
chewing, the machine was stopped and the chewing gum sample (residue) was
placed in a vial. If more release time points are needed (release profile),
the chewing
buffer must be exchanged with 20 ml of fresh buffer every five minutes. The
content
of CBD was measured in the remaining chewing gum residue. The chewing gum
residue was positioned in a flask and weighted. Subsequently, an organic
solvent was
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added for dissolution purposes, and the mixture was mixed on a laboratory
shaker
overnight. The organic phase was diluted and centrifuged. The supernatant was
injected directly into an HPLC system and analyzed by an assay method.
Example 26
Stability testing method
For stability testing, the ICH guideline is used; 25 C/60%RH (2 years),
30 C/65%RH (1 year), 40 C/75%RH (3 month). All samples were packed in duma
bottles before stored in the conditions. All samples were sensorially and
analytically
evaluated. The content of CBD was measured in the remaining chewing gum
residue.
The chewing gum residue was positioned in a flask and weighted. Subsequently,
an
organic solvent was added for dissolution purposes, and the mixture was mixed
on a
laboratory shaker overnight. The organic phase was diluted and centrifuged.
The
supernatant was injected directly into an HPLC set-up and analyzed by an assay
method. The following method was able to separate and quantify CBD, delta-9
THC,
delta-8 THC and CBN.
Example 27
CBD delivered to the oral mucosa
A sample was chewed in vivo with a chewing frequency of 60 chews pr. minute
for 5
minutes in a test panel of 8 test persons. The test person was not allowed to
swallow
during the procedure. After one minute, saliva was obtained from the test
person and
collected in a vessel for later analysis. In tests for 5 minutes release, the
same
procedure was followed until 5 minutes where the last sample was collected and
added to the same vessel for aggregated analysis. The test person was a
healthy
person appointed on an objective basis according to specified requirements.
the
aggregated saliva sample was collected after 5 minutes, the content of CBD was
measured in the saliva. The content of CBD was also measured in the remaining
chewing gum residue. The chewing gum residue was positioned in a flask and
weighted. Subsequently, an organic solvent was added for dissolution purposes,
and
the mixture was mixed on a laboratory shaker overnight. The organic phase was
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diluted and centrifuged. The supernatant was injected directly into an HPLC
system
and analyzed by an assay method. The gum and saliva was subject to 3 triple
measurements for each of the 8 test persons, giving a total of 24 measurement
for
each sample. An average of the 24 measurements was calculated and the weight %
release was calculated. By comparing the amount of CBD in the remaining
chewing
gum residue and the amount of CBD in the saliva, the amount of CBD delivered
to
the oral mucosa could be estimated.
Example 28
Sensorics evaluation test set-up
Apart from release measurements, either in vivo or in vitro, as well as
stability tests
of the extruded chewing gum, sensorics tests were also performed to reveal
very
important characteristics and properties of the extruded chewing gum. These
sensorics parameters are important as indicators of the structure of the
chewing gum
composition and the behavior of the gum when chewed. The structure is the
underlying guidance as to how the chewing gum resembles the structure of a
comparative chewing gum, which is set as the standard in the test series, i.e.
the
chewing gums are compared to each other in the test series. The test set-up
was
composed of 8 test persons in a test panel. Each of the test persons were
healthy
individuals appointed on an objective basis according to specified
requirements. The
sensory analysis was performed according to ISO 4121-2003 in testing
conditions
following ISO 8589. The result is an average of the results of the 8
individuals.
The test persons gave a rating from "+" to "+++++", where "+" is poor and
"+++++"
is excellent and comparable to the standard, i.e. "+++++" means that the gum
was
comparable to the standard and "+" means that the gum was very far from
comparable to the standard. "0" indicated that it was not tested.
Five different parameters were tested in a test panel:
Initial chew Texture Flavor Sweetness Off-notes
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"Initial chew" ¨ the first impression of the gum when chewed within the first
30
seconds. For instance, a very hard and viscous structure gave a very low
rating and a
very brittle structure also gave a very low rating.
"Texture" ¨ the overall impression of the gum after 30 seconds of chewing gum
or
when the gum has gained the structure of a steady state. For instance, a very
hard
structure gave a very low rating and a very smooth structure also gave a very
low
rating.
"Flavor" ¨ the overall impression of the gum during chewing with respect to
flavor.
For instance, a very low flavor experience gave a very low rating and a too
high
flavor experience that was not comparable to the standard also gave a very low
rating.
"Sweetness" ¨ the overall impression of the taste of the gum during chewing
with
respect to sweetness. For instance, if the sweetness was decreasing rapidly a
very low
rating was given and if the sweetness was too high giving an uncomfortable
feeling a
very low rating was also given.
"Off-notes" ¨the overall impression of the off-note from the one or more
cannabinoids in the composition during chewing. For instance, if off-notes
(grass,
bitter notes, irritation in the throat) were experienced in the throat, a low
rating was
given and if other uncomfortable sensations was experienced a low rating was
also
given.
Example 29
Sensorics evaluation of cannabinoid chewing gum
CG Initial chew Texture Flavor Sweetness Off-notes
CG 100 +++++ ++++ +-F-H- +-HE+
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CG 101 +-H-++ +++++ ++++ ++++ ++++
CG 102 +++++ +++++ ++++ ++++ ++++
CG 103 ++++ +++ +++ H-H-+ ++++
CG 104 1 I I -H-++ +A-F+ -FAH- ++++
CG 105 ' +++++ +++++ +H-P+ ' +-14+
CG 106 +++++ +++++ ++++ I +
. .
CG 107 +++++ I +++ +1 + + + ++++
CG 108 ++++ A--r+ + +++ +++
CG 109 +-F+ ++++ +-HF+ +d- +++
CG 110 0 0 +-H-++ +-H-+ -I-F+-i-i-
!
CG 111 0 0 ++++ +++++
CG 112 0 0 +1 I + +++++ -H-+-H-
. .
CG 113 0 0 ++++ +-H-+ ++++
CG 114 0 0 I ++ +-H-+ +++++
CG 115 +++++ +++++ +-H-+ +-1-H- ++++
CG 116 +++++ +-H-++ ++++ ++++ I 1 +
. . .
CG 117 ++ + -i-i- + +
CG 118 + + ++ + +
CG 119 ++ ++ -F-H- + ++
CG 120 ++++ -P-k+ ++ +-F ++
CG 121 +-1-1-++ +++++ + + + 1 1 + ++++
CG 122 ++++ AH-F+ A-I- ++ ++
CG 123 +++++ I + ++ ++++ ++++
CG 124 +++++ ++ +-H-+ -F-F++ ++++
CG 125 +-p++ I + +-I-F+ +-H-+ ++++
CG 126 -H-++ ++++ ++++ +-H-+ +++
CG 127 +++++ -1-F++ + I 1 +-H-+ ++++
CG 128 ++++ I + ++++ +d-p+ ++++
CG 129 +++ +++ +++ I +++
CG 130 ++++ ++++ ++++ ++++ ++++
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CG 131 +++++ +++++ ++++ +-4-1-+ ++-f--1-
CG 132 ++-H-+ -H-H-+ +-H-++ +++ +++
CG 133 ++-H-+ +++++ +-i-F++ + I +
CG 134 +++-F+ +++-H- ++++ ++++
++++
CG 135 +++++ +++++ +-H-+ +-H-+ ++++
CG 136 ++-H-+ i-F+-H- -I-1-F+ ++++
++++
CG 137 +++++ -H-+++ -H-+ +++ +++
CG 138 +++++ +++++ I -H- +++
CG 139 +++++ A¨F+++ AH-- + +++
CG 140 +++++ +++++ ++++ + + ++1
CG 141 +++++ -H-+++ ++++ +-i-F + ++++
CG 142 i I + -H-++ +-H-+ ++++ ++++
CG 143 +++++ +++++ +++++ +++++ +++-1-F
CG 144 +++++ +++++ +-i¨E++ +++++ +++++
Table 2A ¨ Evaluation of Examples 14-22 according to Example 28.
Example 30
Release of cannabinoid from extruded chewing gum
CG Number CG100 CG101 CG102 CG103 CG104
3 minutes 12 11 12 8 7
5 minutes 17 16 17 12 11
Table 2B: Chewing gum samples from Example 14 was tested for release after 3
or
5 minutes of in vivo chewing according to the test method of Example 24. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
CG Number CG100 CG101 CG102 CG103 CG104
3 minutes 13 12 14 7 6
5 minutes 15 14 16 11 10
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Table 2C: Chewing gum samples from Example 15 was tested for release qfter 3
or
minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
5 The result shows that in the outer end of the ranges according to the
invention, the
release was lower, but still acceptable (CG103 and CG104). However, the ranges
should be seen combined, such that the range of each of elastomer plasticizers
and
natural resin contributes in combination to the overall effect and release
properties of
the chewing gum. Hence, if an amount in the end of the range for natural resin
is
applied, the amount of elastomer plasticizer may to some extend counteract the
negative effect.
Example 31
Release of cannabinoid from extruded chewing gum
CG Number CG105 CG106 CG107 CG108 CG109
3 minutes 12 11 11 8 7
5 minutes 17 15 17 13 12
Table 2D: Chewing gum samples from Example 15 was tested for release after 3
or
5 minutes of in vivo chewing according to the test method of Example 24. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
CG Number CG105 CG106 CG107 CG108 CG109
3 minutes 13 11 14 7 6
5 minutes 15 13 16 12 11
Table 2E: Chewing gum samples from Example 16 was tested for release after 3
or
5 minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
The result shows that in the outer end of the ranges according to the
invention, the
release was lower, but still acceptable (CG108 and CG109). However, the ranges
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should be seen combined, such that the range of each of elastomer plasticizers
and
natural resin contributes in combination to the overall effect and release
properties of
the chewing gum. Hence, if an amount in the end of the range for natural resin
is
applied, the amount of elastomer plasticizer may to some extend counteract the
negative effect.
The release of CG 110-114 was comparable to CG105-109.
Example 32
Release of cannabinoid from extruded chewing gum
CG Number CGI15 CG116 CG117 CG118 CG1I9
3 minutes 12 11 6 4 7
5 minutes 17 16 7 6 9
Table 2F: Chewing gum samples from Example 17 was tested for release after 3
or 5
minutes of in vivo chewing according to the test method of Example 24. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
CG Number CG115 CG116 CG117 CG118 CG119
3 minutes 13 12 3 2 6
5 minutes 15 14 6 5 8
Table 2G: Chewing gum samples from Example 17 was tested for release after 3
or
5 minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
The result is clear in the sense that addition of VA-VL to the composition
provides a
much lower release (CG 117-119) than by the use of the polymers and natural
resin
according to the present invention. In addition, the sensorics properties by
the use of
VA-VL (see above) also makes it clear that VA-VL is not preferred.
Example 33
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Release of cannabinoid from extruded chewing gum
CG Number CG120 CG121 CG122 CG123 CG124
3 minutes 7 12 6 10 11
minutes 8 17 8 12 16
Table 214: Chewing gum samples from Example 18 was tested for release after 3
or
5 minutes of in vivo chewing according to the test method of Example 24. The
value
5 indicates weight % of cannabinoid released from the chewing gum sample
(CG).
CG Number CG120 CG121 CG122 CG123 CG124
3 minutes 6 13 7 10 12
5 minutes 7 15 8 11 14
Table 21: Chewing gum samples from Example 18 was tested for release after 3
or 5
minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
The addition of talc to the composition was expected to give a higher release
of CBD
since it was expected that talc would provide a more porous structure to the
extruded
chewing gum and thereby promote better release of CBD. However, this was not
seen (CG120 and CG122) and it appears that the amount of sugar alcohols is
more
important for release characteristics than previously expected.
Example 34
Release of cannabinoid from extruded chewing gum
CG Number CG125 CG126 CG127 CG128 CG129
3 minutes 7 11 12 14 18
5 minutes 8 13 17 19 22
Table 2J: Chewing gum samples from Example 19 was tested for release after 3
or 5
minutes of in vivo chewing according to the test method of Example 24. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
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CG Number CG125 CG126 CG127 CG128 CG129
3 minutes 6 10 13 15 17
minutes 7 12 14 16 21
Table 2K: Chewing gum samples from Example 19 was tested for release after 3
or
5 minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
5
The results shows that a too low amount of sugar alcohol in the gum (CG125)
caused
problems with the release of cannabinoids and that a higher amount was
desirable.
Overall, this was a surprise. However, a too high amount of sugar alcohol
(CG129)
affected other properties of the chewing gum as seen in the sensorics results
which
was not expected.
Example 35
Release of cannabinoid from extruded chewing gum
CG Number CG130 CG131 CG132 CG133 CG134
3 minutes 19 12 8 18 11
5 minutes 23 17 11 22 16
Table 2L: Chewing gum samples .from Example 20 was tested for release after 3
or
5 minutes of in vivo chewing according to the test method of Example 24. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
CG Number CG130 CG131 CG132 CG133 CG134
3 minutes 18 13 7 17 12
5 minutes 22 15 10 21 14
Table 2M: Chewing gum samples from Example 20 was tested for release after 3
or
5 minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
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The result shows that CBD 10% (CG130 and CG133) contributes with a higher
release from the extruded chewing gum than CBD 52% (CG130 and CG134). This
result is very surprising and appears to be a general trend that has not
previously
been recognized. Addition of an isolate (CG 132) resulted in a little lower
release
from the gum, but still acceptable. It appears unknown why the release differs
as
seen. This result may be used to specifically design a controlled release
profile of
cannabinoids. A certain amount of for instance CBD 52% together with a certain
amount of CBD 10% makes it possible to design the release of CBD, given that
the
release profiles are different.
Example 36
Release of cannabinoid from extruded chewing gum
CG Number CG135 CG136 CG137 CG138 CG139
3 minutes 11 12 11 12 14
5 minutes 16 17 18 19 20
Table 2N: Chewing gum samples from Example 21 was tested for release after 3
or
5 minutes of in vivo chewing according to the test method of Example 24. The
value
indicates weight % of cannabinoid releasedfrom the chewing gum sample (CG).
Generally, a slightly higher release of CBD was obtained with a higher amount
of
high-intensity sweetener in the extruded chewing gum formulation. This was
highly
unexpected since the amount of high-intensity sweetener is relatively low in
the
extruded chewing gum. However, as seen in the sensorics test above, when the
amount of high-intensity sweetener is in the high end (such as CG139), it may
impact
other properties of the extruded chewing gum.
Example 37
Release of cannabinoid from extruded chewing gum
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CG Number CG140 CG141 CG142 CG143
CG144
3 minutes 11 5 8 15 18
minutes 16 7 10 18 22
Table 2L: Chewing gum samples from Example 22 was tested for release after 3
or
5 minutes of in vivo chewing according to the test method of Example 24. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
CG Number CG140 CG141 CG142 CG143
CG144
3 minutes 12 6 9 14 20
5 minutes 14 7 10 17 25
5 Table 2M: Chewing gum samples from Example 22 was tested for release
after 3 or
5 minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
The overall result shows that release promoting systems, such as a
cyclodextrin
complex with CBD (CG143) or self-emulsifiers systems (CG144), may be a
particular advantage according to the invention if a higher release is
desirable.
However, the use of microcrystalline cellulose as a carrier in a 10% MCC-
system
(CG142) did provide a lower overall release which was even lower for a 5% MCC-
system (CG141).
Example 38
Stability test
CG132 CBD THC
LC (mg/piece) % LC LC (mg/piece) % LC
0 months 5 96 0 0
14 days 5 94 0 0
1 month 5 84 0 0
3 months 5 56 0 0
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Table 2N: Chewing gum sample CG132 was tested under extreme conditions,
60 C/4% RH in accordance with Example 26. In this example, CBD was present as
CBD isolate in accordance with Example 8. Sorbitol was substituted with
isomalt in
CG132.
In comparative studies for other delivery vehicles, it has been seen that CBD
degrades to THC and later to CBN under extreme conditions. However, the
results of
this study shows that CBD was not degraded to THC or later to CBN when
extruded
chewing gum was used as the delivery vehicle. This was highly surprising and
indicates that CBD is better protected in an extruded chewing gum matrix.
Example 39
Preparation of cannabinoid chewing gum formulation with specific order
The time of addition of CBD 52% according to Example 13 was changed in this
Example. While the time of addition was 8 minutes in Examples 13, the
following
additional time table was prepared in order to reveal the substantive meaning
of the
time of addition on the release of cannabinoids:
Specified order of addition in the preparation of chewing gum (CG100)
Ingredient Content in weight % Application time in min.
CBD 52%* 1 0
CBD 52%* 1 3
CBD 52%* 1 5
CBD 52%* 1 8
CBD 52%* 1 12
Total 13
Table 3A: It was secured that CBD was thoroughly mixed into the composition
and
that a homogeneous mixture was obtained. Sugar alcohol* was prepared as a
premix
with CBD according to Example 9. Here, the content in weight % is calculated
as the
sugar alcohol content, excluding the CBD content in the premix. CBD 52%* was
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prepared according to Example 6. The chewing gum composition was abbreviated
CG100 (Example 14).
Example 40
Release of cannabinoid from extruded chewing gum
Application time in min. Release %
0 7
3 9
5 10
8 14
12 15
Table 3B: Chewing gum samples from Example 14 (CG100) was tested for release
of CBD after 5 minutes of in vivo chewing according to the specification of
Example
13. The test method of Example 24 was applied. The value indicates weight % of
cannabinoid released from the chewing gum sample (CG).
The result shows that release of the one or more cannabinoids may be dependent
on
the application order during the manufacturing process of extruded chewing
gum. In
this example, it was seen that application of the one or more cannabinoids
after half
the mixing time was favorable, just as long as the cannabinoids were
homogeneously
distributed in the extruded gum. The application time of 8 minutes in this
example or
even later was particularly favorable.
Example 41
Coating with CBD
CG Number CG145 CG146
3 minutes 60 55
5 minutes 59 61
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Table 3C: Chewing gum samples from Example 23 was tested for release after 3
or
minutes of in vitro chewing according to the test method of Example 25. The
value
indicates weight % of cannabinoid released from the chewing gum sample (CG).
5 The result was highly surprising since it was expected that a major
amount of CBD
from the coating was absorbed in the chewing gum upon chewing. However, the
result shows that application of one or more cannabinoids into a coating, such
as a
hard coating, may be a promising way to deliver cannabinoids. Also, by
combining
the application of one or more cannabinoids in the coating as well as in the
extruded
chewing gum, controlled release of cannabinoids may be obtained. This may also
be
used to provide a biphasic release of cannabinoids, such that an initial high
release is
provided by the coating and a more sustained release is provided by
incorporating the
cannabinoids in the extruded chewing gum.
Example 42
CBD delivered to the oral mucosa
Tests were conducted in accordance with the test method of Example 27. The
tests
were performed for CG100 and CG101. The values for the CBD content in saliva
and in the chewing gum residue were measured after 5 min of chewing. From
these
values, the content of CBD delivered to the oral mucosa could be calculated.
CG Number CG100 CG101
CBD in saliva 0.1 0.1
CBD in residue 87 88
CBD delivered to mucosa 12.9 11.9
Table 3D: Chewing gum samples from Example 14 were tested for content of CBD
delivered to the oral mucosa after 5 minutes of in vivo chewing according to
the test
method of Example 27. The values indicate weight % of cannabinoid based on the
one or more cannabinoids present in the initial formulation.
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The results of the tests were very surprising as almost all CBD released after
5
minutes of chewing was delivered to the oral mucosa. It was expected that a
much
higher amount of CBD was present in the saliva after 5 minutes of chewing, but
only
a very low amount of CBD was found in the saliva. Based on the released amount
of
CBD (13% respective 12%), it could be calculated that < 1% of the released CBD
was present in the saliva and accordingly > 99% CBD was delivered to the oral
mucosa. Hence, the chewing gum formulation of the invention is very suitable
for
delivery of cannabinoids to the oral mucosa, much better than would have been
expected.
Example 43
CBD delivered to the oral mucosa
Tests were conducted in accordance with the test method of Example 27. The
tests
were performed for CG145 and CG146. The values for the CBD content in saliva
and in the chewing gum residue were measured after 5 min of chewing. From
these
values, the content of CBD delivered to the oral mucosa could be calculated.
CG Number CG145 CG146
CBD in saliva 35 35
CBD in residue 40 45
CBD delivered to mucosa 25 30
Table 3E: Chewing gum samples from Example 23 were tested for content of CBD
delivered to the oral mucosa after 5 minutes of in vivo chewing according to
the test
method of Example 27. The values indicate weight % of cannabinoid based on the
one or more cannabinoids present in the initial formulation.
The results of the tests were surprising as a very high amount of CBD released
after
5 minutes of chewing was delivered to the oral mucosa. It was expected that a
much
higher amount of CBD was present in the saliva after 5 minutes of chewing. The
total content of CBD delivered to the oral mucosa could be calculated to be
about the
double of the total content of CBD delivered to the oral mucosa when CBD was
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present in the chewing gum (Example 42) compared to the coating (Example 43).
It
was not expected that such a high content of CBD could be delivered to the
oral
mucosa with the present chewing gum formulation. In fact, the content of CBD
would be higher if polysorbate was not applied in the coating suspension since
polysorbate facilitates emulsifying properties of the saliva which prevent CBD
to be
delivered to the oral mucosa to an even higher degree.
By varying the content of CBD in the coating and the content of CBD in the
chewing
gum, a controlled delivery system may be established.
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