Note: Descriptions are shown in the official language in which they were submitted.
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CANNABINOID COMPOSITION AND PROCESSES OF MANUFACTURE
Technical Field
[001] The technology relates to compositions comprising a cannabinoid or a
cannabinoid
mixture adsorbed onto at least one mesoporous silica wherein the cannabinoid
mixture
comprises a cannabinoid and a surfactant. Preferably the composition is in the
form of a
free flowing powder.
Background
[002] Cannabinoids are compounds derived from Cannabis sativa, an annual plant
in the
Cannabaceae family. The plant contains over 100 cannabinoids. The most active
naturally
occurring cannabinoid is tetrahydrocannabinol (THC), which is used for the
treatment of a
wide range of medical conditions, including glaucoma, AIDS wasting,
neuropathic pain,
treatment of spasticity associated with multiple sclerosis, fibromyalgia and
chemotherapy-
induced nausea. Additionally, THC has been reported to exhibit a therapeutic
effect in the
treatment of allergies, inflammation, infection, epilepsy, depression,
migraine, bipolar
disorders, anxiety disorder, and drug dependency and withdrawal syndromes. THC
is
particularly effective as an anti-emetic drug and is administered to curb
emesis, a common
side effect accompanying the use of opioid analgesics and anaesthetics, highly
active anti-
retroviral therapy and cancer chemotherapy.
[003] Because of their hydrophobic nature, cannabinoids are poorly absorbed
systemically
from oral dosage forms in the aqueous environment of the gastrointestinal
tract, and simple
oral formulations of cannabinoids, therefore, tend to exhibit low
bioavailability.
[004] The physicochemical properties of cannabinoids, such as high
lipophilicity, low
aqueous solubility, high viscosity, and sensitivity to light and oxygen,
present unique
product formulation challenges. For example, at room temperature, these
materials can be
solids or viscous liquids, with the resinous or crystalline behavior depending
on the
particular cannabinoid, its purity, and extraction and isolation methods.
Oily, viscous liquids
can be particularly troublesome to formulate, process, and handle.
[005] The primary solubility-enhancing technologies currently applied in the
cannabis
industry are self nano-emulsifying drug delivery technologies (SNEDDS),
cyclodextrins, and
liposomes. However, these technologies suffer from the disadvantage that novel
or high
amount of excipients are needed for solubilization and stabilization of a
cannabinoid.
[006] There is a need for processes for formulating liquid, semisolid and
highly viscous
materials, such as cannabinoids, into free-flowing powders.
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[007] The present inventors have developed a cannabinoid composition that
exists as a
free-flowing powder at room temperature. Advantageously, the compositions may
improve
ease of processing and flexibility for further formulation and process
development. A further
advantage of the composition is that they may increase the aqueous dissolution
rate of the
cannabinoid. The cannabinoid compositions may also enable the dissolution rate
of the
cannabinoid to be controlled by varying the amount or proportion of one or
more of the
constituents in the composition.
Summary
[008] In a first aspect, there is provided a powder composition comprising a
cannabinoid
or a cannabinoid mixture adsorbed onto at least one mesoporous silica wherein
the
cannabinoid mixture comprises a cannabinoid and a surfactant.
[009] The cannabinoid may be selected from the group consisting of a plant
extract,
cannabigerolic acid (CBGA); cannabigerolic acid monomethylether (CBGAM),
cannabigerol
(CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA),
cannabichromevarin (CBCV), cannabichromenic acid (CBCA) cannabichromene (CBC),
cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethyl ether
(CBDM),
cannabidiol-04 (CBD-D4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV),
cannabidiorcol (CBD-D1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-
9-
tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinol (D9-THC),
delta-9-
tetrahydrocannabinolic acid 04 (THCA-04), delta-9-tetrahydrocannabinol-04 (THC-
04),
delta-9-tetrahydrocannabivarinic acid (THCVA), delta-9-tetrahydrocannabivarin
(THCV),
delta-9-tetrahydrocannabiorcolic acid (THCA-C1), ), delta-9-
tetrahydrocannabiorcol (THC-
C1), delta-7-cis-iso-tetrahydrocannabivarin (D7-THCV), delta-8-
tetrahydrocannabinolic (D8-
THCA), delta-8-tetrahydrocannabinol (D8-THC), cannabicycloic acid (CBLA),
cannabicyclol
(CBL), cannabicyclovairn (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic
acid B
(CBEA-B), cannabielsoin (CBE), cannabinolic acid (CBNA), cannabinol (CBN),
cannabinol
methylether (CBNM), cannabinol-04 (CBN-04), cannabinol-02 (CBN-02),
cannabivarin
(CBV), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabinodivarin (CBVD),
cannabitriol (CBT), 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-
dihydroxy-
delta-6a-tetrahydrocannabinol, cannabitriolvarin (CBTV), ethoxy-
cannabitriolvarin (CBTVE),
dehydrocannabifuran (DCBG), cannabifuran (CBF), cannabichromanon (CBCN),
cannabicitran (CBT), 10-oxo-delta-6a-tetrahydrocannabinol (OTHC), delta-9-cis-
tetrahydrocannabinol (cis-THC), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-
trimethy1-9-n-
propy1-2,6-methano-2H-1-benzoxoxin-5-methanol (OH-iso-HHCV), cannabiripsol
(CBR),
and trihydroxy-delta-9-tetrahydrocannabinol (tri0H-THC).
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[010] In one embodiment the cannabinoid is delta-9-THC or delta-8-THC.
[011] The surfactant may be an anionic, cationic, or zwitterionic surfactant.
In one
embodiment the surfactant is an anionic surfactant. In a preferred embodiment,
the anionic
surfactant may be sodium lauryl sulfate.
[012] In one embodiment, the concentration of the surfactant in the
composition is from
about 0.1% to about 35% (w/w).
[013] The composition may further comprise a terpene or terpenoid.
[014] The cannabinoid or cannabinoid mixture may comprise a diluent. The ratio
of
diluent:cannabinoid may be about 50:1 to about 1:50.
[015] In some embodiments the diluent may be a plant-based oil such as a
vegetable oil.
[016] The mesoporous silica may be ordered mesoporous silica or disordered
mesoporous silica.
[017] In some embodiments the mesoporous silica has an average pore volume of
about
0.50 cm3/g to about 10 cm3/g. The mesoporous silica may have an average pore
size of
about 2nm to about 50nm.
[018] In some embodiments the mesoporous silica may be a mesoporous silica
particle.
The mesoporous silica particles have an average particle size diameter of
between about 2
pm to at least about 250 pm, for example the average diameter may be about 2
pm, about
pm, about 25 pm, about 50 pm, about 75 pm, about 100 pm, about 125 pm, about
150
pm, about 175 pm, about 200 pm, about 225 pm, or at least about 250 pm.
[019] The ratio of surfactant:mesoporous silica may be from about 1:5 to about
1:50. In
one embodiment the ratio of surfactant:mesoporous silica may be from about
1:25 to about
1:35, for example about 1:29.
[020] In one embodiment, the composition is a flowable powder.
[021] In one embodiment the composition comprises a blend of two or more
mesoporous
silica.
[022] In a second aspect there is provided a formulation comprising an
effective amount of
the composition of the first aspect and at least one carrier, diluent or
excipient. The
excipient may be one or more of microcrystalline cellulose, croscarmellose
sodium, and
magnesium stearate. In preferred embodiments the formulation is a
pharmaceutically
acceptable formulation.
[023] In a third aspect there is provided a process of preparing the
composition of the first
aspect, comprising
a) heating the cannabinoid;
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b) mixing the cannabinoid and the mesoporous silica, wherein the cannabinoid
adsorbs to the mesoporous silica.
[024] In one embodiment step b) further comprises mixing the cannabinoid with
the
surfactant wherein the cannabinoid and the surfactant form a cannabinoid
mixture that
adsorbs to the mesoporous silica.
[025] In a fourth aspect there is provided a process of preparing the
composition of the
first aspect, comprising
a) heating the cannabinoid;
b) mixing the cannabinoid with the surfactant wherein the cannabinoid and the
surfactant form a cannabinoid mixture;
c) mixing the cannabinoid mixture and the mesoporous silica, wherein the
cannabinoid mixture adsorbs to the mesoporous silica.
[026] In a fifth aspect there is provided a process of preparing the
composition of the first
aspect, comprising
a) heating the surfactant;
b) mixing the cannabinoid with the surfactant wherein the cannabinoid and the
surfactant form a cannabinoid mixture;
c) mixing the cannabinoid mixture and the mesoporous silica, wherein the
cannabinoid mixture adsorbs to the mesoporous silica.
[027] In a sixth aspect there is provided a process of preparing the
composition of the first
aspect, comprising
a) mixing the cannabinoid with the surfactant wherein the cannabinoid and the
surfactant form a cannabinoid mixture;
b) heating the cannabinoid mixture;
c) mixing the cannabinoid mixture and the mesoporous silica, wherein the
cannabinoid mixture adsorbs to the mesoporous silica.
[028] In embodiments, the cannabinoid or cannabinoid mixture is heated to a
temperature
that increases fluidity or decreases viscosity. For example the cannabinoid or
cannabinoid
mixture may be heated to a temperature up to about 100 C.
[029] In embodiments where the cannabinoid is crystalline at room temperature,
it is
heated above its melting temperature. For example the cannabinoid may be
heated to
about 20 C above its melting temperature.
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[030] In embodiments where the cannabinoid is resinous at room temperature, it
is heated
above its glass transition temperature. For example the cannabinoid may be
heated to
about 20 C above its glass transition temperature.
[031] The process may further comprise the step of stirring the cannabinoid or
cannabinoid mixture and the mesoporous silica.
[032] In a seventh aspect there is provided a food, beverage or cosmetic
product
comprising the composition of the first aspect.
[033] In an eighth aspect there is provided a method of treatment of a disease
or condition
responsive to a cannabinoid, the method comprising administering to the
subject an
effective amount of a composition of the first aspect or a formulation of the
second aspect.
[034] In a ninth aspect there is provided use of a composition of the first
aspect for the
manufacture of a medicament for treatment of a disease or condition responsive
to a
cannabinoid.
[035] In a tenth aspect there is provided a composition of the first aspect
for use in
treatment of a disease or condition responsive to a cannabinoid.
[036] The disease or condition may be selected from the group comprising pain,
spasticity
associated with multiple sclerosis, nausea, posttraumatic stress disorder,
cancer, epilepsy,
cachexia, glaucoma, HIV/AIDS, degenerative neurological conditions, anorexia
and weight
loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity,
Tourette syndrome,
amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease,
dystonia,
dementia, glaucoma, traumatic brain injury, addiction, anxiety, depression,
sleep disorders,
posttraumatic stress disorder, and schizophrenia.
Definitions
[037] Throughout this specification, unless the context clearly requires
otherwise, the word
"comprise", or variations such as "comprises" or "comprising", will be
understood to imply
the inclusion of a stated element, integer or step, or group of elements,
integers or steps,
but not the exclusion of any other element, integer or step, or group of
elements, integers or
steps.
[038] Throughout this specification, the term 'consisting of' means consisting
only of.
[039] Throughout this specification, the term 'consisting essentially of'
means the inclusion
of the stated element(s), integer(s) or step(s), but other element(s),
integer(s) or step(s) that
do not materially alter or contribute to the working of the invention may also
be included.
[040] Any discussion of documents, acts, materials, devices, articles or the
like which has
been included in the present specification is solely for the purpose of
providing a context for
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the present technology. It is not to be taken as an admission that any or all
of these matters
form part of the prior art base or were common general knowledge in the field
relevant to
the present technology as it existed before the priority date of each claim of
this
specification.
[041] Unless the context requires otherwise or specifically stated to the
contrary, integers,
steps, or elements of the technology recited herein as singular integers,
steps or elements
clearly encompass both singular and plural forms of the recited integers,
steps or elements.
[042] In the context of the present specification the terms 'a' and 'an' are
used to refer to
one or more than one (i.e., at least one) of the grammatical object of the
article. By way of
example, reference to 'an element' means one element, or more than one
element.
[043] In the context of the present specification the term 'about' means that
reference to a
figure or value is not to be taken as an absolute figure or value, but
includes margins of
variation above or below the figure or value in line with what a skilled
person would
understand according to the art, including within typical margins of error or
instrument
limitation. In other words, use of the term 'about' is understood to refer to
a range or
approximation that a person or skilled in the art would consider to be
equivalent to a recited
value in the context of achieving the same function or result.
[044] Those skilled in the art will appreciate that the technology described
herein is
susceptible to variations and modifications other than those specifically
described. It is to
be understood that the technology includes all such variations and
modifications. For the
avoidance of doubt, the technology also includes all of the steps, features,
and compounds
referred to or indicated in this specification, individually or collectively,
and any and all
combinations of any two or more of said steps, features and compounds.
[045] The term 'effective amount' refers to an amount of a cannabinoid
sufficient to
produce a desired therapeutic, pharmacological, or physiological effect in the
subject being
treated. The term is intended to qualify the amount of the cannabinoid that
will achieve the
goal of improvement in disease severity and/or the frequency of incidence over
treatment of
each agent by itself while preferably avoiding or minimizing adverse side
effects. Those
skilled in the art can determine an effective dose using information and
routine methods
known in the art.
[046] As used herein the terms 'adsorbed', 'adsorbed to', 'adsorbed onto' and
'adsorbed'
are equivalent and are used interchangeably. In one or more embodiments,
adsorption may
comprise the cannabinoid mixture being adsorbed into the volume or bulk of the
mesoporous silica. In other embodiments, adsorption of the cannabinoid mixture
to the
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surface of the mesoporous silica may be by way of intermolecular forces
between the
cannabinoid mixture and the mesoporous silica.
[047] A 'carrier, diluent or excipient' includes, but is not limited to, any
medium comprising
a suitable water soluble organic carrier, conventional solvents, oil,
hydrophobic diluent,
dispersion media, fillers, solid carriers, coatings, antibacterial and
antifungal agents, isotonic
and absorption delaying agents. Suitable water-soluble organic carriers
include, but are not
limited to, saline, dextrose, corn oil, dimethylsulfoxide, and gelatin or
hydroxypropylmethylcellulose capsules. Other conventional additives include
lactose,
mannitol, corn starch, potato starch, binders such as microcrystalline
cellulose, cellulose
derivatives such as hydroxypropylmethylcellulose, acacia, gelatins,
disintegrators such as
sodium carboxymethylcellulose, and lubricants such as talc or magnesium
stearate.
[048] 'Subject' includes any human or non-human mammal. Thus, in addition to
being
useful for human treatment, the compounds of the present invention may also be
useful for
veterinary treatment of mammals, including companion animals and farm animals,
such as,
but not limited to dogs, cats, horses, cows, sheep, and pigs. In preferred
embodiments the
subject is a human.
[049] In the context of this specification the term 'administering' and
variations of that term
including 'administer' and 'administration', includes contacting, applying,
delivering or
providing a compound or composition of the invention to a subject by any
appropriate
means.
Description of Embodiments
[050] The compositions disclosed herein comprise a mixture of a cannabinoid
(either
purified or as part of a plant extract) and a surfactant which is adsorbed
onto a mesoporous
silica. In some embodiments the compositions disclosed herein comprise a
cannabinoid
(either purified or as part of a plant extract) which is adsorbed onto a
mesoporous silica.
[051] The technology described herein can provide any one or more of a number
of
advantages. For example, in some embodiments the technology is capable of
achieving a
higher cannabinoid load compared to other solubility enhancing technologies,
due to the
high specific surface area (-- 700 m2/g) and large pore volume (-- 1 cm3/g) of
the
mesoporous silica. In some embodiments described herein, the interaction
between the
mesoporous silica and the cannabinoid mixture is not critical for loading and
stability,
making the technology suitable for a wide range of cannabinoids and plant
extracts
containing cannabinoids.
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Mesoporous Silica
[052] Mesoporous silica is a solid, highly porous material. The nanometer-
scale pores
result in extremely high specific surface areas. As described herein,
adsorption of a mixture
of a cannabinoid or cannabis extract and a surfactant on mesoporous silica
converts a
viscous liquid into a free-flowing powder due to the extremely high specific
surface area of
the silica structure. This improves the flow properties when compared to that
of the
cannabinoid or cannabis extract alone and is advantageous due to ease of
processing for
downstream development. In addition to its process improvement capabilities,
mesoporous
silica can enhance the aqueous solubility of cannabinoids, especially for
cannabinoids that
are crystalline at room temperature. In particular, the crystal structure is
disrupted and the
amorphous form of the drug is confined in the pore structure. This results in
a higher
apparent solubility and dissolution rate when compared to the crystalline
form.
[053] Although the solubility of resinous cannabinoids is enhanced due to the
distribution
of the drug across the large specific surface area of the mesoporous silica,
the incorporation
of solubility enhancing excipients may further enhance the dissolution rate
and solubility of
the cannabinoid. Accordingly, a further advantage of embodiments of the
technology is that
may be used to control and modify the release rate of cannabinoid compounds,
which is a
key attribute for obtaining desired drug release properties. In one
embodiment, release rate
may be controlled or modified based on pore size. In other embodiments, the
choice of
surfactant can be used to modify release rate.
[054] Mesoporous silica exhibits excellent thermostability properties, making
it an
excellent material to preserve the physicochemical stability of the cannabis
extract during
processing and storage, which is especially beneficial for cannabis extracts
comprising
volatile terpenes and terpenoids. In particular, adsorption of the cannabinoid
mixture onto
mesoporous silica reduces the volatility of the terpenes and terpenoids,
thereby reducing
evaporative losses of these compounds. Moreover, mesoporous silica is
biologically inert
and biocompatible. This is in contrast to alternative technologies that use
cyclodextrins,
novel excipients or large amounts of excipients to solubilise and stabilise an
active (e.g.
SNEDDS, solid dispersions).
[055] Any of several variants of mesoporous silica can be used to prepare the
compositions of the invention. Pharmaceutical grade mesoporous silica is
typically prepared
by a sol-gel process, producing either a disordered mesoporous structure (DMS)
or ordered
mesoporous structure (OMS) pore structure. Both are available in a wide range
of particle
sizes, specific surface areas, and pore volumes, making them applicable for a
variety of
cannabinoids and drug delivery approaches. DMS is commercially available and
used in the
pharmaceutical, cosmetic, food, and beverage industries for a wide variety of
applications.
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[056] DMS is commercially available and is comprised of a coherent and rigid
network of
continuous pores. DMS may be manufactured by any known means. In some
embodiments,
DMS may be synthesized via sol-gel chemistry where the particle
characteristics are
produced into this highly porous material.
[057] Ordered Mesoporous Silicas (OMS) were first synthesized as molecular
sieves and
are now applied to a variety of fields such as adsorption, chromatography,
catalysis, and
optics. As with DMS, the mesopore structure is synthesized via sol-gel
synthesis but utilizes
a template such as surfactant or polymeric micelles to control pore structure.
After the silica
is polymerized, the template is removed, leading to its porosity and narrow
pore size
distribution. It should be noted that they are referred to as "ordered"
despite their
amorphous walls. Examples of OMS material types are MCM-41 and SBA-15, which
form a
hexagonal porous structure.
[058] Silica is "Generally Recognized As Safe" by the United States Food and
Drug
Administration (FDA). Recently, silica nanoparticles in the form of Cornell
dots (C dots)
received FDA approval for a Phase I human clinical trial for targeted
molecular imaging. It
was reported that mesoporous silica exhibited a three-stage degradation
behavior in
simulated body fluid, suggesting that MSNs might degrade after administration,
which is
favorable for cargo release. Several in vivo biodistribution studies of MSNs
have been
reported. One study evaluated the systematic toxicity of MSNs after
intravenous injection of
single and repeated dose to mice. The results of clinical features,
pathological
examinations, mortalities, and blood biochemical indices indicated low in vivo
toxicity of
MSNs. It was also reported that MSNs were mainly excreted through feces and
urine
following different administration routes.
[059] According to the International Union of Pure and Applied Chemistry (I
UPAC), pore
sizes in mesoporous silica are in the range of 2-50 nm and an ordered
arrangement of
pores. The pore size of the mesoporous silica can be controlled during
production. The pore
volume may be about 0.5 cm3/g, 1 cm3/g, 2 cm3/g, 3 cm3/g, 4 cm3/g, 5 cm3/g, 6
cm3/g, 7
cm3/g, 8 cm3/g, 9 cm3/g, or about 10 cm3/g. In some embodiments, the pore
volume is
around 2 cm3/g when the pore size is less than 15 nm and surface area is about
1000 m2/g.
[060] The interaction of cannabinoid with mesopores is a surface phenomenon.
The
amount of cannabinoid mixture adsorbed can be determined by changes in pore
volume. In
ordered mesoporous material, many consecutive loadings of the cannabinoid
mixture can
result in almost complete filling of mesopores, indicating that the amount of
cannabinoid is
directly proportional to pore volume. That is, while a greater pore volume
will enable a
greater cannabinoid loading, the remaining pore volume will decrease with the
amount of
drug loaded.
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[061] For both DMS and OMS the surface area of the mesoporous silica is a
determining
factor for the quantity of adsorbed cannabinoids, although it is believed that
surface
chemistry may also be influential. To control the amount of incorporated
cannabinoid
mixture in the matrix, two different approaches are used, namely modifying
(increasing or
decreasing) the surface area and modifying the affinity of the surface for the
cannabinoid.
The amount of cannabinoid mixture (or other drug) adsorbed is directly
proportional to
specific surface area. For example, MCM-41 is synthesized by specific surface
area (SBET
value) 1157 m2g-1 and SBA-15 with specific surface area value of 719 m2g-1.
For example,
when alendronate is loaded in mesoporous silica particles under same
conditions, 139
mg.g-1 of drug is loaded in MCM-41 while 83 mg.g-1 in SBA-15. This indicates
that specific
surface area value is closely related to the maximum loading of the drug.
[062] In some embodiments the mesoporous silica is a particle having an
average
diameter from 2 ¨ 250 pm.
[063] The mesoporous silica particles may have an average diameter of between
about 2
pm to at least about 250 pm, for example the average diameter may be about 2
pm, about
10 pm, about 25 pm, about 50 pm, about 75 pm, about 100 pm, about 125 pm,
about 150
pm, about 175 pm, about 200 pm, about 225 pm, or at least about 250 pm.
[064] The structural characteristics of some mesoporous silica suitable for
use in the
invention are listed in Table 1.
Table 1: Characteristics of selected mesoporous silica
Pore Size Pore Volume
Name Pore Symmetry
(nm) (cm3ig)
MCM-41 2D hexagonal P6mm 1.5-8 >1,0
MCM-48 30 cubicla3d 2-5 >1.0
MCM-50 Lamellar p2 2-5 >1.0
SBA-11 3D cubic Pm3m 2.1-3.6 0.68
3D hexagonal
SBA-12 3,1 0.83
P631mrnc
SBA-15 20 hexagonal p6mm 6-12 1.17
SBA-16 Cubic Irn3m 5-15 0.91
KIT-5 Cubic Fm3m 9,3 0.45
COK-12 2D Hexagonal P6mm 6-12 1.17
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[065] Other mesoporous silicas may be used in the compositions and
formulations of the
invention, including for example FSM-16, which has folded sheets of mesoporous
materials.
Various other commercially available mesoporous silica products can be used
including
those developed by Technical Delft University (TUD-1), Hiroshima Mesoporous
Material-33
(HMM-33), Centrum voor Oppervlaktechemie en Katalyse/Centre for Research
Chemistry
and Catalysis (COK-12), all of which vary in their pore symmetry and shape.
[066] In some embodiments SYLOID 63FP/AL-1, SYLOID 72FP SYLOID 244FP,
SYLOI DO XDP 3050, SYLOI DO XDP 3150, may also be used. In a preferred
embodiment
the mesoporous silica is SYLOID 3050 XDP. The characteristics of the Syloid
mesoporous silicas are presented in Table 2.
Table 2: Syloide silica
Property SYLOID SYLOID SYLOID SYLOID SYLOID
63FP/AL-1 72FP 244FP XDP 3050 XDP
3150
Avg particle 7.5 6.0 3.5 50 150
size (pm)
Avg Pore 0.4 1.2 1.6 1.7 1.7
Volume
(cm3/g)
[067] In other embodiments fumed silica (such as Aeropearle by evonik) and
magnesium
aluminium silica (for example Neuseline) may be used.
Cannabinoids
[068] The cannabinoid can be synthetic or a naturally occurring cannabinoid
derived from
a plant. Typically, the plant is of the genus Cannabis. Cannabinoids that
occur in other plant
genera can also be used in the formulations. For example, cannabinoids derived
from
plants of the genera Echinacea, Acme/la, Helichiysum, and Radula can be used
in the
compositions. For example, the lipophilic alkamides (alkylamides) from
Echinacea species
including the cis/trans isomers dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-
isobutylamide can
be used. Other suitable cannabinoids include beta-caryophyllene and
anandamide.
[069] Cannabinoid compounds suitable for use in the invention include, but are
not limited
to, tetrahydrocannabinoids, their precursors, alkyl (particularly propyl)
analogues,
cannabidiols, their precursors, alkyl (particularly propyl) analogues,
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[070] The cannabinoid may be selected from the group consisting of:
cannabigerolic acid
(CBGA); cannabigerolic acid monomethyl ether (CBGAM), cannabigerol (CBG),
cannabigerol monomethyl ether (CBGM), cannabigerovarinic acid (CBGVA),
cannabichromevarin (CBCV), cannabichromenic acid (CBCA) cannabichromene (CBC),
cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethyl ether
(CBDM),
cannabidiol-04 (CBD-D4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV),
cannabidiorcol (CBD-D1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-
9-
tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinol (D9-THC),
delta-9-
tetrahydrocannabinolic acid 04 (THCA-04), delta-9-tetrahydrocannabinol-04 (THC-
04),
delta-9-tetrahydrocannabivarinic acid (THCVA), delta-9-tetrahydrocannabivarin
(THCV),
delta-9-tetrahydrocannabiorcolic acid (THCA-C1), ), delta-9-
tetrahydrocannabiorcol (THC-
C1), delta-7-cis-iso-tetrahydrocannabivarin (D7-THCV), delta-8-
tetrahydrocannabinolic (D8-
THCA), delta-8-tetrahydrocannabinol (D8-THC), cannabicycloic acid (CBLA),
cannabicyclol
(CBL), cannabicyclovairn (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic
acid B
(CBEA-B), cannabielsoin (CBE), cannabinolic acid (CBNA), cannabinol (CBN),
cannabinol
methylether (CBNM), cannabinol-04 (CBN-04), cannabinol-02 (CBN-02),
cannabivarin
(CBV), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabinodivarin (CBVD),
cannabitriol (CBT), 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-
dihydroxy-
delta-6a-tetrahydrocannabinol, cannabitriolvarin (CBTV), ethoxy-
cannabitriolvarin (CBTVE),
dehydrocannabifuran (DCBG), cannabifuran (CBF), cannabichromanon (CBCN),
cannabicitran (CBT), 10-oxo-delta-6a-tetrahydrocannabinol (OTHC), delta-9-cis-
tetrahydrocannabinol (cis-THC), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-
trimethy1-9-n-
propy1-2,6-methano-2H-1-benzoxoxin-5-methanol (OH-iso-HHCV), cannabiripsol
(CBR),
and trihydroxy-delta-9-tetrahydrocannabinol (tri0H-THC), cannabichromene,
cannabichromene propyl analogue, ajulemic acid, cannabinor, and any
combination of two
or more of these cannabinoids.
[071] In some embodiments the cannabinoid may be present in an extract of a
plant.
Accordingly, 'cannabinoid mixtures' as used herein includes mixtures
containing two or more
cannabinoids, including plant extracts comprising a mixture of two or more
cannabinoids. For
example the silicas may be two different types of silica(e.g. Syloid 244 and
Syloid 3050) or
two or more portions of the same type of silica each with a different particle
size distribution.
[072] Plant extracts containing cannabinoids may also contain one or more
terpenes and/or
terpenoids. For example the plant extracts may contain a terpene selected from
the group
comprising t-carophyllene, myrcene, a-humulene, a-pinene, a-bisabolol, p-
pinene, limonene,
ocimene and/or terpinolene, guaiol, a-terpineol, and terpinolene, linalool,
fenchol, guaiene,
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and 3-careen. Accordingly, 'cannabinoid mixtures' as used herein may contain
one or more
terpenes.
[073] The cannabinoid or cannabinoid mixture may be present in any amount
suitable for
a desired application. For example, the cannabinoid or plant extract
containing the
cannabinoid may be present in an amount ranging from less than about 1% to
about 90
weight %, relative to the weight of the composition. A higher or lower
concentration of the
cannabinoid mixture may be used, and the concentration may vary within the
aforementioned range. For example, the cannabinoid may be present in an amount
ranging
from about 0.01 % to about 50%, about 1 % to about 50%, about 2 to about 5%,
about 5%
to about 10%, about 10 % to about 20%, about 20 % to about 30%, about 30 % to
about
40%, or about 40 % to about 50% by weight of the formulation. In some
embodiments, the
cannabinoid may be present in an amount ranging from about 25% to about 30%,
about
30% to about 35%, or about 35% to about 40% by weight of the formulation. In
some
embodiments a desired amount of cannabinoid or cannabinoid mixture may be
achieved by
repeatedly loading the mesoporous silica with the cannabinoid or the
cannabinoid mixture.
Surfactants
[074] In some embodiments the compositions of the invention comprise a
surfactant to
improve loading of the cannabinoid onto the mesoporous silica. The surfactant
also facilitates
improved desorption of the cannabinoid from the mesoporous silica into aqueous
solution
and/or desorption of the cannabinoid. In some embodiments, the cannabinoid and
the
surfactant are mixed to form a cannabinoid mixture prior to adsorption
(loading) on to a
mesoporous silica. In other embodiments, the cannabinoid, surfactant and the
mesoporous
silica are mixed together and the cannabinoid mixture forms concomitantly with
loading.
[075] Surfactants play important roles in the compositions. First, a
surfactant lowers the
surface tension of a liquid. This facilitates loading solution-based drugs
into nano-sized pores.
Second, through reduction of surface tension, surfactants facilitate (in vivo)
wetting of the
finished dosage form. This is an important step in dissolution of the drug and
helps increase
the delivery of the drug from the dosage form.
[076] In some embodiments the surfactant is an anionic surfactant. Suitable
anionic
surfactants include alkyl sulfonates, aryl sulfonates, alkyl phosphates, alkyl
phosphonates,
potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl
polyoxyethylene
sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidic acid
and their salts,
sodium carboxymethylcellulose, bile acids and their salts, cholic acid,
deoxycholic acid,
glycocholic acid, taurocholic acid, and glycodeoxycholic acid, and calcium
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carboxymethylcellulose, stearic acid and its salts, (e.g., calcium stearate),
phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose
sodium,
dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid,
diethanolamine lauryl
sulfate, sodium lauryl sulfate and phospholipids. A preferred surfactant is
sodium lauryl
sulfate or sodium dodecylsulfate.
[077] In some embodiments the surfactant is a cationic surfactant. Suitable
cationic
surfactants include quaternary ammonium compounds, benzalkonium chloride,
cetyltrimethylammonium bromide, chitosans, lauryldimethylbenzylammonium
chloride, acyl
carnitine hydrochlorides, alkyl pyridinium halides, cetyl pyridinium chloride,
cationic lipids,
polymethylmethacrylate trimethylanmonium bromide,
sulfonium compounds,
polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate,
hexadecyltrimethyl
ammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl-
di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride,
coconut
trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride,
coconut
methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl
hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride
bromide,
012-15-dimethyl hydroxyethyl ammonium chloride, C12-15-dimethyl hydroxyethyl
ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride,
coconut
dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl
sulfate,
lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium
bromide, lauryl
dimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium
bromide,
N-alkyl (012-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)dimethyl-
benzyl
ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate,
dimethyl
didecyl ammonium chloride, N-alkyl and (012-14) dimethyl 1-napthylmethyl
ammonium
chloride, trimethylammonium halide alkyl-
trimethylammonium salts, dialkyl-
dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salts, ethoxylated trialkyl ammonium salts,
dialkylbenzene
dialkylammonium chloride, N-didecyldimethyl ammonium
chloride, N-
tetradecyldimethylbenzyl ammonium chloride monohydrate, N-alkyl(012-14)
dimethyl 1-
naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride,
dialkyl
benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride,
alkylbenzyl methyl
ammonium chloride, alkyl benzyl dimethyl ammonium bromide, 012 trimethyl
ammonium
bromides, C15trimethyl ammonium bromides, 017 trimethyl ammonium bromides,
dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium
chloride
(DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides,
tricetyl
methyl ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium
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bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium
chloride,
"POLYQUAT 10" (a mixture of polymeric quartenary ammonium compounds),
tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters,
benzalkonium chloride, stearalkonium chloride, cetyl pyridinium bromide, cetyl
pyridinium
chloride, halide salts of quaternized polyoxyethylalkylamines, "MIRAPOL,"
(polyquaternium-
2) "ALKAQUAT", alkyl pyridinium salts, amines, amine salts, imide azolinium
salts, protonated
quaternary acrylamides, methylated quaternary polymers, and cationic guar gum,
benzalkonium chloride, dodecyl trimethyl ammonium bromide, triethanolamine,
and
poloxamines.
[078] In some embodiments the surfactant is a nonionic surfactant. Suitable
nonionic
surfactants include polyoxyethylene fatty alcohol ethers, polyoxyethylene
sorbitan fatty acid
esters, polyoxyethylene fatty acid esters, sorbitan esters, glyceryl esters,
glycerol
monostearate, polyethylene glycols, polypropylene glycols, polypropylene
glycol esters, cetyl
alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols,
polyoxyethylene-
polyoxypropylene copolymers, poloxamers, poloxamines, methylcellulose,
hydroxycellulose,
hydroxymethylcellulose, hydroxypropylcellulose,
hydroxypropylinethylcellulose,
noncrystalline cellulose, polysaccharides, starch, starch derivatives,
hydroxyethylstarch,
polyvinyl alcohol, polyvinylpyrrolidone, triethanolamine stearate, amine
oxides, dextran,
glycerol, gum acacia, cholesterol, tragacanth, glycerol monostearate,
cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers,
polyoxyethylene
castor oil derivatives, polyoxyethylene sorbitan fatty acid esters,
polyethylene glycols,
polyoxyethylene stearates, hydroxypropyl celluloses, hydroxypropyl
methylcellulose,
methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose phthalate,
noncrystalline cellulose, polyvinyl alcohol,
polyvinylpyrrolidone, 4-(1, 1,3,3-
tetramethylbutyl)phenol polymer with ethylene oxide and formaldehyde,
poloxamers, alkyl
aryl polyether sulfonates, mixtures of sucrose stearate and sucrose
distearate,
018H370H20(0)N(CH3)CH2(CHOH)4(CH2OH)2, p-isononylphenoxypoly(glycidol),
decanoyl-N-
methylglucam ide, n-decy1-8-D-glucopyranoside, n-decy1-8-D-maltopyranoside, n-
dodecy1-8-
D-glucopyranoside, n-dodecy1-8-D-maltoside, heptanoyl-N-methylglucamide, n-
hepty1-8-D-
glucopy-ranoside, n-hepty1-8-D-thioglucoside, n-hexy1-8-D-glucopyranoside;
nonanoyl-N-
methylglucamide, n-nony1-8-D-glucopyranoside, octanoyl-N-methylglucamide, n-
octy1-8-D-
glucopyranoside, octy1-8-D-thioglucopyranoside, PEG-cholesterol, PEG-
cholesterol
derivatives, PEG-vitamin A, PEG-vitamin E, and random copolymers of vinyl
acetate and vinyl
pyrrolidone.
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[079] In some embodiments the surfactant is a zwitterionic surfactant.
Suitable zwitterionic
surfactants include zwitterionic phospholipids, for example
phosphatidylcholine,
phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine (such as
dimyristoyl-
glycero-phosphoethanolamine (DMPE), dipalmitoyl-glycero-phosphoethanolamine
(DPPE),
distearoyl-glycero-phosphoethanolamine (DSPE), and
dioleolyl-glycero-
phosphoethanolamine (DOPE)). Mixtures of phospholipids that include anionic
and
zwitterionic phospholipids may be employed in this invention. Such mixtures
include but are
not limited to lysophospholipids, egg or soybean phospholipid or any
combination thereof.
[080] In preferred embodiments the surfactant is sodium lauryl sulfate.
[081] The ratio of surfactant:mesoporous silica can be used to modulate
adsorption of the
cannabinoid onto the mesoporous silica. Similarly, the ratio of
surfactant:mesoporous silica
can be used to modulate desorption of the cannabinoid.
[082] In some embodiments, the ratio of surfactant:cannabinoid is between
about 1:1 to
about 1:50. For example the ratio may be about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10,
1:11, 1:12, 1:13,
1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26,
1:27, 1:28, 1:29,
1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42,
1:43, 1:44, 1:45,
1:46, 1:47, 1:48, 1:49, or about 1:50.
[083] In one embodiment, the mass ratio of surfactant:mesoporous silica is
from about 1:25
to about 1:35, for example 1:29 which in an exemplary formulation corresponds
to about 1.5%
w/w surfactant and about 43% (w/w) mesoporous silica.
[084] In preferred embodiments, the mass ratio of surfactant:mesoporous silica
is about
1:29.
Diluents
[085] The cannabinoid may be diluted with a suitable diluent. Dilution may be
desired for
example to achieve a desired dosage of the cannabinoid in the composition or
to facilitate
ease of handling of the cannabinoid prior to incorporation into the
composition. Alternatively
or in addition, dilution may be used to impart other desirable characteristics
such as flavour
or aroma to the composition. Alternatively or in addition dilution may be used
to mask
undesirable taste or smell.
[086] In some embodiments, the ratio of diluent:cannabinoid is between about
1:1 to about
1:50. For example the ratio may be about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7,
1:8, 1:9, 1:10,
1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23,
1:24, 1:25, 1:26,
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1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39,
1:40, 1:41, 1:42,
1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, or about 1:50.
[087] In other embodiments the ratio of diluent:cannabinoid is between about
50:1 to
about 1:1. For example the ratio may be about 50:1, 1:49, 1:48, 1:47, 1:46,
1:45, 1:44, 1:43,
1:42, 1:41, 1:40, 1:39, 1:38, 1:37, 1:36, 1:35, 1:34, 1:33, 1:32, 1:31, 1:30,
1:29, 1:28, 1:27,
1:26, 1:25, 1:24, 1:23, 1:22, 1:21, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14,
1:13, 1:12, 1:11,
1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or about 1:1.
[088] Suitable diluents include oils and waxes that are known to be safe for
administration
to a subject. For example, suitable diluents may be mineral oils, vegetable
oils, fluorinated or
perfluorinated oils, natural or synthetic waxes, silicones, cationic polymers,
proteins and
hydrolyzed proteins, ceramide type compounds, fatty amines, fatty acids and
their derivatives,
as well as mixtures of these different compounds.
[089] The synthetic oils include polyolefins, e.g., poly-a-olefins such as
polybutenes,
polyisobutenes and polydecenes.
[090] The mineral oils suitable for use in the compositions of the invention
include
hexadecane and oil of paraffin.
[091] Animal and vegetable oils may be used as diluents including oil from
olive, sunflower,
safflower, canola, corn, soy, avocado, jojoba, squash, raisin seed, sesame
seed, nuts (for
example peanut, walnut, hazelnut, etc.), fish, eucalyptus, lavender, vetiver,
litsea cubeba,
lemon, sandalwood, rosemary, chamomile, savory, nutmeg, cinnamon, hyssop,
caraway,
orange, geranium, cade, bergamot, glycerol tricaprocaprylate, purcellin oil,
mint oil (e.g.
peppermint, spearmint) and blends thereof.
[092] Natural or synthetic waxes may also be used as diluents, these include
carnauba wax,
candelila wax, alfa wax, paraffin wax, ozokerite wax, vegetable waxes such as
olive wax, rice
wax, hydrogenated jojoba wax, absolute flower waxes such as black currant
flower wax,
animal waxes such as bees wax, modified bees wax (cerabellina), marine waxes
and
polyolefin waxes such as polyethylene wax, and blends thereof.
Cannabinoid Mixture
[093] Preparation of the cannabinoid mixture involves the addition of the
surfactant to the
purified cannabinoid or plant extract. In an alternative embodiment, the
cannabinoid is added
to surfactant. In one embodiment this may occur as a separate step prior to
loading the
mesoporous silica with the mixture. In other embodiments the surfactant,
purified cannabinoid
or plant extract and the mesoporous silica are combined in a single step and
the cannabinoid
mixture is formed concomitantly with loading.
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[094] In preferred embodiments, it may be advantageous to use a concentration
of
surfactant that is at or near the CMC (critical micelle concentration). In
other embodiments
the surfactant concentration may be in excess of the CMC so that at least a
portion of the
cannabinoid is contained in micelles of the surfactant.
[095] Accordingly, the ratio of surfactant:cannabinoid is between about 1:1000
to about
1:5. For example the ratio may be about 1:1000, 1:950, 1:900, 1:850, 1:800,
1:750, 1:700,
1:650, 1:600, 1:550, 1:500, 1:450, 1:400, 1:350, 1:300, 1:250, 1:200, 1:150,
1:100, 1:50,
1:25, 1:10, or about 1:5.
Manufacturing Process
[096] In one embodiment the compositions disclosed herein are prepared by
heating the
cannabinoid, particularly if it is not already a liquid at room temperature,
in order to increase
its fluidity and/or reduce its viscosity. The surfactant is mixed with the
cannabinoid and the
mesoporous silica. The cannabinoid and the surfactant form a cannabinoid
mixture that
adsorbs to the mesoporous silica, that is the cannabinoid mixture is loaded
into the
mesoporous silica.
[097] In an alternative embodiment the cannabinoid is heated as above and
mixed with the
surfactant to form a cannabinoid mixture. The cannabinoid mixture is then
mixed with the
mesoporous silica, wherein the cannabinoid mixture adsorbs to the mesoporous
silica.
[098] If the cannabinoid is a low-to-medium viscosity liquid at room
temperature the heating
step may not be required. However, typically cannabinoids exist as viscous
oils, or in
crystalline form at room temperature. In these cases the cannabinoid is heated
to a
temperature that increases the fluidity and/or decreases the viscosity of the
cannabinoid in
order to facilitate ease of handling. For example the cannabinoid can be
heated to about
25 C, about 30 C, about 35 C, about 40 C, about 45 C, about 50 C, about 55 C,
about 60 C,
about 65 C, about 70 C, about 75 C, about 80 C, about 85 C, about 90 C, about
95 C, or
about 100 C.
[099] In embodiments where the cannabinoid is crystalline at room temperature,
it is
heated above its melting temperature. The cannabinoid may be heated to about
20 C
above its melting temperature. For example the cannabinoid may be heated to 5
C, 10 C,
15 C or 20 C above its melting temperature. The melting temperature of
cannabinoids that
are crystalline at room temperature are known in the art or can readily be
determined by a
skilled person.
[0100] In embodiments where the cannabinoid is resinous at room temperature,
it is heated
above its glass transition temperature. The cannabinoid may be heated to about
20 C above
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its glass transition temperature. For example the cannabinoid may be heated to
5 C, 10 C,
15 C or 20 C above its glass transition temperature. The glass transition
temperature of
cannabinoids that are resinous at room temperature are known in the art, or
can readily be
determined by a skilled person.
[0101] The cannabinoid may be heated in the absence or in the presence of the
surfactant.
The process may further comprise the step of stirring the cannabinoid mixture
and the
mesoporous silica.
[0102] In some embodiments the cannabinoid mixture is primarily located in the
pores of the
mesoporous silica, with little or no mixture outside the pores. In other
embodiments, the
cannabinoid mixture is located outside the pores of the mesoporous silica.
Both embodiments
require the cannabinoid mixture to be loaded or adsorbed onto the mesoporous
silica.
[0103] In embodiments where the composition is formulated into a dosage form,
it is
advantageous to minimize the size of the dosage form, and it is typically
advantageous to
maximize the drug loading. Given the challenges in loading high amounts of
cannabinoid
mixture into nano-sized pores, several loading techniques have been developed.
The loading
techniques require the cannabinoid mixture to be fluidized, either as a liquid
solution or
through heating (e.g. melt) as described above. Loading the mixture as a melt
provides an
advantage in that no subsequent evaporation step is necessary to remove the
solvent
medium.
[0104] During loading, one or more diluents may be incorporated (e.g., Medium
Chain
Triglyceride) when loading resinous cannabinoids with the melt method. The
inventors have
observed that viscosity of the cannabinoid or cannabinoid mixture has an
influence on the
desorption process. In many cases, melts of cannabinoids can still have high
viscosities that
hinder both drug loading and desorption. A diluent can be used to 'thin' the
cannabinoid,
making it easier to handle during formulation and can facilitate loading
(i.e., flow) into the
pores of the mesoporous silica. The diluent can also provide a competitive
interaction
between the silica surface and the cannabinoid or cannabinoid mixture during
loading. Upon
contact with the aqueous media, this diluent facilitates desorption and
improves the extent of
cannabinoid release, especially when combined with a solubilizer or
emulsifier.
[0105] Various other methods may be used to load the cannabinoid mixtures
described
herein into mesoporous silica.
[0106] Solvent-based approaches may be used. These require a subsequent drying
step to
evaporate the solvent(s), which can be accomplished using many different
available drying
techniques that are well known to those skilled in art, including for example,
use of a Rotavap
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(rotary evaporator). For example, this method can involve soaking mesoporous
silica in a
solution of cannabinoid mixture in a solvent, typically with stirring while
preventing solvent
evaporation. The solvent is then typically removed with a rotary evaporator.
[0107] In the heat method, the cannabinoid mixture and the mesoporous silica
are heated to
allow the mixture to become a liquid or to reduce the viscosity of the liquid.
This is followed
by mixing to load the cannabinoid mixture into the pores (i.e., allowing
adsorption to occur).
In some cases, a portion of cannabinoid mixture may also be loaded onto the
external surface
of the mesoporous silica.
[0108] In some embodiments, heating is not required. In these embodiments the
cannabinoid
mixture and mesoporous silica are combined at room temperature and the mixture
is
adsorbed to the mesoporous silica at room temperature.
[0109] An alternative method to load the cannabinoid mixture onto the
mesoporous silica
involves dissolving the cannabinoid or cannabinoid mixture in a liquid solvent
medium before
combining it with the mesoporous silica. The solvent can then be evaporated
using any
method known in the art such as evaporation or filtration. Similarly, in an
incipient wetness
impregnation approach, a concentrated solution of dissolved cannabinoid is
mixed with
mesoporous silica and the liquid is taken up through capillary forces. Using
multiple cycles of
loading and solvent evaporation, the cannabinoid mixture is loaded in multiple
stages into the
mesopores until the target theoretical load is achieved. This is a preferred
method for
crystalline cannabinoids because the majority of the solvent can be removed
before the next
loading cycle. In comparison, when this approach is used with resinous
cannabinoids much
of the solvent can remain in the pores making multiple loading cycles less
effective.
[0110] Spray-drying can also be used to load the mesoporous silica and provide
a
composition of the invention. This process can be divided into four
subprocesses: (1)
feedstock preparation, (2) atomization, (3) drying, and (4) collection. The
liquid feedstock
consists of a suspension of mesoporous silica in a concentrated cannabinoid
solution (see
above). The resulting particle size and morphology can be fine tuned according
to the
excipients and process parameters used.
[0111] Another loading method utilizes the fluidized bed approach in mixing,
granulation (if
required), and drying are all carried out in the same equipment. First, a
suspension of a given
cannabinoid-to-silica ratio is formulated and thoroughly mixed. The solvent in
this suspension
is then evaporated by spraying the suspension with the fluidized bed
equipment.
[0112] Co-milling may also be used. In this solvent-free mechanical shearing
process is
reportedly disrupts the crystalline structure of a cannabinoid without causing
significant
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chemical degradation through use of a low-energy jar-milling configuration.
Physical mixtures
of crystalline compounds (such as cannabinoids) and a mesoporous silica at
suitable
proportions are coground at room temperature. This leads to what is known as
spontaneous
amorphization in which the cannabinoid or cannabinoid mixture are adsorbed
onto the
mesoporous silica.
[0113] In the case of resinous cannabis material, cryogenic milling is a
suitable method for
adsorption onto mesoporous silica.
Cannabinoid release
[0114] The invention provides compositions that have enhanced or controlled
release of the
cannabinoid.
[0115] The release rate is influenced by a combination of the properties of
the loaded
cannabinoid mixture and the mesoporous silica, including pore diameter and
pore
morphology. The pore diameter of the mesoporous silica is an important factor
affecting the
release rate of the cannabinoid, with the release rate tending to increase as
pore diameter
increases. In addition to pore size, the pore morphology can also be modified
in order to
control the release rate of the cannabinoid. The particle size and shape
affect the length of
the pathway that a cannabinoid needs to diffuse in order to be released. For
example,
spherical SBA-15 particles have a larger number of pore openings compared to
fiber-like
particles. Pore length also influences the release rate and, in general,
compositions that
have delayed cannabinoid release comprise mesoporous silica having pores with
a more
tortuous diffusion route. This makes the deeper parts of the particle less
accessible to a
solvent and hence the selection of mesoporous silica is important for
controlling the release
profile of a cannabinoid. Accordingly, the release rate of the cannabinoid can
be controlled
by choice of mesoporous silica, in particular the pore size and pore geometry.
[0116] In some embodiments the compositions have enhanced cannabinoid release.
The
rate of dissolution of the cannabinoid from the mesoporous silica is related
to the confined
space inside the pores that prevents long range ordering, thus preventing the
crystallization
of the loaded substances. This stabilized amorphous form of the cannabinoid
can improve
its dissolution rate.
[0117] In particular, on contact with an aqueous release medium (such as a
bodily fluid,
stomach or intestinal contents), water penetrates the pores and the adsorbed
hydrophobic
cannabinoid mixture is displaced from the hydrophilic silica surface and
transported by way
of Fickian diffusion. The release rate depends on factors such as porosity,
the
cannabinoid's solubility in the release medium, the initial load, and the
diffusion coefficient
of the cannabinoid molecules in the medium.
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Formulations
[0118] The compositions disclosed herein may be formulated into any known
dosage form.
The formulations described herein may comprise one or more pharmaceutically
acceptable
excipients including carriers, vehicles and diluents. The term "excipient"
herein means any
substance, not itself an active agent, used as a diluent, adjuvant, or vehicle
added to a
formulation to improve its handling or storage properties or to permit or
facilitate formation
of a solid dosage form such as a tablet, capsule, or a solution or suspension
suitable for
oral, parenteral, intradermal, subcutaneous, or topical application.
Excipients can include,
by way of illustration and not limitation, diluents, disintegrants, binding
agents, adhesives,
wetting agents, polymers, lubricants, glidants, stabilizers, and substances
added to mask or
counteract a disagreeable taste or odor, flavors, dyes, fragrances, and
substances added to
improve appearance of the composition. Acceptable excipients include (but are
not limited
to) stearic acid, magnesium stearate, magnesium oxide, sodium and calcium
salts of
phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, acacia gum,
sodium
alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches,
gelatin, cellulosic
materials, such as cellulose esters of alkanoic acids and cellulose alkyl
esters, low melting
wax, cocoa butter or powder, polymers such as polyvinyl-pyrrolidone, polyvinyl
alcohol, and
polyethylene glycols, and other pharmaceutically acceptable materials.
Examples of
excipients and their use is described in Remington's Pharmaceutical Sciences,
20th Edition
(Lippincott Williams & Wilkins, 2000). The choice of excipient will to a large
extent depend
on factors such as the particular mode of administration, the effect of the
excipient on
solubility and stability, and the nature of the dosage form.
[0119] The formulations of the invention are suitable for oral, rectal,
vaginal, or topical
delivery. Non-limiting examples of particular formulation types include
tablets, troches,
capsules, caplets, powders, granules, ready-to-use solutions or suspensions,
lyophilized
materials, gels, creams, lotions, ointments, drops, and suppositories. Solid
formulations
such as the tablets or capsules may contain any number of suitable
pharmaceutically
acceptable excipients or carriers described above.
[0120] Tablets and capsules for oral administration may be in unit dose
presentation form,
and may contain conventional excipients such as binding agents, for example,
acacia,
gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example
lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants,
for example,
magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for
example, potato
starch; or acceptable wetting agents such as sodium lauryl sulphate. The
tablets may be
coated according to methods well known in pharmaceutical practice.
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[0121] Oral liquid preparations may be in the form of, for example, aqueous or
oily
suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a
dry product
for reconstitution with water or other suitable vehicle before use. Such
liquid preparations
may contain conventional additives, such as suspending agents, for example,
sorbitol,
methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,
carboxymethyl cellulose,
aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for
example,
lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may
include edible
oils), for example, almond oil, oily esters such as glycerin, propylene
glycol, or ethyl alcohol;
preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid;
and, if
desired, conventional flavouring or colouring agents.
[0122] The effective amount of the cannabinoid in the formulation that is
administered and
the dosage regimen with the compositions and/or formulations of the present
invention
depends on a variety of factors, including the age, weight, sex, and medical
condition of the
subject, the severity of the disease, the route and frequency of
administration, the particular
compound employed, as well as the pharmacokinetic properties (e.g.,
adsorption,
distribution, metabolism, excretion) of the individual treated, and thus may
vary widely. Such
treatments may be administered as often as necessary and for the period of
time judged
necessary by the treating physician or other medical professional. One of
skill in the art will
appreciate that the dosage regimen or therapeutically effective amount of the
compound to
be administrated may need to be optimized for each individual.
[0123] The compositions may contain active ingredient in the range of about
0.1 mg to
2000 mg, typically in the range of about 0.5 mg to 500 mg and more typically
between about
1 mg and 200 mg. A daily dose of about 0.01 mg/kg to 100 mg/kg body weight,
typically
between about 0.1 mg/kg and about 50 mg/kg body weight, may be appropriate,
depending
on the route and frequency of administration.
[0124] In one embodiment, the formulations are consumed orally. A single dose
is at from
0.1mg but may be up to about 250 mg. For example a single dose may be 1 mg, 2
mg, 3
mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15
mg, 16
mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27
mg, 28
mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39
mg, 40
mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50mg, 55mg,
60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg,
120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg,
175mg, 180mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg,
235mg, 240mg, 245mg, 250mg, 275mg, 300mg, 325mg, 350mg, 400mg, 450mg, 475mg,
or
at least about 500 mg.
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[0125] A subject may consume one or multiple doses per day. For example, a
subject may
take 1, 2, 3, 4 or 5 doses per day. In some embodiments, the dosing interval
is selected
from the group consisting of once per week dosing, twice per week dosing,
three times per
week dosing, four times per week dosing, five times per week dosing, six times
per week
dosing, weekly dosing, and twice-monthly dosing. In other embodiments, dosing
may be as
needed or as desired by the user.
Pharmaceutical use
[0126] The compositions and formulations described herein contain cannabinoids
and the
invention also relates to a method of treating a condition or disease
responsive to a
cannabinoids such as pain (including chronic pain), spasticity associated with
multiple
sclerosis, nausea (chemotherapy-induced nausea and vomiting), posttraumatic
stress
disorder, cancer, epilepsy, cachexia, glaucoma, HIV/AIDS, degenerative
neurological
conditions, anorexia and weight loss associated with HIV, irritable bowel
syndrome,
epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis,
Huntington's disease,
Parkinson's disease, dystonia, dementia, traumatic brain injury, addiction,
anxiety,
depression, sleep disorders, and schizophrenia and other psychoses.
[0127] A further embodiment relates to the use of the compositions disclosed
herein for the
manufacture of a medicament for treating a disease or condition responsive to
a
cannabinoid, such as those listed above.
[0128] The compositions of the present invention may be administered along
with a
pharmaceutical carrier, diluent or excipient as described above.
Alternatively, or in addition,
the compounds may be administered in combination with other agents, for
example, other
therapeutic agents.
[0129] The terms "combination therapy" or "adjunct therapy" in defining use of
a compound
of the present invention and one or more other pharmaceutical agents, are
intended to
embrace administration of each agent in a sequential manner in a regimen that
will provide
beneficial effects of the drug combination, and is intended as well to embrace
co-
administration of these agents in a substantially simultaneous manner, such as
in a single
formulation having a fixed ratio of these active agents, or in multiple,
separate formulations
of each agent.
[0130] In accordance with various embodiments of the present invention, the
composition
may be formulated or administered in combination with one or more other
therapeutic
agents. Thus, in accordance with various embodiments of the present invention,
a
composition may be included in combination treatment regimens with known
treatments or
therapeutic agents, and/or adjuvant or prophylactic agents.
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[0131] Combination regimens may involve the active agents being administered
together,
sequentially, or spaced apart as appropriate in each case. Combinations of
active agents
including compounds of the invention may be synergistic.
[0132] For example, the composition may further comprise pharmacologically
active agents
that are poorly soluble in water. Examples of suitable agents include:
= anesthetics such as bupivacaine, lidocaine, proparacaine, and tetracaine;
analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen,
voltaren,
phenacetin, and salicylamide;
= anti-inflammatories selected from the group consisting of naproxen and
indomethacin;
= antihistamines, such as chlorpheniramine maleate, phenindamine tartrate,
pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate,
diphenhydramine hydrochloride, promethazine, brompheniramine maleate,
dexbrompheniramine maleate, clemastine fumarate and triprolidine;
= broad and medium spectrum, antimicrobial agents such as erythromycin,
penicillin
and cephalosporins and their derivatives;
= Skeletal muscle relaxants (dantrolene sodium, baclofen), benzodiazepines
(diazepam), alpha2-adrenergic agonists (clonidine, tizanidine), botulinum
toxins
(onabotulinumtoxinA, abobotulinumtaxinA, incobotulinumtoxinA,
rirnabotulinurntoxinB);
= 5-HT3 inhibitors such as dolasteron (Anzemet), granisetron (Kytril,
Sancuso), and
ondansetron (Zofran) palonosetron (Aloxi));
= NK1 inhibitors (e.g. substance P inhibitor aprepitant (Emend),
Netupitant, Rolapitant;
= Olanzapine;
= A combination of palonosetron and dexamethasone;
= Dopamine D2 receptor antagonist e.g. Metoclopramide;
= Histamine blockers such as diphenhydramine or meclozine;
= acetazolamide, carbamazepine, clobazam clonazepam, diazepam,
ethosuximide,
fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam,
methsuximide, nitrazepam, oxcarbazepine, paraldehyde, phenobarbital,
phenytoin,
pregabalin, primidone, rufinamide, stiripentol, topiramate, valproic acid,
vigabatrin,
felbamate, tiagabine hydrochloride, zonisamide Lorazepam, diazepam
= Progestagens such as megestrol acetate and medroxyprogesterone acetate,
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= Omega-3 fatty acids (e.g. EPA)
= bortezomib
= thalidomide
= ghrelin
= COX-2 inhibitors
= branched chain amino acids
= oxandrolone
= alpha-adrenergic agonists
= carbonic anhydrase inhibitors
= parasympathomimetics
= Anti-retrovirals
= Fluphenazine, haloperidol (HaIdol), risperidone (Risperdal) and pimozide
(Orap);
quetiapine
= Riluzole (Rilutek), Edaravone (Radicava)
= Tetrabenazine, amantadine, levetiracetam.
[0133] The co-administration of compounds of the invention may be effected by
the
compounds being in the same unit dose as another active agent, or the
compounds and
one or more other active agent(s) may be present in individual and discrete
unit doses
administered at the same, or at a similar time, or at different times
according to a dosing
regimen or schedule. Sequential administration may be in any order as
required, and may
require an ongoing physiological effect of the first or initial compound to be
current when the
second or later compound is administered, especially where a cumulative or
synergistic
effect is desired.
Consumer Products
[0134] In other embodiments the compositions may be included in consumer
products such
as food products, cosmetics, and sunscreen.
[0135] The food product may be a baked good (for example a bread, cake,
biscuit or
cookie, beverage (e.g., tea, soda or flavored milk), breakfast food (e.g.,
cereal), muesli bar,
tinned food, snack food (e.g., chips, crisps, corn snacks, nuts, seeds),
confection,
condiment, marinade, dairy product, dips, spreads or soups.
[0136] The cosmetic may be a be liquid, lotion, cream, powder (pressed or
loose), a
dispersion, an anhydrous cream or stick. For example, the cosmetic may be a
spray,
perfume, foundation, mascara, lipstick, lip gloss, lip liner, lip plumper, lip
balm, lip stain, lip
conditioner, lip primer, lip booster, lip butter, deodorant, bath oils, bubble
baths, bath salts,
body butter, nail polish, hand sanitizer, shampoo, conditioner, hair colors,
hair sprays, hair
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gels, primer, concealer, highlighter, bronzer, mascara, eye shadow, eyebrow
pencils,
eyebrow cream, eyebrow wax, eyebrow gel, eyebrow powder, moisturizer, or
toner.
[0137] The consumer product may contain less than about 1% (w/w) of the
composition or
about 1% (w/w), or about 2% (w/w), or about 3% (w/w), or about 4% (w/w), or
about 5%
(w/w), or about 6% (w/w), or about 7% (w/w), or about 10% (w/w), or about 11%
(w/w), or
about 12% (w/w), or about 13% (w/w), or about 14% (w/w), or about 15% (w/w),
or about
16% (w/w), or about 17% (w/w), or about 18% (w/w), or about 19% (w/w), or
about 20%
(w/w), or about 25% (w/w), or about 30% (w/w), or about 35% (w/w), or about
40% (w/w), or
about 45% (w/w), or about 50% (w/w) of the composition.
[0138] It will be appreciated by persons skilled in the art that numerous
variations and/or
modifications may be made to the technology as shown in the specific
embodiments without
departing from the spirit or scope of technology as broadly described. The
present
embodiments are, therefore, to be considered in all respects as illustrative
and not
restrictive.
EXAMPLES
Example 1: Delta-9-THC mesoporous silica composition
[0139] Syloid 3050 XDP (50 pm median particle size) was selected as the
mesoporous silica
carrier and sodium lauryl sulfate (SLS) as the anionic surfactant. A delta-9-
THC distillate with
85% purity, as determined by HPLC, was selected for method development and
optimization
purposes. To improve the ease of handling, the viscosity of the distillate was
decreased by
placing it in a 40 C oven for approximately 15 minutes prior to weighing.
Following removal
from the oven, it was immediately added to the pre-weighed Syloid 3050 XDP and
SLS to a
target drug load of 35-40% (w/w) delta-9-THC (-40-45% cannabis extract) and 4%
(w/w) SLS.
The mixture was blended using a standard overhead laboratory mixer until all
of the distillate
visually appeared to be adsorbed onto the silica. The dry powder blend was
then sieved
through a 60 pm sieve.
[0140] The potency of the drug loaded silica/SLS mixture was then analyzed by
HPLC-UV
by diluting samples to -100 pg/mL in acetonitrile (ACN) and analyzed (n=3
replicates) at room
temperature. All standard curves were linear over the concentration range of
0.7 - 700 pg/mL.
The measured potency was evaluated against the theoretical potency with an
acceptance
criterion set to 10()/0 (i.e., 90-100% of the theoretical maximum loading
capacity). This
resulting potency was then used to determine the target weight to achieve a 25
mg delta-9-
THC dose in a 175 mg tablet (14.3% w/w).
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Example 2: Immediate Release Oral Tablet (delta-9-THC)
[0141] The tablet blend was prepared (see example below) using an optimized
blending
procedure and analyzed using HPLC for potency and homogeneity with acceptance
criteria
of 5% for both. Following this, tablets were prepared by direct compression
using standard
tableting excipients. Tablets were also analyzed for potency and batch
homogeneity using
HPLC. Finally, the tablet weight, thickness, and hardness were also assessed
and compared
against the batch release specifications prior to sale.
Table 3: delta-9-THC ingredients
Material Function Weight
(%)
d9-THC distillate (-85% purity)* Active 14.3
Syloid 3050 XDP* (mesoporous silica) Adsorbent 43.0
Sodium Lauryl Sulfate* Surfactant 1.5
Avicel PH-101 (microcrystalline cellulose) Binder 35.0
Ac-Di-Sol (croscarmellose sodium) Disintegrant 5.0
Mg Stearate Lubricant 1.0
Terpenoids (cannabis derived, steam distilled) Active
0.2
Total 100.0
* Combined during drug loading step and analyzed prior to
blending/compression.
[0142] In vitro observations were consistent with the above findings during
development
with delta-8-THC and delta-9-THC distillate. The resulting HPLC potency was
consistently
25-30% below the theoretical loading. This is attributed to insufficient
desorption from the
silica surface. However, this was mitigated through the use of sodium lauryl
sulfate, a
surface active agent ("surfactant").
[0143] The incorporation of 1.5% SLS to the drug loaded silica improved the
potency to
within 10% of the theoretical value. Follow-up investigations evaluating the
influence of
higher surfactant concentrations (up to 10% SLS) did not improve delivery.
Example 3: CBD mesoporous silica tablets
[0144] The tablet blend was prepared in accordance with table 4 and tablets
were prepared
by direct compression
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Table 4: CBD ingredients
Material Function Weight
(%)
CBD (76.5% purity) Active 2.6
Syloid 244 (mesoporous silica) Adsorbent 1.0
Xylitol Filler/binder 19.4
Orange oil Flavour 1.3
Spearmint oil Flavour 2.7
Ac-Di-Sol (croscarmellose sodium) Disintegrant 1.5
Kollidone (Crospovidone) Disintegrant 5.0
Ludiflash 0 Filler/binder/disintegrant 65.5
Mg Stearate Lubricant 1.0
Total 100.0
Example 4: CBD mesoporous silica tablets
[0145] The tablet blend was prepared in accordance with table 5 and tablets
were prepared
by direct compression
Table 5: CBD ingredients
Material Function Weight
(%)
CBD (76.5% purity) Active 12.9
Aerosil (mesoporous silica) Glidant 1.7
Ac-Di-Sol (croscarmellose sodium) Disintegrant 4.8
Microcrystalline cellulose Filler/binder/disintegrant 79.4
Mg Stearate Lubricant 1.2
Total 100.0
Example 5: Incipient wetness loading of resinous distillate onto mesoporous
silica
[0146] Resinous distillate was dissolved in 99% isopropanol (iso-propyl
alcohol) to a
concentration of 147.25 mg/ml. A portion of this solution was added to the
mesoporous silica
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(either Syloid 3050 XDP or Syloid 244). The portion of the solution added to
the silica is equal
or slightly less than the pore volume of the silica. After the cannabinoid is
adsorbed onto the
silica the isopropanol is removed by evaporation and another portion of the
solution is added
to silica. This process is repeated until the desired amount of distillate
(30% by weight of
silica) was added.
Example 6: Incipient wetness loading of Delta-9-THC onto mesoporous silica
[0147] In this example a solution of 113.9 mg/ml Delta-9-THC in 99%
isopropanol was
prepared. A mixture of Syloid 244 and Syloid 3050 XDP was prepared in a 1:3
ratio.,
specifically 157mg of Syloid 244 was mixed with 471mg of Syloid 3050 XDP
(total weight of
628mg). 0.2 ml of the Delta-9-THC solution was added incrementally to the
silica mixture until
a total of 6 ml of the solution was added, for a total of 683.4 mg Delta-9-
THC. After the last of
the solvent was removed by evaporation the weight of the silica had increased
to 1311.4mg
indicating that all of the Delta-9-THC was loaded onto the silica and the
total load of Delta-9-
THC was 52%. The loaded silica was a flowable powder.
[0148] When this test was repeated the total load of Delta-9-THC was 49%.
Again, the loaded
silica was a flowable powder.
[0149] The test was repeated using Delta-9-THC in isopropanol and 1:4 and 1:5
mixtures of
Syloid 244 : Syloid 3050 XDP. Although it was found that at these ratios the
total load of
Delta-9-THC was slightly lower (44%), these mixtures had more desirable flow
characteristics
than the 1:3 mixture of Syloid 244: Syloid 3050. Syloid 3050 (150 um particle
size) flows very
well in comparison to Syloid 244 (2 um particle size). The incorporation of
244 can create
harder tablets due to filling of the powder blend 'voids'. Syloid 244 is also
more suitable for
crystalline cannabinoids.
Example 7: Scale-up incipient wetness loading of resinous distillate onto
mesoporous
silica
[0150] In this example a 1:4 mixture of Syloid 244: Syloid 3050 was prepared
using 3.19g
Syloid 244 and 12.32g Syloid 3050 (a total of 15.51g silica).
[0151] A solution of 60.36 mg/ml resinous distillate in isopropanol was
prepared by first
softening the distillate by hearting then adding the isopropanol.
[0152] The silica mixture was separated into three portions and the volume of
the resinous
distillate solution required to achieve 25%, 37.5% and 50% loading of the
silica was
calculated.
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[0153] As for previous examples the silica mixture was loaded by incrementally
adding the
aliquots of the solution of resinous distillate to the silica. Solvent was
removed using a rotary
evaporator (Rotovape) before the addition of more solution.
Example 8: Delta-9-THC tablets
[0154] The tablet blend was prepared in accordance with table 6 and tablets
were prepared
by direct compression
Table 6: Ingredients
Material Function Weight
(%)
Loaded silica (from example 6. 1:4
mixtures of Syloid 244 : Syloid 3050
loaded with Delta-9-THC). Active 42.2
Ac-Di-Sol (croscarmellose sodium) Disintegrant 4.1
Microcrystalline cellulose
Filler/binder/disintegrant 52.4
Mg Stearate Lubricant 1.3
Total 100.0
Example 9: CBG tablets
[0155] The tablet blend was prepared in accordance with table 7 and tablets
were prepared
by direct compression
Table 7: Ingredients
Material Function Weight
(%)
CBG (98.3% purity) Active 17.0
Aerosil (mesoporous silica) Glidant 1.6
Ac-Di-Sol (croscarmellose sodium) Disintegrant 4.7
Microcystalline cellulose
Filler/binder/disintegrant 75.6
Mg Stearate Lubricant 1.1
Total 100.0
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Example 10: Controlled release Delta-9-THC tablets
[0156] A 1:4 mixture of Syloid 244:Syloid 3050 was loaded with delta-9-THC as
described in
Example 6. Once loaded the dried silica mixture contained 40% delta-9-THC by
weight. This
loaded silica was used to prepare the tablet blend in accordance with table 8.
Following this,
tablets were prepared by direct compression.
Table 8: Ingredients
Material Function Weight
(%)
Loaded Silica Active 26.8
Hydroxypropyl methylcellulose Controlled release agent 11.5
Ac-Di-Sol (croscarmellose sodium) Disintegrant 6.4
Microcystalline cellulose Filler/binder/disintegrant 54
Mg Stearate Lubricant 1.3
Total 100.0
Example 11: HPLC method to quantitate cannabinoids
[0157] It was found that the Luna Omega C18 HPLC column provides resolution
for
cannabinoids under the following conditions:
= mobile phase: 5 mM ammonium acetate (pH 4.5 with acetic acid) in 80:20,
acetonitrile: water
= flow rate: 1.0 mlimin
= pressure: 2000 psi (138 bar)
= column temp.: room temperature
= detector: UV, 214 nm
[0158] Cannabinoids were eluted from the column and identified by reference to
known
controls eluted from the column under the same conditions. Cannabinoids were
quantitated
by reference to a calibration curve of peak area vs concentration of the known
controls.
[0159] The relative standard deviation (c/oRSD) for measurements of THC and
CBD using
this method is 3.2% (n=5) and 0.7% (n=3), respectively. Recovery is greater
than 95%.
Example 12: Cannabinoid release from loaded silica
[0160] A silica blend loaded with 37.5% delta-9-THC was prepared as per
Example 7.
Samples of the blend containing a calculated 7.5mg of delta-9-THC were mixed
with 900 pL
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33
of acetonitrile. HPLC was performed according to Example 11 and it was found
that the
amount of delta-9-THC recovered from the silica blend was 23.54% (RSD of 6.4%,
n=3).
[0161] Similarly, when 220mg aliquots of the blend were extracted with
methanol overnight
before HPLC recovery of delta-9-THC, around 80% of the total cannabinoid
loaded (RSD of
0.9%, n=3).
Example 13: Inclusion of surfactant increases cannabinoid release from loaded
silica
[0162] 1.5% (w/w) sodium lauryl sulfate was added to a silica blend loaded
with 37.5%
delta-9-THC prepared as per Example 7 before mixing with acetonitrile in
accordance with
Example 12. HPLC was performed according to Example 11 and it was found that
the
amount of delta-9-THC recovered from the silica blend was on average 33.9%
(n=3), i.e.
about 90% of the cannabinoid loaded onto the silica was recovered.
[0163] When this test was repeated using a 1.5% (w/w) sodium lauryl sulfate
added to a
Syloid 3050 silica loaded with 37.5% delta-9-THC prepared as per Example 7 it
was found
that 94.76% of delta-9-THC loaded was recovered.
[0164] When the sodium lauryl sulfate was mixed with the cannabinoid prior to
loading (see
Examples 1 and 2) the recovery of delta-9-THC was within 10% of the calculated
amount
that was loaded.
