Note: Descriptions are shown in the official language in which they were submitted.
to = 0
TABLETED CHEWING GUM WITH ENHANCED DELIVERY 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 a
tableted chewing gum composition providing enhanced delivery of cannabinoids
to
the oral mucosa.
BACKGROUND OF THE INVENTION
Various attempts have been reported in the prior art with respect to delivery
of
cannabinoids to patients in need thereof. While cannabinoids may be
administered
and delivered to patients in need thereof through alveoli in the lungs by
smoking,
other administration forms provide cannabinoids in vapor for lung absorption.
Mouth
sprays have also been provided for medical indications, such as multiple
sclerosis.
Only few examples of chewing gum as a vehicle for cannabinoids have been
reported
in the prior art. While focus has generally been directed to clinical studies
supporting
various effects of cannabinoids to the human body, only very limited attention
is
given in the prior art with respect to improvements of chewing gum as a
delivery
vehicle of cannabinoids.
In particular, one of the critical factors associated with delivery of
cannabinoids from
chewing gum is uptake of cannabinoids through the oral mucosa. Chewing gum
formulations that may promote a high delivery of cannabinoids to the oral
mucosa
without adversely affecting sensorics properties may be particularly
preferred. If
cannabinoids contained in chewing gum are released to the oral saliva without
being
delivered to the oral mucosa, the uptake and associated health benefits may be
absent
or limited to a substantial degree.
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 has
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been a challenge to provide chewing gum platforms that offer a beneficial
delivery of
cannabinoids to the oral mucosa. One of the problems is that cannabinoids may
be
released to the oral saliva without being delivered to the oral mucosa. An
associated
problem is that a slow transfer of cannabinoids from oral saliva to the oral
mucosa,
caused by an improper chewing gum formulation, may lead to excessive
swallowing
of cannabinoids which in effect may cause adverse effects and limited health
benefits.
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
conventional gum bases are used in formulating the chewing gum disclosed, it
appears unknown if such chewing gum is able to offer a beneficial delivery of
cannabinoids to the oral mucosa.
In general, less attention is addressed in the prior art to the impact of the
chewing
gum platform and components in the gum base for the delivery of cannabinoids
to
the oral mucosa. Also, less attention is given on the impact of the chewing
gum
platform 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
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that support appropriate delivery of cannabinoids to the oral mucosa combined
with
beneficial sensorics properties.
SUMMARY OF THE INVENTION
Accordingly, there is provided a tableted chewing gum composition for oral
administration of cannabinoids, the composition comprising water-soluble
chewing
gum ingredients and water-insoluble gum base located in a plurality of
particles,
wherein the chewing gum composition comprises one or more cannabinoids, and
wherein the chewing gum composition generates saliva and delivers more than
20%
by weight of the one or more cannabinoids to the oral mucosa during the first
5
minutes of chewing.
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 offers a high degree of delivery of cannabinoids to the oral mucosa. If
cannabinoids contained in chewing gum are released to the oral saliva without
being
delivered to the oral mucosa, the uptake and associated health benefits may be
absent
or limited to a substantial degree.
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 has
been a challenge to provide chewing gum platfoiins that offer a beneficial
delivery of
cannabinoids to the oral mucosa. One of the problems is that cannabinoids may
be
released to the oral saliva without being delivered to the oral mucosa. An
associated
problem is that a slow transfer of cannabinoids from oral saliva to the oral
mucosa,
caused by an improper chewing gum formulation, may lead to excessive
swallowing
of cannabinoids which in effect may cause adverse effects and limited health
benefits.
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Generally, the chewing gum platform applied in the present invention is a
particulate
chewing gum formulation that is tableted into a coherent tablet. The specific
platform
of the present invention provides some beneficial properties compared to
chewing
gum that is made by rolling and scoring, so-called extruded chewing gum.
Delivery of one or more cannabinoids to the oral mucosa of at least 20% by
weight
of the one or more cannabinoids to the oral mucosa during the first 5 minutes
of
chewing is considered to be high in the present context. It is required that
the
chewing gum is formulated to generate saliva that may help transporting
cannabinoids to the oral mucosa. Hence, the tableted chewing gum according to
the
invention is inherently formulated to generate saliva. Saliva may be promoted
by the
content of water-insoluble gum base upon mechanical actions from chewing.
Saliva
may also be promoted by release of one or more water-soluble chewing gum
ingredients upon chewing.
Specifically, the provision of a plurality of particles is beneficial in terms
of delivery
of cannabinoids, where a first population of particles may comprise water-
insoluble
gum base and a second population of particles may comprise water-soluble
chewing
gum ingredients, the second population of particles being free of water-
insoluble
gum base. This special construction of delivering cannabinoids provides some
benefits that are not envisaged in conventional extruded chewing gum.
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.
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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 delivery 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
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 delivery 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 delivery 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 delivery 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.
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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, at least 10% by weight of the one or more
cannabinoids are present 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 are 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.
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.
In an embodiment of the invention, at least 90% by weight of the one or more
cannabinoids are present in unbound form.
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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 chewing gum composition delivers more
than
30% by weight of the one or more cannabinoids to the oral mucosa during the
first 5
minutes of chewing.
In an embodiment of the invention, the chewing gum composition delivers at
least
40% by weight of the one or more cannabinoids to the oral mucosa during the
first 5
minutes of chewing.
In an embodiment of the invention, the chewing gum composition delivers at
most
75% by weight of the one or more cannabinoids to the oral mucosa during the
first 5
minutes of chewing.
In certain embodiments of the invention, the delivery may be relatively high.
This
may for instance be the case when cannabinoids are located in different
particles,
different areas of the tableted chewing gum or both located in the tableted
chewing
gum and at the same time in an outer hard coating of the tableted 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 and avoid adverse side effects of cannabinoids.
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In an embodiment of the invention, the chewing gum composition delivers more
than
20 and less than 75% by weight of the one or more cannabinoids to the oral
mucosa
during the first 5 minutes of chewing.
In certain embodiments of the invention, the delivery may be within the range
of
more than 20 to less than 75% by weight of the one or more cannabinoids within
the
first 5 minutes upon oral administration. A delivery of more than 75% may be
critical
in some embodiments. In some circumstances, it is beneficial that the delivery
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 be located in the tableted chewing gum composition
in
locations such as in different particles, different areas of the tableted
chewing gum or
both located in the tableted chewing gum and at the same time in an outer hard
coating of the tableted 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 and avoid adverse side effects of eannabinoids.
In an embodiment of the invention, the chewing gum composition delivers at
most
60% by weight of the one or more cannabinoids to the oral mucosa during the
first 5
minutes of chewing.
In some circumstances, it is beneficial that the delivery 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 be located in the tableted chewing
gum
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composition in locations such as in different particles, different areas of
the tableted
chewing gum or both located in the tableted chewing gum and at the same time
in an
outer hard coating of the tableted chewing gum.
In an embodiment of the invention, the chewing gum composition delivers more
than
20 and less than 60% by weight of the one or more cannabinoids to the oral
mucosa
during the first 5 minutes of chewing.
In certain embodiments of the invention, a preferred delivery may be within
the
range of more than 20 and less than 60% by weight of the one or more
cannabinoids
within the first 5 minutes upon oral administration. A delivery of more than
20% is
considered to be at an advantageous level.
In an embodiment of the invention, the amount of the one or more cannabinoids
is at
least 5 mg.
In an embodiment of the invention, the amount of the one or more cannabinoids
is at
least 10 mg.
In an embodiment of the invention, delivery of the one or more cannabinoids is
measured when chewing 60 chews each minute.
In an embodiment of the invention, delivery of the one or more cannabinoids is
measured when saliva is not swallowed during the 5 minutes of chewing.
In an embodiment of the invention, delivery of the one or more cannabinoids is
measured when saliva is collected during and after the 5 minutes of chewing
and
analyzed for content of the one or more cannabinoids.
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In an embodiment of the invention, delivery of the one or more cannabinoids is
measured when chewing 60 chews each minute and saliva is not swallowed during
the 5 minutes of chewing.
In an embodiment of the invention, delivery of the one or more cannabinoids is
measured when chewing 60 chews each minute and when saliva is collected during
and after the 5 minutes of chewing and analyzed for content of the one or more
cannabinoids.
In an embodiment of the invention, delivery of the one or more cannabinoids is
measured when saliva is not swallowed during the 5 minutes of chewing and when
saliva is collected during and after the 5 minutes of chewing and analyzed for
content
of the one or more cannabinoids.
In an embodiment of the invention, delivery of the one or more cannabinoids is
measured when chewing 60 chews each minute and when saliva is not swallowed
during the 5 minutes of chewing and when saliva is collected during and after
the 5
minutes of chewing and analyzed for content of the one or more cannabinoids.
In an embodiment of the invention, delivery of the one or more cannabinoids is
partly controlled by means of the composition of the water-insoluble gum base.
One of the aims of the present invention is to provide a chewing gum
formulation
that both offers a relatively high delivery 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 delivery of cannabinoids without addition
of
components that may interact with sensorics properties of the gum.
In an embodiment of the invention, the gum base is comprising one or more
natural
resins in an amount of 10-40% by weight of the gum base.
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In an embodiment of the invention, delivery 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 delivery properties of cannabinoids and sensorics
properties.
In an embodiment of the invention, the gum base comprising 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.
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 delivery properties of cannabinoids
and
sensorics properties.
In an embodiment of the invention, delivery of the one or more cannabinoids is
partly controlled by means of the amount of the one or more elastomer
plasticizers.
The provision of one or more elastomer plasticizers is particularly
advantageous for
the delivery characteristics of cannabinoids. It was unexpected to the present
inventors that the combination of the specific chewing gum platform according
to the
invention with the one or more elastomer plasticizers would contribute to
improved
delivery 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
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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
delivery characteristics of the present invention.
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 delivery
characteristics of cannabinoids. It was unexpected to the present inventors
that the
combination according to the invention would contribute to improved delivery
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 delivery characteristics of the present invention.
In an embodiment of the invention, the gum base comprising one or more
polyvinyl
acetate elastomer plasticizers in an amount of 8-50% by weight of the gum
base.
Traditionally, water-insoluble gum base is seen as a matrix that does not
offer a high
degree of delivery of cannabinoids. In particular, with respect to
cannabinoids, it is a
surprise that improved delivery may be seen when polyvinyl acetate elastomer
plasticizers are applied in the gum base.
In an embodiment of the invention, the one or more polyvinyl acetate elastomer
plasticizers are present in an amount of 15-35% by weight of the gum base.
A particularly preferred range of polyvinyl acetate elastomer plasticizers is
15-35%
by weight of the gum base. Here, very advantageous results were achieved with
respect to delivery of cannabinoids and sensorics characteristics, such as
initial chew,
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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 polyvinyl acetate elastomer plasticizers would have a
combined
effect of improved sensorics properties.
In other embodiments of the invention, the one or more 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 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 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 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 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 water-insoluble gum base is a natural
gum
base comprising natural ingredients, such as chicle.
In an embodiment of the invention, delivery 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 delivery properties of
cannabinoids and sensorics properties.
In an embodiment of the invention, the plurality of particles including a
first
population of particles comprising water-insoluble gum base and a second
population
of particles comprising water-soluble chewing gum ingredients.
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Specifically, the provision of at least two populations of particles is
beneficial in
terms of delivery of cannabinoids, where a first population of particles
comprises
water-insoluble gum base and a second population of particles comprises water-
soluble chewing gum ingredients, the second population of particles being free
of
water-insoluble gum base. This special construction of delivering cannabinoids
provides some benefits that are not envisaged in conventional extruded chewing
gum.
In an embodiment of the invention, the first population of particles is
present in an
amount of at least 15% by weight of the tableted chewing gum composition.
Generally, since the first population of particles comprise gum base, the
amount of
these types of particles impact the content of gum base in the tableted
chewing gum.
For instance, when the content of gum base is about 100% by weight of the
first
population of particles, the gum base content of the tableted chewing gum may
be as
low as 15% by weight of the tableted chewing gum composition. On the other
hand,
when the content of gum base is about 40% by weight of the first population of
particles, the gum base content of the tableted chewing gum may also be as low
as
15% by weight of the tableted chewing gum composition. In this case, the
amount of
the first population of particles is higher than 15% by weight of the tableted
chewing
gum composition.
In an embodiment of the invention, wherein the first population of particles
is present
in an amount of 15 to 95% by weight of the tableted chewing gum composition.
Typically, the gum base content of the tableted chewing gum composition is
higher
than 15% by weight of the tableted chewing gum composition, such as about 40%
by
weight of the tableted chewing gum composition. In this case, the amount of
the first
population of particles may be 40% by weight of the tableted chewing gum
composition when the gum base content in the first population of particles is
about
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100% by weight of the first population of particles. In another case, the
amount of
the first population of particles may be 80% by weight of the tableted chewing
gum
composition when the gum base content in the first population of particles is
about
50% by weight of the first population of particles. This gives an amount of
gum base
of the tableted chewing gum composition of about 40% by weight of the tableted
chewing gum composition.
In an embodiment of the invention, the first population of particles is
present in an
amount of 15 to 90% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the first population of particles is present in
an amount
of 20 to 95% by weight of the tableted chewing gum composition. In an
embodiment
of the invention, the first population of particles is present in an amount of
20 to 90%
by weight of the tableted chewing gum composition. In an embodiment of the
invention, the first population of particles is present in an amount of 20 to
80% by
weight of the tableted chewing gum composition.
In an embodiment of the invention, the first population of particles is
present in an
amount of at least 20% by weight of the tableted chewing gum composition.
Preferably, the gum base content of the tableted chewing gum composition is
about
40% by weight of the tableted chewing gum composition. In some embodiments of
the invention, the amount of the first population of particles may be 40% by
weight
of the tableted chewing gum composition and the gum base content in the first
population of particles is about 100% by weight of the first population of
particles.
In some other embodiments of the invention, the amount of the first population
of
particles may be about 90% by weight of the tableted chewing gum composition
and
the gum base content in the first population of particles is about 40% by
weight of
the first population of particles. This gives an amount of gum base of the
tableted
chewing gum composition of about 36% by weight of the tableted chewing gum
composition. In this case, the first population of particles may be the
dominant
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particles of the composition, preferably containing a majority of the water-
soluble
ingredients of the present invention. In some embodiments of the invention,
the
second population of particles mainly contains flavors and auxiliary
ingredients,
while the water-soluble chewing gum ingredients are primarily contained in the
first
population of particles together with gum base.
In an embodiment of the invention, the first population of particles is
present in an
amount of at least 30% by weight of the tableted chewing gum composition. In
an
embodiment of the invention, the first population of particles is present in
an amount
of at least 40% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the first population of particles is present in
an amount
of at least 50% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the first population of particles is present in
an amount
of at least 70% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the first population of particles is present in
an amount
of at least 90% by weight of the tableted chewing gum composition.
In an embodiment of the invention, the first population of particles is
present in an
amount of 20 to 60% by weight of the tableted chewing gum composition.
While a preferred amount of gum base in the tableted chewing gum composition
is
about 40% by weight of the tableted chewing gum composition, the amount of gum
base may be varied according to the invention.
In an embodiment of the invention, the first population of particles is
present in an
amount of 30 to 60% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the first population of particles is present in
an amount
of 30 to 50% by weight of the tableted chewing gum composition.
In an embodiment of the invention, the second population of particles is
present in an
amount of at least 40% by weight of the tableted chewing gum composition.
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While the first population of particles contains gum base, the second
population of
particles does not contain gum base. The second population of particles may
essentially consist of water-soluble ingredients, which is presently
preferred.
However, the second population of particles may also contain water-insoluble
ingredients, such as talc, cellulose, or other water-insoluble tableting
material.
In some other embodiments of the invention, the amount of the second
population of
particles may be about 60% by weight of the tableted chewing gum composition
and
the content of water-soluble ingredients in the second population of particles
may be
about 100% by weight of the second population of particles. This gives an
amount of
water-soluble ingredients of the tableted chewing gum composition of about 60%
by
weight of the tableted chewing gum composition. In this case, the second
population
of particles may be the dominant particles of the composition, preferably
containing
a majority of the water-soluble ingredients of the present invention.
In an embodiment of the invention, the second population of particles is
present in an
amount of 40 to 80% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the second population of particles is present in
an
amount of 40 to 70% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the second population of particles is present in
an
amount of 50 to 80% by weight of the tableted chewing gum composition. In an
embodiment of the invention, the second population of particles is present in
an
amount of 50 to 70% by weight of the tableted chewing gum composition.
In an embodiment of the invention, the content of water-insoluble gum base of
the
first population of particles is more than 30% by weight of the first
population of
particles. In an embodiment of the invention, the content of water-insoluble
gum
base of the first population of particles is more than 40% by weight of the
first
population of particles. In an embodiment of the invention, the content of
water-
insoluble gum base of the first population of particles is more than 50% by
weight of
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the first population of particles. In an embodiment of the invention, the
content of
water-insoluble gum base of the first population of particles is more than 70%
by
weight of the first population of particles.
In an embodiment of the invention, the content of water-insoluble gum base of
the
first population of particles is more than 90% by weight of the first
population of
particles, such as about 100% by weight of the first population of particles.
In an embodiment of the invention, the content of water-soluble chewing gum
ingredients of the second population of particles is more than 50% by weight
of the
second population of particles, the second population of particles being free
of water-
insoluble gum base.
Preferably, the water-soluble chewing gum ingredients comprise one or more
sugar
alcohols. In the alternative, the water-soluble chewing gum ingredients
comprise one
or more sugars.
In an embodiment of the invention, the content of water-soluble chewing gum
ingredients of the second population of particles is more than 60% by weight
of the
second population of particles. In an embodiment of the invention, the content
of
water-soluble chewing gum ingredients of the second population of particles is
more
than 70% by weight of the second population of particles.
In an embodiment of the invention, the content of water-soluble chewing gum
ingredients of the second population of particles is more than 90% by weight
of the
second population of particles, the second population of particles being free
of water-
insoluble gum base.
In an embodiment of the invention, the first population of particles is
reduced in
volume and cohered together resulting in a matrix of discrete areas of the
tablet.
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According to the invention, tableting implies that the population of particles
is
reduced in volume as a result of pressure applied in the tableting apparatus.
Hence,
while the population of particles may be free-flowing before tableting, once
the
particles have been pressed as part of a population of particles, and
optionally
additional population of particles, the volume of the particles is reduced,
and the
particles are cohered together into a continuous matrix, which in the present
context
is denoted a 'layer'.
In the present context, it is to be understood that the individual particles
are not
merged after tableting but remain individual 'discrete' areas after tableting,
constituting the individual particles. For instance, if a particle of the
first population
of particles has a size of about 1 mm, the size of such a particle may be 0.9
mm after
tableting and have an appearance of a discrete area cohered together randomly
with
particles at the outer borders of the particle, including particles of the
second
population of particles. Some integration of the particles may be present but
generally the particles remains discrete areas of the tablet.
In an embodiment of the invention, the second population of particles is
reduced in
volume and cohered together resulting in a matrix of discrete areas of the
tablet.
In the present context, it is to be understood that the individual particles
are not
merged after tableting but remain individual 'discrete' areas after tableting,
constituting the individual particles. For instance, if a particle of the
second
population of particles has a size of about 0.1 mm, the size of such a
particle may be
0.09 mm after tableting and have an appearance of a discrete area cohered
together
randomly with particles at the outer borders of the particle, including
particles of the
first population of particles.
In an embodiment of the invention, the first population of particles and the
second
population of particles are reduced in volume and cohered together resulting
in a
matrix of discrete areas of the tablet.
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In an embodiment of the invention, the first population of particles and the
second
population of particles are substantially homogeneously distributed in the
tableted
chewing gum composition.
Preferably, the first population of particles and the second population of
particles are
homogeneously distributed in the tableted chewing gum composition. This may be
secured by using adequate mixing containers and avoid segregation of particles
before applying the particles to the tableting apparatus. Due to potential
size
difference between the first population of particles and the second population
of
particles, the two types of particles may be mixed in a mixing container
immediately
before tableting is applied.
In an embodiment of the invention, the plurality of particles comprise one or
more
further population of particles.
While it is preferred that two populations of particles are applied, one or
more further
population of particles may be applied in the present invention. For instance,
a
population of particles consisting of water-insoluble tableting aids, such as
talc, may
be applied according to the invention. In other embodiments, one or more
additional
population of particles containing water-soluble ingredients may be applied as
well
as one or more further populations of particles with a content of gum base.
The aim
of the annotation 'first population of particles' and 'second population of
particles' is
to make a distinction between particles that contain gum base and particles
that do
not contain gum base.
In an embodiment of the invention, the tableted chewing gum composition
comprises
one or more further population of particles.
In an embodiment of the invention, the one or more cannabinoids are present in
the
first population of particles comprising water-insoluble gum base.
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In an embodiment of the invention, the one or more cannabinoids are present in
the
second population of particles comprising water-soluble chewing gum
ingredients.
In an embodiment of the invention, the first population of particles and the
second
population of particles are substantially homogeneously distributed in a first
layer of
the tableted chewing gum composition.
In the present context, a 'layer' is to be understood as a matrix resulting
from
pressing one portion of particles according to the invention. Hence, if only
one
portion of particles according to the invention is applied in the tableting
apparatus,
and this portion is pressed into a coherent tablet, this would correspond to
one 'layer'
or a 'first layer'. This portion may comprise one or more populations of
particles.
Optionally, such layer may be pressed in two steps with varying pressure. On
the
other hand, if another portion of particles according to the invention is
applied to the
tableting apparatus on top of the already pressed layer, this would correspond
to
another 'layer' or a 'second layer'. In the context of the invention, the
second layer
may also be applied in the tableting apparatus first and the first layer may
be applied
in the tableting apparatus in a second step.
Due to the inherent nature of conventional tablet pressing, the individual
layers of a
tableted composition would have a sharp line between the layers when the
layers are
pressed in two or more subsequent steps. This is seen from a side view of the
tablet
as distinct layers on top of each other. In an alternative embodiment, two or
more
portions are applied in subsequent steps to the tableting apparatus and
pressed in one
sequence. In this case there will not be a sharp line between the layers from
a side
view, but this would still be considered a layered tablet according to the
invention,
although the line between the layers would be irregular. Accordingly, in some
embodiments, it is not required that layers are processed in separate
tableting steps.
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In an embodiment of the invention, the water-insoluble gum base is partly
located in
a first layer of the chewing gum composition and the water-soluble chewing gum
ingredients are partly located in a second layer of the chewing gum
composition.
Preferably, when a multi-layered tableted chewing gum composition is applied,
it
may be beneficial to partly locate the water-insoluble gum base in one layer
and a
part of the water-soluble chewing gum ingredients in another layer. This may
both
influence the delivery of the one or more cannabinoids of the composition as
well as
the sensorics properties of the tableted chewing gum composition.
In an embodiment of the invention, the water-insoluble gum base is partly
located in
a first layer of the chewing gum composition and the water-soluble chewing gum
ingredients are partly located in a second layer of the chewing gum
composition
together with the one or more cannabinoids.
In an embodiment of the invention, the water-insoluble gum base is located in
a first
layer of the chewing gum composition and the water-soluble chewing gum
ingredients are partly located in a second layer of the chewing gum
composition.
In one embodiment, when a multi-layered tableted chewing gum composition is
applied, it may be beneficial to only locate the water-insoluble gum base in
one
layer, and a part of the water-soluble chewing gum ingredients in another
layer or
layers. This may both influence the delivery of the one or more cannabinoids
of the
composition as well as the sensorics properties of the tableted chewing gum
composition.
In an embodiment of the invention, the water-insoluble gum base is located in
a first
layer of the chewing gum composition and the water-soluble chewing gum
ingredients are partly located in a second layer of the chewing gum
composition
together with the one or more cannabinoids.
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In an embodiment of the invention, the water-insoluble gum base is partly
located in
a first layer of the chewing gum composition and partly in a second layer of
the
chewing gum composition.
In certain embodiments of the invention, a two-layered tableted chewing gum
composition is provided with two layers comprising gum base. This
configuration
may be beneficial with respect to the delivery of the one or more cannabinoids
of the
composition as well as the sensorics properties of the tableted chewing gum
composition.
In an embodiment of the invention, the water-soluble chewing gum ingredients
are
partly located in a first layer of the chewing gum composition and partly in a
second
layer of the chewing gum composition.
In an embodiment of the invention, the content of water-insoluble gum base of
the
first layer is more than 30% by weight of the first layer.
In an embodiment of the invention, the content of water-insoluble gum base of
the
first layer is more than 35% by weight of the first layer. In an embodiment of
the
invention, the content of water-insoluble gum base of the first layer is more
than 40%
by weight of the first layer.
In an embodiment of the invention, the content of water-insoluble gum base of
the
first layer is more than 90% by weight of the first layer.
In an embodiment of the invention, the content of water-insoluble gum base of
the
first layer is from 30 to 90% by weight of the first layer. In an embodiment
of the
invention, the content of water-insoluble gum base of the first layer is from
30 to
70% by weight of the first layer. In an embodiment of the invention, the
content of
water-insoluble gum base of the first layer is from 30 to 60% by weight of the
first
layer. In an embodiment of the invention, the content of water-insoluble gum
base of
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the first layer is from 35 to 70% by weight of the first layer. In an
embodiment of the
invention, the content of water-insoluble gum base of the first layer is from
35 to
60% by weight of the first layer. In an embodiment of the invention, the
content of
water-insoluble gum base of the first layer is from 30 to 50% by weight of the
first
layer
In an embodiment of the invention, the content of water-soluble chewing gum
ingredients of the second layer is more than 50% by weight of the second layer
In an embodiment of the invention, the content of water-soluble chewing gum
ingredients of the second layer is more than 90% by weight of the second
layer.
In an embodiment of the invention, the content of water-soluble chewing gum
ingredients of the second layer is about 100% by weight of the second layer.
In an embodiment of the invention, the tableted chewing gum composition
consists
of two layers where a first layer is cohered to and adjacent to a second
layer.
In the present context 'cohered to and adjacent to' is intended to mean that
two layers
are pressed together on one top side and one bottom side of two portions of
particles
comprising one or more populations of particles. Hence, one surface of a layer
is
attached to one surface of another layer, whereas additional surfaces of the
portions
are not exposed to each other. Seen from a side view, the layers have a tablet-
slice
appearance.
In an embodiment of the invention, the tableted chewing gum composition
consists
of three layers where one middle layer is cohered to and adjacent to two outer
layers.
In the present context 'cohered to and adjacent to' is intended to mean that
two outer
layers are located on and attached to one top side and one bottom side of a
middle
layer. Seen from a side view, the layers have a tablet-slice appearance.
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In an embodiment of the invention, the water-soluble chewing gum ingredients
comprise one or more sugar alcohols or one or more sugars in an amount of 35-
80%
by weight of the tableted chewing gum composition.
In an embodiment of the invention, the water-soluble chewing gum ingredients
comprise one or more sugar alcohols or one or more sugars in an amount of 40-
70%
by weight of the tableted chewing gum composition.
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 delivery 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 delivery. In addition,
due to
the specific properties of cannabinoids, it was a surprise to discover that
the delivery
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
weight of the chewing gum. However, contrary to expectations, the sensorics
properties were improved in combination with an improved delivery 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 one or more sugar alcohols partly located in a first layer of the
chewing
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gum composition and partly in a second layer of the chewing gum composition,
and
wherein the same type of sugar alcohols is present in both layers.
In an embodiment of the invention, the water-soluble chewing gum ingredients
comprise one or more sugar alcohols partly located in a first layer of the
chewing
gum composition and partly in a second layer of the chewing gum composition,
and
wherein different types of sugar alcohols are present in the layers.
In an embodiment of the invention, the one or more cannabinoids are part of
the
water-soluble chewing gum ingredients.
In an embodiment of the invention, delivery of the one or more cannabinoids is
partly controlled by means of the location of the one or more cannabinoids in
the
chewing gum composition.
In an embodiment of the invention, the one or more cannabinoids are located in
a
first layer of the chewing gum composition.
In an embodiment of the invention, the one or more cannabinoids are located in
a
second layer of the chewing gum composition.
In an embodiment of the invention, the one or more cannabinoids are both
comprised
in a first layer of the chewing gum composition and in a second layer of the
chewing
gum composition.
In an embodiment of the invention, delivery of the one or more cannabinoids is
partly controlled by means of further release enhancing ingredients.
In an embodiment of the invention, the gum base comprises less than 50% by
weight
of gum base polymers.
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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 delivery of cannabinoids may be improved and that the sensorics properties
of the
chewing gum may be improved. In particular, when vinyl laurate-vinyl acetate
copolymers are applied, it appears critical that the content of gum base
polymers
should be below 50% by weight of the gum base polymers. 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.
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.
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In an embodiment of the invention, the gum base comprising one or more natural
resins 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 gum base comprising one or more
elastomers
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 amount of gum base in the chewing gum
composition is 15-60 % by weight of the tableted chewing gum composition.
In an embodiment of the invention, the chewing gum composition comprises a pH
regulating agent in an amount of at least 0.5% by weight of the chewing gum
composition.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is more than 20% by weight of the one or more cannabinoids within the first 5
minutes upon oral administration.
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.
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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 is
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.
In an embodiment of the invention, the release rate of the one or more
cannabinoids
is at least 30% 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
30%
within the first 5 minutes after chewing is initiated.
A release rate of more than 30% is considered a relatively rapid, while at the
same
time maintaining beneficial sensorics properties.
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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.
In an embodiment of the invention, the one or more cannabinoids are not part
of a
pre-mixture with microcrystalline cellulose.
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
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 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 3035390 2019-03-01
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comprises CBD, salts and derivatives thereof, including analogues and
homologues.
In an embodiment of the invention said one or more cannabinoids comprises 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-A9-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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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 formulated 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 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 one or more sugars.
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
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 form part of a
complex with cyclodextrin. This complex may enhance the delivery of
cannabinoids
according to the present invention.
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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
delivery of cannabinoids. It was also seen that the lower concentration
applied in the
extract, the higher delivery.
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
delivery according to the present invention.
In an embodiment of the invention, the chewing gum comprises one or more
emulsifiers.
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.
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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.
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 delivery
of
cannabinoids are preferred. Also, if controlled delivery of cannabinoids is
preferred,
it is an advantage to partly 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 delivery 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.
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In an embodiment of the invention, the tableted chewing gum composition
comprises
one or more modules that do not comprise particles.
In the present context, a 'module' is to be understood as a matrix of non-
particulate
matter, cohered together with the tableted particles of the present invention.
A
'module' may for instance be a sheet of conventional extruded chewing gum that
is
applied during the tableting process, such as after a first pressing step in
the tableting
apparatus where the sheet is applied and optionally pressed on top of the
already
pressed tablet. In other embodiments, the extruded sheet may be applied in
other
configurations with the tableted particles of the invention.
Another option is to apply a non-particulate capsule, such as a gel capsule,
and
pressing this capsule together with the particles of the invention. This may
be done
by pressing a first portion of particles and subsequently locate the gel
capsule
centrally in a cavity of the pressed material after which another portion of
particles is
pressed on top of the capsule, fully enclosing the capsule after the second
pressing
step. Another option is to have relatively small gel capsules mixed with the
particles
of the invention and pressing the capsules together with the whole mixture in
one or
more steps. However, an important aspect of the invention is that the main
part of the
tableted chewing gum composition originates from particulate material.
When a module of non-particulate matter is applied in the present invention,
this
would not be a layer in the sense of the invention. Hence, if a gel capsule is
applied
between two 'layers', the tableted chewing gum composition would be annotated
a
two-layered chewing gum composition. Likewise, with a three-layered tableted
chewing gum composition.
In another aspect of the invention, there is provided an intermediate chewing
gum
product for oral administration of cannabinoids, the product comprising the
chewing
gum composition of the first aspect of the invention as described on the
previous
CA 3035390 2019-03-01
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pages. Importantly, this product may comprise the particulate material
according to
the invention before tableting. Also, the product may constitute the
particulate
material according to the invention.
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 a medical condition selected
from the
group consisting 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 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
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 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.
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FIGURES
Fig. la and lb illustrates a tableted chewing gum composition with one layer,
Fig. 2a and 2b illustrates a tableted chewing gum composition with two layers,
Fig. 3a and 3b illustrates a tableted chewing gum composition with three
layers,
Fig. 4 and 5 illustrates a first and a second population of particles, and
Fig. 6 illustrates a first and a second population of particles in a tableted
chewing
gum composition with two layers.
The invention will now be described in more details with reference to Fig.1-6.
These
illustrations are intended to be understood in connection with the rest of the
description, including the Summary of the Invention, the Detailed Description
and
the Examples of the invention.
Fig.la and Fig. lb illustrates an embodiment of a tableted chewing gum
composition
10 with a first layer 11. Fig.la is a cross-section of the tableted chewing
gum
composition and Fig.lb illustrates the tableted chewing gum composition seen
from
above. The tablet comprises an upper surface and a bottom surface as well as a
circular side surface.
Fig.2a and Fig.2b illustrates an embodiment of a tableted chewing gum
composition
20 with two layers 21,22. Fig.2a illustrates a cross-section of the tableted
chewing
gum composition and Fig. 2b illustrates the tableted chewing gum composition
seen
from above. The tablet comprises an upper surface and a bottom surface as well
as a
circular side surface. The tablet comprises a first layer 21 and a second
layer 22.
Fig 3a and Fig.3b illustrates an embodiment of a tableted chewing gum
composition
with three layers 31,32,33. Fig.3a illustrates a cross-section of the tableted
chewing gum composition and Fig. 3b illustrates the tableted chewing gum
30 composition seen from above. The tablet comprises an upper surface and a
bottom
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surface as well as a circular side surface. The tablet comprises a first layer
33 and a
second layer 31 and a third layer 32.
Fig.4 illustrates a closer view 40 of a cross-section of the first layer
11,21,33 of the
tableted chewing gum compositions according to Fig.la-3a. In this embodiment,
a
first population of particles 41 is homogeneously distributed with a second
population of particles 42 according to the invention. In this example the
first and
second population of particles are similar in size. The gum base content is
illustrated
with shadings of the first population of particles 41.
Fig.5 illustrates a closer view 50 of a cross-section of the first layer
11,21,33 of the
tableted chewing gum compositions according to Fig. 1 a-3a. In this
embodiment, a
first population of particles 51 is homogeneously distributed with a second
population of particles 52 according to the invention. In this example the
particles of
the first population of particles are larger in size than the particles of the
second
population of particles. The gum base content is illustrated with shadings of
the first
population of particles 51.
Fig.6 illustrates a closer view 60 of a cross-section of the tableted chewing
gum
compositions according to Fig.2a and 3a in the intersection between the
individual
layers 21,22 and 33,32. In this embodiment, a first population of particles 61
is
homogeneously distributed with a second population of particles 62 in layer
21,33
whereas a second population of particles 63 is present in layer 22,32 without
presence of the first population of particles. The gum base content is
illustrated with
shadings of the first population of particles 61.
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, the Figures and the Examples of the invention.
CA 3035390 2019-03-01
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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,
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 connection with the word comprising or
containing
denote "one or more." The expression "one or more" is intended to mean one,
two,
three or more.
In the present context the phrase "first population of particles", "second
population
of particles" or "further populations of particles" refer to a distinct
population of
particles. The expression "first", "second" or "third" is intended to mean
that the
individual populations have different compositions, e.g. a "first" population
may be a
portion of particles that have a content of gum base whereas a "second"
population
may be a portion of particles that does not have a content of gum base.
However, if a
"first" and "second" population is applied in one layer of a tablet, a "first"
population
in a second layer of the tablet may also have a different composition compared
to a
"first" population in the first layer. This may for instance be the case when
one type
of sugar alcohol is applied as a "first population of particles" in one layer
and another
type of sugar alcohol is applied as a "first population of particles" in
another layer.
The intention with the wording is mainly to distinguish two or more
populations that
are applied together, for instance in a homogeneous mixture. The individual
particles
in a "population" may comprise more than one ingredient, such as for instance
both
water-insoluble gum base and water-soluble chewing gum ingredients, or other
ingredients.
The term "population" as such is intended to mean a statistical population of
particles
characterized by a number of different parameters, e.g. statistical parameters
such as
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distribution of particles, average particle size, particle size distribution
width, etc.
Hence, a "population" may be a portion of particles characterized by having a
normal
distribution of particles with an average particle size, mean particles size
and a
distribution width. However, a "population" may also be a portion of particles
that
5 have undergone sieving where a certain lower or upper limit of particles
size is
present which does not necessarily give a normal distribution of particles.
The term "particle size" relates to the ability of the particles to move
through or be
retained by sieve holes of a specific size. The content of particles having a
particle
10 size in a certain size range is provided as weight percent relative to
the total weight
of the particle population in question. For instance, the population of
particles having
a content of gum base may e.g. comprise 40% (w/w) particles having a size in
the
range of 500-800 microns and 60% (w/w) particles having a size in the range of
800-
1400 microns . An average "particles size" is intended to mean a statistical
average.
The term "plurality of particles" is intended to cover the "population of
particles" in
the sense that the sum of populations are covered by the term "plurality".
The term "portion of particles" or similar wording is intended to mean a
plurality of
particles that collectively may comprise one or more populations of particles.
For
instance, a "portion of particles" may be applied in a tableting apparatus and
pressed
into a first layer of a tableted chewing gum composition. This layer may
comprise
one population of particles or a "first population of particles". However,
this portion
may also comprise two "populations of particles", etc.
The term "particle" or similar wording is intended to denote a single,
discrete
composition of solid matter, such as a granule or individual elements in
powder,
having a certain size that may deviate considerable.
By the terms" water-insoluble gum base" or "gum base" or "gum base matrix" or
similar wording is meant the mainly water-insoluble ingredients and
hydrophobic
CA 3035390 2019-03-01
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gum base ingredients. The "gum base" may contain gum base polymers and
plasticizers, waxes, emulsifiers, fats and/or fillers.
The teiin "water-soluble chewing gum ingredients" intends to mean the mainly
water-soluble and hydrophilic chewing gum ingredients.
The term "tableted" is intended to mean that the chewing gum composition is
pressed
in a tableting apparatus and mainly being composed of particulate matter, such
as
one or more populations of particles or plurality of particles. Although the
term
"tableted" implies a method step, in the present context, the term is intended
to mean
the resulting tablet obtained in tableting a portion of particles. It is noted
that a tablet
or tableted composition that is mentioned to comprise particles eventually is
to be
understood as particles that have been pressed together in a tableting step.
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
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.
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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 vitro"
conditions if not stated otherwise. 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.
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.
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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,
polyurethane or any combination thereof. Preferred elastomers are styrene-
butadiene
copolymers (SBR), polyisobutylene and isobutylene-isoprene copolymers (BR).
Styrene-butadiene 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.
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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 BR 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-
methylpropene. The 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 P1B. Similar to the SBR and butyl,
the high
molecular weight elastomers provide elasticity to the gum. Average molecular
weight may range from 120,000 to 1,000,000 g/mole.
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.
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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.
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.
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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
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,
tableting aids,
anti-caking agents, emulsifiers, antioxidants, enhancers, mucoadhesives,
absorption
enhancers, high intensity sweeteners, softeners, colors, active ingredients,
water-
CA 3035390 2019-03-01
47
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
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,
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48
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 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 in-
vention, reference is made to H.P. Fiedler, Lexicon of excipients in pharmacy,
cosmetics and
adjacent areas, pages 63-64
Date Recue/Date Received 2021-11-15
85124274
49
(1981) and the lists of approved food emulsifiers of the individual countries.
Anionic,
cationic, amphoteric 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
CREMOPHORTm), block copolymers of ethylene oxide and propylene oxide (e.g.
products
sold under trade names PLURONICTM 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 laurylsulfate, polyoxyethylated
hydrogenated castor
oil, blockcopolymers of ethylene oxide and propyleneoxide and polyoxyethylene
fatty alcohol
ether. The solubilizer may either 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
Date Recue/Date Received 2020-07-13
50
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.
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
filler/texturizer is calcium carbonate.
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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 tableted chewing gum according to the invention 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
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
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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 11/2 to 2'/2 hours, depending on the formulation. The
final mass
temperature when dumped may be between 70 C and 130 C. and preferably
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.
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The gum base (or gum composition) may be further processed in an extruder
where
the gum composition is extruded through a die plate into a liquid filled
chamber,
resulting in particles directly applicable for tableting. Alternatively, the
gum base
may be milled into a desired particle range.
The water-soluble chewing gum ingredients of the tab leted 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.
Flavoring agents 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.
The water-soluble chewing gum ingredients of the tableted chewing gum
composition according to the invention may be part of the first population of
particles and subsequently subject to further processing in an extruder where
the gum
composition is extruded through a die plate into a liquid filled chamber,
before
tableting. However, the water-soluble chewing gum ingredients may also be part
of a
second population of particles or further populations of particles that are
not exposed
to a liquid filled chamber but applied together with the first population of
particles to
a tableting apparatus. In yet another embodiments, the water-soluble chewing
gum
ingredients may be part of the particles comprising water-insoluble gum base
and not
exposed to a liquid filled chamber but used directly in a tableting apparatus,
optionally together with additional separate ingredients.
In an embodiment of the invention, the first population of particles,
comprising
water-insoluble gum base, has an average diameter in the range from 0.1 to 2.5
mm.
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In an embodiment of the invention, the first population of particles,
comprising
water-insoluble gum base, has an average diameter in the range from 0.3 to 2.1
mm.
In an embodiment of the invention, the first population of particles,
comprising
water-insoluble gum base, has an average diameter in the range from 0.8 to 1.4
mm.
The tableted chewing gum composition according to the invention is
manufactured
by applying pressure to a content of particles by suitable compression means.
The
particles or powder is then pressed into a compact coherent tablet. The
particles may
for example comprise so-called primary particles or aggregated primary
particles.
When these are pressed, bonds are established between the particles or
granules,
thereby conferring a certain mechanical strength to the pressed tablet.
It should be noted that the above-introduced terms: powder, primary particles
and
aggregated primary particles may be somewhat misleading in the sense that the
difference between primary particles and aggregated primary particles may very
often be looked upon differently depending on the background of the user. Some
may for instance regard a sweetener, such as sorbitol, as a primary particle
in spite of
the fact that sorbitol due to the typically preprocessing performed on
sorbitol when
delivered to the customer should rather be regarded as some sort of aggregated
primary particles. The definition adopted in the description of this invention
is that
aggregated primary particles refer to macro-particles comprising more or less
preprocessed primary particles.
When pressure is applied to the particles, the bulk volume is reduced, and the
amount
of air is decreased. During this process energy is consumed. As the particles
come
into closer proximity to each other during the volume reduction process, bonds
may
be established between the particles or granules. The formation of bonds is
associated with a reduction in the energy of the system as energy is released.
Volume
reduction takes place by various mechanisms and different types of bonds may
be
established between the particles or granules depending on the pressure
applied and
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the properties of the particles or granules. The first thing that happens when
a powder
is pressed is that the particles are rearranged under low compaction pressures
to form
a closer packing structure. Particles with a regular shape appear to undergo
rearrangement more easily than those of irregular shape. As the pressure
increases,
further rearrangement is prevented, and subsequent volume reduction is
obtained by
plastic and elastic deformation and/or fragmentation of the tablet particles.
Brittle
particles are likely to undergo fragmentation, i.e. breakage of the original
particles
into smaller units. Plastic deformation is an irreversible process resulting
in a
permanent change of particle shape, whereas the particles resume their
original shape
after elastic deformation. Evidently, both plastic and elastic deformation may
occur,
when compressing a chewing gum tablet.
Several studies of the bond types in pressed tablets have been made over the
years,
typically in the context of pharmaceuticals and several techniques of
obtaining
pressed tablets on the basis of available powders has been provided. Such
studies
have been quite focused on what happens when the volume reduction is performed
and how the end-product may be optimized for the given purpose. Several
refinements with respect to pressed tablets has for instance been made in the
addition
of for example binders in the tablet raw materials for the purpose of
obtaining a
sufficient strength to the final pressed tablet while maintaining acceptable
properties,
e.g. with respect to release.
Contrary to the tableted chewing gum composition according to the invention,
conventional chewing gum (which is mentioned here for reference purposes) 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 of conventional chewing gum may be mixed by first
melting the gum base and adding it to the running mixer. Colors, active agents
and/or
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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. 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 tableted chewing gum according to the
invention 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 tableted 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
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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 50% by weight.
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
gm.
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
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58
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.
"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 may have high affinity
ligands of CB1 and CB2 receptors.
"Phytocarmabinoids" 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 (CB1 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
substantially
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.
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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
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, Pharrnacopoeial grade cannabinoids.
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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
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),
cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA),
cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV),
cannabicyclol (CBL), eannabinol (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. 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
within the scope of the present invention.
Cannabinoids can be split into different groups as follows: Phytocannabinoids;
Endocannabinoids; and Synthetic cannabinoids.
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
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cannabidiol, produced by the cannabis plant); and, synthetic cannabinoids
(such as
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
carboxylic acid form to decarboxylate.
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
CB1 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 arachidonyI ethanolamide
(anandamide). Structurally related endogenous molecules have been identified
that
share similar structural features, but that display weak or no activity
towards the
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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.
In one embodiment the cannabinoid is palmitoylethanolamide (PEA) which is an
endogenous fatty acid amide belonging to the class of nuclear factor agonists.
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.
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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.
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
A: Preparation of water insoluble gum base particles
Twenty different water-insoluble gum base compositions were prepared. The gum
base compositions were prepared in the process as described below. In
subsequent
examples, the specific compositions of the gum bases (GB 10 to GB29) are
outlined.
In all of the gum base examples, the amount of the various ingredients is
given as %
by weight of the gum base.
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-
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64
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.
Once the
polymers and the natural resins had softened in the composition, additional
ingredients were
added, such as triacetin, emulsifier, wax, antioxidants, calcium carbonate,
talc, titan dioxide
and vegetable fat. A part of the calcium carbonate or talc may be substituted
by titan dioxide.
After a total mixing time of about 90-105 minutes, the mixture was discharged
into a pan and
allowed to cool at room temperature. 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 110-115
minutes depending on the amount of optional fillers.
The gum compositions were further processed in an extruder (LeistritsTm ZSE/BL
360 kw 104,
available from GALA GmbH, Germany). The gum compositions were extruded through
a die
plate into a liquid filled chamber (granulator AS PAC 6, available from GALA
GmbH,
Germany).
The extruder delivered the composition at a feed rate of 250 kg/h to the die
plate. The extruder
screw speed was 247 rpm. The temperature in the extruder was about 80 C. and
was mainly
regulated by the temperature of the gum compositions that were only allowed to
cool slightly
prior to being introduced into the extruder. The extruder produced a pressure
difference of 71
bar.
The gum composition was extruded through the die plate, which was heated to a
temperature
of 177 C. and had 336 holes with diameter 0.36 mm. In the granulator chamber
the extruded
composition was cut to particles by a cutter with 8 blades and cutter speed
about 2000 rpm. The
particles were cooled and transported to a strainer unit (a centrifugal dryer
TWS 20, available
from GALA GmbH, Germany) in water with temperature about 10 C. and flow 22
m3/h. The
Date Recue/Date Received 2020-07-13
85124274
average cooling and transport time in water was approx. 2 seconds. The granule
rate was 250
kg/h and the average diameter of the obtained particles was 1.24 mm. The
particles correspond
to a first population of particles comprising water-insoluble gum base. These
particles were
used for tableting.
5
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 (VinnapasTm B 1.5
sp., supplied
10 by Wacker); PIB = polyisobutylene (Oppanol B1 21m, supplied by BASF); BR
= butyl rubber
(isobutylene-isoprene copolymer); Nat. resin = glycerol ester ofhydrogenated
gum rosin; Veg.
fat = vegetable fat.
Example 3
Date Recue/Date Received 2020-07-13
. ,
. = , =
66
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.,
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
Various gum base formulations
GB number GB20 GB21 GB22 GB23 GB24
PVA 18 18 18 18 18
P1B 10 10 10 10 10
BR 5 5 5 5 5
Nat. ' 20 20 20 20 20
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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 - -
K
Menthol 3 - 3 - 3
BHT - - 0,04 0,04
¨
Total 100 100 100 100 100
Table 1C: Gum base compositions, P VA ¨ 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; 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
PM 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); FIB = 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 500/40VL, 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 applied as a thin
layer on
top of one or more sugar alcohol particles, here isomalt. After mixing until
CBD was
homogeneously distributed in the isomalt, the mixture was sieved through a
1400
microns sieve.
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 applied
as a
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thin layer on top of one or more sugar alcohol particles, here isomalt. After
mixing
until CBD was homogeneously distributed in the isomalt, the mixture was sieved
through a 1400 microns sieve.
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 applied in a premix with one
or
more sugar alcohol particles, here isomalt. After mixing until CBD was
homogeneously distributed in the isomalt, the mixture was sieved through a
1400
microns sieve.
Example 9
Preparation of cannabinoid sugar alcohol premix
A premix was made with CBD and sugar alcohol particles, here isomalt. The
premix
was made in a weight ratio of about 1:20 of CBD and isomalt with either one of
the
forms of CBD outlined in Examples 6-8. CBD was added to the sugar alcohol
particles and the powder was blended.
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 was slowly added and
mixed into a solution with 10% cyclodextrin to form a CBD-cyclodextrin
complex.
The water was removed, whereupon the complex was applied in a premix with
water-soluble chewing gum ingredients, here isomalt. After mixing until CBD
was
homogeneously distributed in the isomalt, the mixture was sieved through a
1400
microns sieve.
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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.
5 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
AvicelTm PH 102 from FMC Biopolymer. This was then mixed in a KitchenaidTvi
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
10 premix was obtained.
Example 12
A: Preparation of tableted chewing gum with one gum layer
A first population of particles comprising water-insoluble gum base prepared
according to
15 Example 1 and formulated according to Examples 2-5 (GB) was mixed with a
second
population of particles comprising water-soluble chewing gum ingredients.
Optionally, further
population of particles were added as well as further optional ingredients.
The mixture was blended in a mixing container at 7-12 rpm and optionally
loaded with
20 processing aid in order to improve free-flowing properties of the
particles. The mixture was
subsequently led to a standard tablet pressing machine (3090i, available from
Fette GmbH)
comprising dosing apparatus (P 3200 C, available from Fette GmbH, Germany) and
pressed
into tableted chewing gum compositions. The filling depth in the apparatus was
7.5 mm and
the diameter 15.0 mm. The tablets were pressed using a pressing pressure of
33.0-33.6 kN and
25 optionally prepressed with a pressing pressure of 1-7 kN. There were 75
punches on the rotor,
and the rotor speed used was 11 rpm. The individual tablets had a weight of
approx. 1.35 g.
B: Preparation of tableted chewing gum with one gum layer
Date Recue/Date Received 2020-07-13
,
71
A first population of particles comprising water-insoluble gum base in an
amount of
36% by weight of particles was prepared according to Example 1 and formulated
according to Examples 2-5 (GB). In this Example, about 56% of isomalt was
included in the first population of particles (unless stated otherwise), i.e.
gum base
and isomalt was included in the same individual particles. Optionally, further
population of particles were added as well as further optional ingredients.
The mixture was blended in a mixing container at 7-12 rpm and optionally
loaded
with processing aid in order to improve free-flowing properties of the
particles. The
mixture was subsequently led to a standard tablet pressing machine (3090i,
available
from Fette GmbH) comprising dosing apparatus (P 3200 C, available from Fette
GmbH, Germany) and pressed into tableted chewing gum compositions. The filling
depth in the apparatus was 7.5 mm and the diameter 15.0 mm. The tablets were
pressed using a pressing pressure of 33.0-33.6 kN and optionally prepressed
with a
pressing pressure of 1-7 kN. There were 75 punches on the rotor, and the rotor
speed
used was 11 rpm. The individual tablets had a weight of approx. 1.35 g.
Example 13
A: Preparation of tableted chewing gum with one layer free of gum base
A population of particles comprising water-soluble chewing gum ingredients was
provided. Optionally, further population of particles were added as well as
further
optional ingredients. However, gum base particles were not applied.
Before pressing, the mixture was blended in a mixing container at 7-12 rpm and
optionally loaded with processing aid in order to improve free-flowing
properties of
the particles. The mixture was subsequently led to a standard tablet pressing
machine
(3090i, available from Fette GmbH) comprising dosing apparatus (P 3200 C,
available from Fette GmbH, Germany) and pressed into a layer of the tableted
chewing gum compositions. The filling depth in the apparatus was 7.5 mm and
the
diameter 15.0 mm. The layer of the tablet was pressed using a pressing
pressure of
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33.0-33.6 IN. There were 75 punches on the rotor, and the rotor speed used was
11
rpm.
Subsequently, a layer according to Example 12A was tableted on top of the
prepared
layer (does not apply for B-F below). The weight ratio of the two layers was
55 to 45
(gum base free layer to gum base layer). The individual tablets had a weight
of
approx. 1.6 g.
B: Preparation of tableted chewing gum with one layer free of gum base
One layer was prepared according to Example 13A. Subsequently, another layer
according to Example 12B was tableted on top of the prepared layer. The weight
ratio of the two layers was 50 to 50 (Gum base free layer to gum base layer).
The
individual tablets had a weight of approx. 1.6 g.
C: Preparation of tableted chewing gum with two gum base layers
One layer was prepared according to Example 12A. Subsequently, another layer
according to Example 12A was tableted on top of the prepared layer. The weight
ratio of the two layers was 50 to 50 (Gum base layer to gum base layer). The
individual tablets had a weight of approx. 1.6 g.
D: Preparation of tableted chewing gum with three layers
One layer was prepared according to Example 13A. Subsequently, another layer
according to Example 12A was tableted on top of the prepared layer.
Subsequently, a
further layer according to Example 13A was tableted on top of the layer from
Example 12A. The weight ratio of the three layers was 35 to 30 to 35 (gum base
free
layer to gum base layer to gum base free layer). The individual tablets had a
weight
of approx. 1.6 g.
E: Preparation of tableted chewing gum with two layers and a gel capsule
module
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One layer was prepared according to Example 13A. Subsequently, a module of non-
particulate material was located centrally on top of the prepared layer. In
this
example the non-particulate material was a gel capsule. Subsequently, another
layer
according to Example 12A was tableted on top of and fully enclosing the non-
particulate material. The weight ratio was 45 to 10 to 45 (gum base free layer
to non-
particulate material to gum base layer). The individual tablets had a weight
of
approx. 1.6g.
F: Preparation of tableted chewing gum with two layers and gum module
One layer was prepared according to Example 13A. Subsequently, a module of non-
particulate material was located on top of the prepared layer. In this example
the non-
particulate material was a sheet of conventional extruded chewing gum.
Subsequently, another layer according to Example 12A was tableted on top of
the
sheet of extruded gum, the sheet being visible as a layer from a side view of
the
tablet. The weight ratio was 45 to 10 to 45 (Gum base free layer to non-
particulate
material to gum base layer). The individual tablets had a weight of approx.
1.6 g.
Example 14
Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 12A was made with
the formulations outlined in the examples below. The tableted chewing gum had
a
weight of about 1.35 g for each piece and a content of CBD of 10 mg 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
GBIO 36
GB11 36
GB12 36
GB13 36
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GB14 - - - - 36
Isomalt 56.4 56.4 56.4 56.4 56.4
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
Processing aid 2.1 2.1 2.1 2.1 2.1
CBD 52%* 1.4 1.4 1.4 1.4 1.4
Total 100 100 100 100 100
Table 1E: It was secured that CBD was thoroughly mixed into the prernixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
Example 15
Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 12A was made with
the formulations outlined in the examples below. The tableted chewing gum had
a
weight of about 1.35 g for each piece and a content of CBD of 10 mg 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 36 - - - -
GB16 - 36 - - -
GB17 - - 36 -
GB18 - - - 36 -
- GB19 - - - 36
Isomalt 56.4 56.4 56.4 56.4 56.4
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05
0.05
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Sucralose 0.05 1 0.05 0.05
0.05 0.05
Processing aid 2.1 2.1 2.1 2.1 2.1
CBD 52%* 1.4 1.4 1.4 1.4 1.4
Total 100 100 100 100 100
Table 1F: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
Example 16
5 Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 12A was made with
the formulations outlined in the examples below. The tableted chewing gum had
a
weight of about 1.35 g for each piece and a content of CBD of 10 mg for each
piece.
In all of the chewing gum examples, the amount of the various ingredients is
given as
10 % by weight of the chewing gum.
CG Number CG110 CG111 CG112 CG113
CG114
GB20 36 - - - -
GB21 - 36 - - -
GB22 - - 36 - -
GB23 - - - 36 -
GB24 - - - - 36
Isomalt 56.4 56.4 56.4 56.4
56.4
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05
0.05
Sucralose 0.05 0.05 0.05 0.05
0.05
Processing aid 2.1 2.1 2.1 2.1 2.1
CBD 52%* 1.4 1.4 1.4 1.4 1.4
Total 100 100 100 100 100
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Table 1G: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
Example 17
Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 12A was made with
the formulations outlined in the examples below. The tableted chewing gum had
a
weight of about 1.35 g for each piece and a content of CBD of 10 mg 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.
CGNumber CG115 CG116 CG117 CG118
CG119
GB25 36 - - - -
GB26 - 36 - - -
GB27 - - 36 - -
GB28 - - - 36 -
GB29 - - - - 36
Isomalt 56.4 56.4 56.4 56.4 56.4
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
Processing aid 2.1 2.1 2.1 2.1 2.1
CBD 52%* 1.4 1.4 1.4 1.4 1.4
-
Total 100 100 100 100 100
Table 1H: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
Example 18
Composition of tableted cannabinoid chewing gum
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Cannabinoid chewing gum based on the procedure in Example 12A (CG120-121)
and 12B (CG122-123) was made with the formulations outlined in the examples
below. One reference example was made with extruded chewing gum made by
rolling and scoring according to conventional principles (CG124). The chewing
gum
had a weight of about 1.35 g for each piece and a content of CBD of 10 mg 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 CG123
CG124*
GB10 36 36 36 36 36
lsomalt 40.6 56.4 40.6 56.4 56.4
Talc 15.8 15.8
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
Processing aid 2.1 2.1 2.1 2.1 2.1
CBD 52%* 1.4 1.4 1.4 1.4 1.4
Total 100 100 100 100 100
Table 11: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6. CG124 is
a reference example made by rolling and scoring (conventional extruded chewing
gum).
Example 19
Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 12A was made with
the formulations outlined in the examples below. The tableted chewing gum had
a
weight of about 1.35 g for each piece and a content of CBD of 10 mg 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
GB10 62.4 52.4 42.4 32.4
22.4
Isomalt 30 40 50 60 70
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05
0.05
Sucralose 0.05 0.05 0.05 0.05
0.05
Processing aid 2.1 2.1 2.1 2.1 2.1
CBD 52%* 1.4 1.4 1.4 1.4 1.4
Total 100 100 100 100 100
Table 1J: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
Example 20
Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13A (CG130-133)
and 13B (CG134) were made with the formulations outlined in the examples
below.
The tableted chewing gum had a weight of about 1.6 g for each piece and a
content
of CBD of 10 mg for each piece. The weight ratio of the two layers was 55 to
45
(gum base free layer to gum base layer) for CG130-133 and 50 to 50 for CG134.
In
all of the chewing gum examples, the amount of the various ingredients is
given as %
by weight of the layer of the tableted chewing gum.
CG Number CG130 CG131 CG132 CG133
CG134
Layer 1
GB10 36 60 60 80 36
Isomalt 58.9 34.9 32.2 14.9
58.9
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
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Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
Processing aid 1 1 1 1 1
CBD 52%* - - 2.7 - -
Total 100 100 100 100 100
Table 1K: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
CG Number CG130 CG131 CG132 CG133 CG134
Layer 2
GBIO - - -
Isomalt 94.2 94.2 96.4 94.2 94.0
Menthol powder 2.5 2.5 2.5 2.5 2.5
Eucalyptus Powder - - -
Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
_
Processing aid 1 1 1 1 1
CBD 52%* 2.2 2.2 - 2.2 2.4
Total 100 100 100 100 100
Table 1L: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
Example 21
Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 13C (CG135-137)
and 13D (CG138-139) were made with the formulations outlined in the examples
below. The tableted chewing gum had a weight of about 1.6 g for each piece and
a
content of CBD of 10 mg for each piece. The weight ratio of the two layers was
50 to
50 for CG135-137 and 35 to 30 to 35 for CG138-139. In all of the chewing gum
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examples, the amount of the various ingredients is given as % by weight of the
layer
of the tableted chewing gum.
CG Number CG135 CG136 CG137 CG138 CG139
Layer 1
GBIO 36 60 60 36 60
Isomalt 58.9 34.9 32.5 58.9 34.9
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
Processing aid 1 1 1 1 1
CBD 52%* - - 2.4 - -
Total 100 100 100 100 100
Table 1M: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6.
CG Number CG135 CG136 CG137 CG138* CG139*
Layer 2 (and 3*)
GB10 36 36 36 - -
Isomalt 56.5 56.5 58.9 94.7 94.7
Menthol powder 2 2 2 2.5 2.5
Eucalyptus Powder 2 2 2 - -
Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
Processing aid 1 1 1 1 1
CBD 52%* 2.4 2.4 - 1.7 1.7
Total 100 100 100 100 100
Table 1N: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6. It is
noted
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that CG 138* and CG 139* were made with 3 layers, where layer 1 was the middle
layer and layer 2 and 3 were located on opposite sides of layer 1. CG 135-137
were
made with two gum layers.
Example 22
Composition of tableted cannabinoid chewing gum
Cannabinoid chewing gum based on the procedure in Example 12A was made with
the formulations outlined in the examples below. The tableted chewing gum had
a
weight of about 1.35 g for each piece and a content of CBD of 10 mg 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 C6144
GB10 36 36 36 36 36
Isomalt 56.4 43.0 50.4 54.8 55.4
Menthol powder 2 2 2 2 2
Eucalyptus Powder 2 2 2 2 2
Acesulfame K 0.05 0.05 0.05 0.05 0.05
Sucralose 0.05 0.05 0.05 0.05 0.05
Anti-sticking agent 2.1 2.1 2.1 2.1 2.1
CBD 52%* 1.4 - - - 1.4
CBD-MCC 5%* - 14.8 - -
CBD-MCC 10%* - - 7.4 - -
CBD-cyclodex* - - - 3.0 -
Self-emulsifying* - - - - 1
Total 100 100 100 100 100
Table 10: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. CBD 52%* was prepared according to Example 6. CBD-
MCC 5%* was prepared according to Example 11. CBD-MCC 10%* was prepared
according to Example 11 with a higher amount of CBD. CBD-cyclodex* is CBD-
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cyclodextrin complex prepared according to Example 10 and 25% loaded. Self
emulsibiing* was prepared with a selfemulsifier, here polysorbate.
Example 23
Coating of tableted chewing gum
A hard coating was prepared for selected samples with the following
composition:
Hard coating
Ingredients % by weight
Number CG145 CG146
Maltitol 56.9 56.9
Water 22.7 24.8
Mannitol 11 11
gummi arabicum 4 4
Titandioxid 1 1
Polysorbate 0.1 0.1
CBD 52%* 4.3
CBD isolate* 2.2
Total 100 100
Table 1P: It was secured that CBD was thoroughly mixed into the premixture as
outlined in Example 9. 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 1.35g
tableted chewing gum with the formulation of CG100 in Example 15, except that
CBD 52% or CBD isolate was substituted with isomalt in CG100. Hence, CBD was
not present in the tableted chewing gum, but only in the coating. A total of
10 mg
CBD was present in the coated tablet. The suspension was applied in 3
subsequent
steps according to conventional coating techniques to a total of 0.45 g
coating to the
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1.35g tableted chewing gum. This corresponds to a ratio of tableted chewing
gum to
coating on 75:25.
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 degrees 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%R11 (2 years),
30 C/65%RH (1 year), 40 C/75%RH (3 months). 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 %
5 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
10 Sensorics evaluation test set-up
Apart from release measurements, either in vivo or in vitro, as well as
stability tests
of the tableted chewing gum, sensorics tests were also performed to reveal
very
important characteristics and properties of the tableted chewing gum. These
sensorics
parameters are important as indicators of the structure of the chewing gum
15 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 of preferably 5
samples.
The test set-up was composed of 8 test persons in a test panel. Each of the
test
20 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.
25 The test persons gave a rating from "+" to "+++++", where "+" is poor
and "1++++"
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.
30 Five different parameters were tested in a test panel:
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Initial chew Texture Flavor Sweetness Off-notes
"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
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CG Initial chew Texture Flavor Sweetness Off-notes
CG 100 +++++ +4+-H- +-1-i-+ ++++ ++++
CG 101
CG 102 - + 1 1 1 + +-H-++ ++++ + ++++
CG 103 ++++ +++ -H-+ +-H- ++++
CG 104 +-H-+ ++++ + I + ++++ ++++
CG 105 +++++ +++++ + i I + ++++ ++++
CG 106 +++++ +++++ ++++ +-H-+ ++++ '
CG 107 +++++ -H-+++ -F I I + +-H-+ ++++
CG 108 ++++ +++ +++ -H--F +++
CG 109 +++ -H-++ ++-F+ I I I +++
CG 110 0 0 +-i¨E++ ++4+ -H-+-H-
CG 111 0 0 +-H-+ +++++ -H-+++
CG 112 0 0 +-H-++ +++++ -H-+-H-
CG 113 0 0 ++++ I I ++++
CG 114 0 0 +++++ +-H-+
CG 115 +++++ -HE+++ ++++ -H-++ ++ I I
CG 116 +++++ A¨F+++ ++++ ++++ ++I I
CG 117 -H- ++ + + 1 1 +
CG 118 + + -H- + ++++
CG 119 ++ ++ +++ +++ ++++
CG 120 +++-F -1--H-+ +++ I I +++
CG 121 +++-H- +++++ +-H-+ ++++ +-H-+ -
CG 122 ++++ -H-++ +-H- +++ +++
CG 123 ++1 i + +-F++ ++++ I + ++++
-
CG 124 ++ ++ +++ ++ ++
CG 125 +++ -H-++ I I '
CG 126 ++++ -H-++ ++++ + I I +++
CG 127 ++ I ++ ++-H-+ + I I I -1--H-+
CG 128 +++++ +++++ +++++ ++-F-F-F ++++
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CG 129 ++++ ++++ ++++ +++ +++
CG 130 +++++ -H-+++ +-H-++ +-H-+
CG 131 +++++ +++++ ++++ -H-F+ +-F+
CG 132 +-H-+ -H-++ ++-F+ +++++ ++++
CG 133 ++++ -H-++ ++++ +-H-+ ++++
CG 134 -F-F+++ +++++ +-H-+ I I + ++++
CG 135 ++++ +++-F ++++ ++++ ++++
CG 136 +++++ d¨F+++ +4-1-+ ++++ ++++
CG 137 ++-F+ ++++ -H-F ++++ ++++
CG 138 +++++ +++++ +-F-+ +4-F ++++
CG 139 +++++ +++++ ++++ +++++ -H-+++
CG 140 +++++ I+++ ++-1-+ +-I-1-+ ++++
CG 141 +++++ +++++ I I + ++++ ++++
CG 142 ++++ ++++ +-H-+ +-H-+ ++++
CG 143 + I I + I +++ +-H-++ +-H-+ +++
CG 144 I 1+ -Hh+++ +++++ ++++ +
Table 2A ¨ Evaluation of Examples 14-22 according to Example 28.
Example 30
Release of cannabinoid
CG Number CG100 CG101 CG102 CG103 CG104
3 minutes 39 37 40 34 30
5 minutes 43 42 44 38 36
Table 2B: Chewing gum samples from Example 14 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 (CG103 and CG104). However, the ranges
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89
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
CG Number CG105 CG106 CG107 CG108 CG109
3 minutes 38 39 43 33 31
5 minutes 43 44 45 37 35
Table 2C: Chewing gum samples from Example 15 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
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
CG Number CG115 CG116 CG117 CG118 CG119
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3 minutes 39 37 9 8 16
minutes 43 42 17 16 19
Table 2D: 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).
5 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
Release of cannabinoid
CG Number CG120 CG121 CG122 CG123 CG124
3 minutes 31 39 30 38 10
5 minutes 34 43 35 41 14
Table 2E: 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
tableted
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. With respect
to the
extruded gum reference example (CG124), it is seen that the release properties
were
significantly lower than the examples according to the invention.
Example 34
Release of cannabinoid
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CG Number CG125 CG126 CG127 CG128 CG129
3 minutes 30 35 39 40 44
minutes 34 41 43 46 56
Table 2F: 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 low amount of sugar alcohol in the gum (CG125) has an
effect on the release of cannabinoids and that a higher amount was desirable.
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. It is
noted
that the release properties should be seen in combination with the sensorics
properties.
Example 35
Release of cannabinoid
CG Number CG130 CG131 CG132 CG133 CG134
3 minutes 65 60 48 54 66
5 minutes 68 63 54 58 70
Table 2G: 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).
The result shows that the best release rate was obtained with a formulation of
CG130
and CG134. In these examples, the gum base content was lower than in CG131 and
CG133. When CBD was located in the gum layer, the release was somewhat lower
(CG132).
Example 36
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Release of cannabinoid
CG Number CG135 CG136 CG137 CG138 CG139
3 minutes 37 34 32 71 65
minutes 41 38 33 75 71
Table 211: Chewing gum samples from Example 21 was tested for release after 3
or
5 minutes of in vitro chewing according to the test method of Example 25. The
value
5 indicates weight % of cannabinoid released from the chewing gum sample
(CG).
Generally, a slightly lower release was obtained when the content of gum base
was
increased, both in the two-layered tableted chewing gum and in the three-
layered
tableted chewing gum.
Example 37
Release of cannabinoid
CG Number CG140 CG141 CG142 CG143 CG144
3 minutes 39 17 19 46 49
5 minutes 43 21 25 52 58
Table 21: 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
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Coating with CBD
CG Number CG145 CG146
3 minutes 60 55
minutes 59 61
Table 3A: Chewing gum samples .from Example 23 was tested for release after 3
or
5 minutes of in vitro chewing according to the test method of Example 25. The
value
5 indicates weight % of cannabinoid releasedfrom the chewing gum sample
(CG).
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
tableted
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 tableted chewing gum.
Example 39
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 mm of chewing. From these
values, the content of CBD delivered to the oral mucosa could be calculated.
CG Number CG100 CG101
CBD in saliva 11 9
CBD in residue 57 58
CBD delivered to mucosa 32 33
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=
94
Table 3B: 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.
The results of the tests were very surprising as a major part of the 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 relatively low amount of CBD was found in the saliva. 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 40
CBD delivered to the oral mucosa
Tests were conducted in accordance with the test method of Example 27. The
tests
were performed for CG130 and CG131. The values for the CBD content in saliva
and in the chewing gum residue were measured after 5 mm of chewing. From these
values, the content of CBD delivered to the oral mucosa could be calculated.
CG Number CG130 CG131
CBD in saliva 23 22
CBD in residue 32 34
CBD delivered to mucosa 45 44
Table 3C: Chewing gum samples from Example 20 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 very surprising as a major part of the 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
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,
a relatively low amount of CBD was found in the saliva. 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.
5 Example 41
CBD delivered to the oral mucosa
Tests were conducted in accordance with the test method of Example 27. The
tests
were performed for CG135 and CG136. The values for the CBD content in saliva
and in the chewing gum residue were measured after 5 min of chewing. From
these
10 values, the content of CBD delivered to the oral mucosa could be
calculated.
CG Number CG135 CG136
CBD in saliva 8 7
CBD in residue 59 62
CBD delivered to mucosa 33 31
Table 3D: Chewing gum samples from Example 21 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
15 one or more cannabinoids present in the initial formulation.
The results of the tests were very surprising as a major part of the 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
20 a relatively low amount of CBD was found in the saliva. 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 42
25 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
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96
and in the chewing gum residue were measured after 5 mm of chewing. From these
values, the content of CBD delivered to the oral mucosa could be calculated.
CG Number CG145 CG146
CBD in saliva 28 31
CBD in residue 41 39
CBD delivered to mucosa 31 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. 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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