Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CANNABINOID-CONTAINING COMPOSITION
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a continuation-in-part of U.S. Application No.
16/225,964,
filed December 19, 2018. The present application also claims the benefit of
PCT International
Application No. PCT/IB2019/060799, filed December 13, 2019, which claims the
benefit of U.S.
Application No. 16/225,964, filed December 19, 2018.
BACKGROUND
Cannabis contains more than 500 compounds, including at least 66 cannabinoids
that are
unique to Cannabis and at least 140 terpenes that are widespread throughout
the plant kingdom.
.. (Brenneisen, R., Chemistry and Analysis of Phytocannabinoids and Other
Cannabis Constituents,
in Forensic Science and Medicine: Marijuana and the Cannabinoids. Ed. El
Sohly, MA. Humana
Press Inc., Totowa, NJ. Chapter 2, pgs. 17-49. 2010.)
The term "phytocannabinoid" has been proposed to differentiate naturally-
occurring
cannabinoids from synthetically produced cannabinoids. Synthetically produced
cannabinoids
are cannabinoid compounds that are made synthetically in laboratories.
Phytocannabinoids are
all C21 terpenophenolic compounds, of which tetrahydrocannabinol (THC) and
cannabidiol
(CBD) are perhaps the most studied and best understood for their therapeutic
and recreational
value. However, phytocannabinoids as a whole have become of interest for the
treatment of
various disorders and disease states, such as anxiety disorders, depression,
loss of appetite
(including cachexia), various forms of pain (e.g., acute pain, chronic pain,
neuropathic pain,
trigeminal nerve pain, and pain associated with or accompanying migraine
headaches and
cancer).
The 140 terpenes that are present in Cannabis include monoterpenoids,
sesquiterpenoids,
diterpenoids, and triterpenoids. (Brenneisen, pgs. 17-49.) For the most part,
these terpenes are
hydrophobic and comprise short aliphatic branched chains or substituted
monocyclic
compounds. Terpenes present in Cannabis are responsible for the unpleasant
turpentine or pine
needle tastes and odors that are common to cannabis plant extracts.
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Date Recue/Date Received 2022-06-17
Naturally-occurring cyclodextrins are cyclic polymers of glucose units that
are formed by
the enzymatic action of specific cyclodextrin glycosyltransferases (CGT) on
partially-hydrolyzed
corn starch. Depending on the CGT used, cyclic polymers of six, seven, or
eight glucose units
are produced, which are respectively named a-cyclodextrin,13-cyclodextrin, and
y-cyclodextrin.
The size of the cyclodextrin molecule, and therefore the "pore" formed by the
cyclodextrin
molecule, is dictated by the number of glucose units in the polymer. Thus, a-
cyclodextrin has the
smallest pore, while y-cyclodextrin has the largest. Alpha-cyclodextrin is
known to sequester
small molecules (e.g., fatty acids, nitrobenzene) (McGowan, M. et al., A
peroxidase-coupled
method for the colorimetric determination of serum triglycerides. Clin. Chem.
1983, 29, 538-
542.), while 3-cyclodextrin and y-cyclodextrin sequester larger poly- and
heterocyclic
compounds (e.g., cholesterol, THC or CBD).
Shoyama describes a method for the preparation of pure THC and 3-cyclodextrin
complexes and demonstrates that these complexes are stable. (Shoyama Y. et
al., Preparation and
stability of A9-tetrathydrocannabino1-13-cyclodextrin inclusion complex, J.
Nat. Prod. 1983,
46(5), 633-637.) Hazekamp assesses the water solubility of pure THC in the
presence of cc-
cyclodextrin, 13-cyclodextrin, y-cyclodextrin, and randomly methylated-13-
cyclodextrins and
states that only the randomly methylated-13-cyclodextrins increase the water
solubility of THC.
(Hazekamp, A. et al., Structure elucidation of the tetrahydrocannabinol
complex with randomly
methylated 3-cyclodextrin, Eur. J. Pharm. Sci. 2006, 29, 340-347.) Mannila et
al. describe the
preparation of 3-cyclodextrin complexes with CBD for the sublingual
administration of CBD
and the preparation of methylated-cyclodextrin complexes with CBD and THC.
(U.S. Patent
No. 7,592,328; Mannila J. et al., Precipitation complexation method produces
cannabidio1/13-
cyclodextrin inclusion complex suitable for sublingual administration of
cannabidiol, J. Pharm.
Sci. 2007, 96(2), 312-319.) U.S. Patent No. 7,423,026 describes methylated 3-
cyclodextrin
complexes with cannabinol, THC, and CBD. U.S. Patent No. 8,735,374 describes
the preparation
of an oral mucoadhesive dosage form of THC and y-cyclodextrin and a mixture of
THC and
CBD with a mixture that includes both 0- and y-cyclodextrin.
U.S. Patent No. 2017/0224842 ("Czap") describes y-cyclodextrin complexes of
cannabinoids from partially purified, low terpene containing, hemp oil. In
order to release the
guest cannabinoid molecule from the host cyclodextrin and to alleviate the
concerns surrounding
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Date Recue/Date Received 2022-06-17
undigested cyclodextrins, Czap's complexes are formulated with amylase-like
enzymes that
hydrolyze the cyclodextrin. Czap further discloses that a mixture of
cyclodextrins may be used to
sequentially form inclusion complexes with different size molecules. Czap's
formulation must be
kept dry to prevent premature activation of the amylase-like enzymes. Thus,
Czap's formulation
.. is not feasible for use in beverages, food stuffs, and confections.
Furthermore, hot beverages or a
baking process will likely denature the amylase-like enzymes in Czap's
complexes.
WO 2017/180954 describes the emulsification of specific cannabinoids with a
mixture of
at least two emulsifiers, including a synthetic 13-cyclodextrin. WO
2018/058235 describes the
preparation of a complex using cannabis plant extract, 13-cyclodextrin, and
other ingredients (e.g.,
release-modifying agents and excipients for use in a time-released tablet).
Shimada et al. (Shimada K, Kimiko K, Oshii J and Nakamura T. Structure of
inclusion
complexes of cyclodextrins with triglyceride at vegetable oil/water interface.
J. of Food Science,
1992, 57 (3):655-656.), Artiss and Jen (Compositions comprising dietary fat
complexer and
methods for their use. US Pat. No. 6,890,549, May 10, 2005), Bochot et al.
(Bochot A, Trichard
L, Le Bas G, Alphandary H, Grossiord JL, Duchene D and Fattal E. a-
Cyclodextrin/oil beads:
An innovative self-assembling system. International J of Pharmaceutics, 2007,
339:121-129.),
Trichard et al. (Trichard L, Delgado-Charro MB, Guy RH, Fattal E and Bochot A.
Novel beads
made of alpha-cyclodextrin and oil for topical delivery of a lipophilic drug.
Pharmaceutical
Research, 2007, 25 (2):435-440.), and Bhopate SB and Dhole SN (Preparation and
characterisation of 3-cyclodextrin nebivolol inclusion complex. Int. J. of
Pharmaceutical
Sciences and Research, 2014, 6(5):2205-2213.) all describe the formation of
cyclodextrin
complexes with hydrophobic compounds in a water/oil mixture. For example,
Bhopate and
Dhole describe five different methods for creating cyclodextrin complexes,
each of which
requires water as part of the solvent system. From these publications, we
understand that an
oil:water interface is required for exchange between the two phases.
Furthermore, we learn that
the hydrophobic target in the hydrophobic phase must complex with the water-
soluble
cyclodextrin in order for it to cross into the aqueous phase.
Wadhwa et al. (Wadha G, Kumar S, Chhabra L, Mahant S and Rao R. Essential oil-
cyclodextrin complexes: an updated review. J Incl Phenom Macrocycl Chem, 2017,
89:39-58.),
Al-Marzouqi et al. (Al-Marzouqi AH, Elwy HM, Shehadi I and Adem A.
Physicochemical
3
Date Recue/Date Received 2022-06-17
properties of antifungal drug-cyclodextrin complexes prepared by supercritical
carbon dioxide
and conventional techniques. J Pharm Biomed Analysis, 2009, 49:227-233.), and
Cheirsilp and
Rakmai (Cheirsilp B and Rakmai J. Inclusion complex formation of cyclodextrin
with its guest
and their applications, 2016, Biol Eng Med. 2(1):1-6.) discuss the preparation
of inclusion
.. complexes of cyclodextrins dissolved in water and guest molecules dissolved
in an organic
solvent.
Harada, Li and Kamachi (Harada A, Li J and Kamachi M. Preparation and
properties of
inclusion complexes of poly(ethylene glycol) with a-cyclodextrin.
Macromolecules, 1993,
26:5698-5703.) and Bisson-Boutelliez et al. (Bisson-Boutelliez C, Fontanay S,
Finance C and
Kedzierewicz F. Preparation and physicochemical characterization of
amoxicillin13-cyclodextrin
complexes. AAPS Pharm Sci Tech., 2010, 11(2):574-580.) describe the formation
of
cyclodextrin guest inclusion complexes when both the cyclodextrin and the
guest molecule are
dissolved in water.
In their review article, Maazaoui and Abderrahim (Maazaoui R and Abderrahim R.
Applications of cyclodextrins : formation of inclusion complexes and their
characterization.
Intern J Advan Res., 2015, 3(2):1030-1030.) describe guest molecules, which
have a higher
affinity for the cyclodextrin cavity than they do for the aqueous phase of the
reaction mixture.
Jambhekar and Breen (Jambhekar SS and Breen P. Drug Disc Today, 2016,
21(2):356-362.)
describe ejection of water molecules by the cyclodextrin cavity in favor of
the guest molecule.
The review article of Szejtli (Szejtli J. Past, present and future of
cyclodextrin research.
Pure Appl Chem., 2004, 76(10):1825-1845.) discusses the need for water in the
formation of an
inclusion complex.
Yoshii et al. (Yoshii H, Kometani T, Furuta T, Watanabe Y, Linko YY and Linko
P.
Formation of inclusion complexes of cyclodextrin with ethanol under anhydrous
conditions.
Biosci Biotechnol Biochem. 6(11):2166-2170;1998.) describe a method for
preparing
cyclodextrin complexes with d-limonene in the absence of water. The method is
very
impractical, being labor-intensive and requiring up to about a forty-fold
excess of guest molecule
to form an inclusion complex. This large excess of guest molecule requires
additional rather
aggressive efforts to eliminate adsorbed (as opposed to included) guest
molecules. This, in turn,
leads to a large loss in the molecule of interest. Furthermore, it is not
clear whether or not a
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Date Recue/Date Received 2022-06-17
cannabinoid would survive the aggressive procedures required to eliminate
adsorbed molecules.
As the guest molecule is not only the molecule of interest but also likely the
more expensive of
the two inclusion components, Yoshii's approach is highly inefficient.
SUMMARY OF THE INVENTION
Contrary to prior understanding, it is suggested herein that it is not
necessary to sequester
an entire hydrophobic cannabinoid compound in the pore of a cyclodextrin
molecule (e.g., alpha-
cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin) in order to render it
water soluble.
Rather, it is possible to render a large molecule like a cannabinoid soluble
by sequestering only a
portion of the molecule. Without being bound by theory, it is likely that the
five-carbon alkane
chain common to all cannabinoid molecules is sequestered by the cyclodextrin.
Furthermore, it is
suggested herein, based upon data using alpha-cyclodextrin, that the binding
is a relatively weak
binding process, facilitating rapid release of the partially sequestered
cannabinoid molecule when
it comes in contact with mucosal membranes, and thereby facilitating rapid
onset of desired
physio- and psychological effects of a cannabinoid.
The pore size of the larger beta-cyclodextrin is appropriate to sequester most
if not all of
a cannabinoid molecule. However, beta-cyclodextrin is not well tolerated by
the human
gastrointestinal tract and consequently has a much lower Generally Recognised
As Safe (GRAS)
threshold than does alpha-cyclodextrin.
An advantage of alpha-cyclodextrin over the larger beta-cyclodextrin or gamma-
cyclodextrin is that alpha-cyclodextrin is the correct size to complex many of
the foul-tasting
terpenes that tend to be found in cannabinoid extracts. By complexing these
terpene molecules,
they are rendered both water soluble and tasteless which is of benefit in the
preparation of
beverages, confectionaries and other edibles.
As provided herein, it has now unexpectedly been found that a cyclodextrin is
not
required to be dissolved in water or other aqueous solvent in order to form a
complex between
the hydrophobic cannabinoid and cyclodextrin. Unexpectedly, and indeed
surprisingly, for
example in light of Jambhekar and Breen (Jambhekar SS and Breen P. Drug Disc
Today, 2016,
21(2):356-362.), the phase transfer occurs even between a cannabinoid
dissolved in a low
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Date Recue/Date Received 2022-06-17
molecular weight alcohol (e.g., ethyl alcohol or propyl, including isopropyl
alcohol) and a dry
powdered alpha-cyclodextrin.
This unexpected and surprising non-aqueous approach, as provided herein,
facilitates a
simpler and more efficient route to complex formation. According to an aspect
of the invention
this method is advantageous in avoiding the need to remove water once mixing
and complex
formation is complete.
According to an aspect of the invention there is provided a method for making
a
composition comprising complexes of a-cyclodextrin and one or more
cannabinoids, one or
more terpenes, or mixtures of such complexes, the method comprising the steps
of:
(a) combining a first composition comprising at least one cannabinoid and/or
at least one
terpene or mixtures of such cannabinoids and terpenes with a non-aqueous a-
cyclodextrin-
containing composition; and
(b) mixing the first composition and the non-aqueous a-cyclodextrin-containing
composition for a sufficient time to form complexes between the a-cyclodextrin
and at least one
cannabinoid and/or at least one terpene.
In accordance with another aspect of the invention the first composition is a
non-aqueous
solid.
In accordance with another aspect of the invention the first composition is
dissolved in
ethyl or isopropyl alcohol.
In accordance with another aspect of the invention the method further
comprises the step
of:
(c) removing diluents from step (b).
In accordance with another aspect of the invention the first composition is a
cannabis
plant extract comprising one or more phytocannabinoids or a composition
comprising one or
more synthetically-produced cannabinoids.
In accordance with another aspect of the invention the phytocannabinoid is
THC, CBD,
cannabinol, or mixtures thereof and wherein the synthetic cannabinoid is 1-
penty1-3-(1-
naphthoyl)indole (JWH-018), 1-buty1-3-(1-naphthoyl)indole (JWH-073), 14244-
morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200), 5-(1,1-dimethylhepty1)-2-
[(1 R, 3 S)-3-
hydroxycyclohexyl]-phenol (CP-47,497), and 5-(1,1-dimethylocty1)-2-[(1 R, 3 S)-
3-
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Date Recue/Date Received 2022-06-17
hydroxycyclohexyl]-phenol (cannabicyclohexanol; CP-47,497 C8 homologue)
dronabinol,
nabilone, or mixtures thereof.
In accordance with another aspect of the invention the non-aqueous a-
cyclodextrin-
containing composition is a powder, crystals, or granules.
In accordance with another aspect of the invention the non-aqueous a-
cyclodextrin
comprises about 1000:1 to about 2:1 w/w of a-cyclodextrin to the first
composition.
In accordance with another aspect of the invention the mixture is dried by
evaporating the
mixture in dishes or pans at ambient or moderately elevated temperatures, at
atmospheric or
reduced pressure, or in a rotary evaporator.
In accordance with an aspect of the present invention there is provided a
method for
complexing a compound in a Cannabis plant extract with a non-aqueous a-
cyclodextrin
comprising the steps of:
(a) combining the Cannabis plant extract with the non-aqueous a-cyclodextrin
to produce
a mixture,
(b) mixing the mixture from step (a) for sufficient time to form a composition
comprising
complexes of a-cyclodextrin with the compound in the Cannabis plant extract,
wherein the compound is a cannabinoid, a terpene, and/or mixtures thereof.
In accordance with another aspect of the invention the compound in the
Cannabis plant
extract is a cannabinoid selected from the group consisting of cannabinol,
THC, and CBD.
In accordance with an aspect of the invention is a food product comprising a
composition
comprising complexes of one or more cannabinoids and a-cyclodextrin produced
by one or more
of the methods described herein.
In accordance with another aspect of the invention the food product is a
farinaceous food
product, a non-farinaceous food product, or a confection.
In accordance with another aspect of the invention wherein the food product is
a
farinaceous food product selected from the group consisting of cake, muffin,
brownie, cookie,
cracker, doughnut, and biscuit or, the food product is a confection selected
from the group
consisting of caramel, chocolate, nougat, lozenge, chewing gum, toffee,
fondant, halvah, jelly,
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Date Recue/Date Received 2022-06-17
gelatin, gummies, suckers, lollipops, licorice, marshmallow, taffy, or
marzipan, or the food
product is a beverage selected from the group consisting of a water, a tea, a
coffee, a juice, a
carbonated or uncarbonated beverage, an alcoholic beverage, a mocktail, a
sports drink, or a
smoothie.
In accordance with an aspect of the invention is a topical formulation
comprising a
composition comprising complexes of a-cyclodextrin and cannabinoids, complexes
of a-
cyclodextrin and terpenes, or mixtures of such produced one or more of the
methods described
herein.
In accordance with another aspect of the invention the topical formulation is
a lotion, a
cream, or an oil.
In accordance with an aspect of the invention here is provided a composition
comprising
complexes of a non-aqueous a-cyclodextrin and a phytocannabinoid, complexes of
non-aqueous
a-cyclodextrin and a synthetically produced cannabinoid, complexes of non-
aqueous a-
cyclodextrin and terpenes, or mixtures of two or more of such complexes,
formulated such that
the complexes are water soluble.
In accordance with an aspect of the invention is a food product comprising the
composition.
In accordance with an aspect of the present invention there is provided a
method of
treating a subject having a disorder, comprising administering a
therapeutically effective amount
of the composition to the subject having the disorder.
In accordance with an aspect of the invention there is provided use of a
therapeutically
effective amount of the composition to treat a disorder in a subject.
In accordance with an aspect of the invention the disorder is agitation,
Alzheimer's
dementia, anxiety disorders, jet lag, depression, anorexia, Attention Deficit
Hyperactivity
Disorder (ADHD) with or without hyperactivity, Autism Spectrum Disorder (ASD),
cachexia,
cancer, chronic cluster headaches, Crohn's disease, convulsions, epilepsy,
gastrointestinal tract
distress (i.e., heartburn indigestion, stomach ache, etc.), glaucoma,
HIV/AIDS, Huntington's
disease, inflammation (chronic or acute), inflammatory bowel disease (IBS),
irritable bowel
syndrome (IBS) with or without diarrhea or constipation, migraine headaches
whether hormone
.. mediated or not, muscle spasms, nausea, neurodegenerative diseases
including Lou Gehrig's
disease, all forms of pain (i.e., acute chronic, neuropathic, trigeminal nerve
pain, and pain
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Date Recue/Date Received 2022-06-17
associated with or accompanying migraine headaches and cancer), Parkinson's
disease and
Parkinsonian-type symptoms, spinal-cord injuries, postmenstrual syndrome
(PMS), Post-
Traumatic Stress Disorder (PTSD), seasonal affective disorder (SAD), seizures,
seizures
associated with Lennox-Gastaut syndrome or Dravet syndrome, sleep disorders
such as
insomnia, spasticity from multiple sclerosis, ulcerative colitis (UC), or
vomiting.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1 to 10 are colour photographs.
Fig. 1 depicts the results of adding an overly concentrated cannabis plant
extract to a
slurry of a-cyclodextrin in water.
Fig. 2 depicts a commercially-available cannabinoid-containing oil diluted
with vegetable
oil when first mixed with a slurry of a-cyclodextrin and water.
Fig. 3 depicts a commercially-available cannabinoid-containing oil diluted
with vegetable
oil mixed with a slurry of a-cyclodextrin in water after gentle mixing for
several hours.
Fig. 4A and 4B depict a comparison between water with (Fig. 4A) or without
(Fig. 4B)
the addition of a dried cannabis plant extract composition comprising THC and
an aqueous a-
cyclodextrin prepared as described herein. Fig. 4A depicts a graduated
cylinder containing
100 mL water mixed with 863mg of a dried cannabis plant extract composition
comprising lmg
THC and a-cyclodextrin (final concentration, 10mg/L THC). The concentration of
THC in the
aqueous mixture was 10 mg/L. Fig. 4B depicts a graduated cylinder containing
100 mL water
without the addition of the THC/ a-cyclodextrin-containing cannabis plant
extract.
Fig. 5 depicts a pure, white free-flowing powder of alpha-cyclodextrin
starting material.
Fig. 6 depicts a viscous, dark green/black, undiluted full spectrum distillate
(58% CBD,
2.8% THC, 2.4% CannaBiChromene, 0.8% CannaBiGerol, 0.3% CannaBiDiVarin and
0.2%
Other Cannabinoids).
Fig. 7 depicts a CBD full spectrum organic distillate following dilution with
ethyl
alcohol.
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Date Recue/Date Received 2022-06-17
Fig. 8 depicts a damp powder containing a cannabinoid/terpene/a-cyclodextrin
mixture
following blending.
Fig. 9 depicts a dried cannabinoid-containing powder after evaporation of
ethyl alcohol.
Fig. 10 depicts a full spectrum cannabinoid-containing powder dissolved in
water at
15mg/L CBD.
Fig. 11 depicts absorption of cannabinoid complexed with an a-cyclodextrin.
DESCRIPTION OF THE INVENTION
Described herein is a method for preparing a composition comprising water
soluble
complexes of a-cyclodextrin and a cannabinoid by mixing one or more
cannabinoids with an
aqueous a-cyclodextrin-containing composition under conditions wherein the a-
cyclodextrin
forms complexes with the cannabinoids. Also described herein is an unexpected
and surprising
method for preparing complexes of a non-aqueous a-cyclodextrin and a
cannabinoid by mixing
one or more cannabinoids with a non-aqueous a-cyclodextrin-containing
composition under
conditions wherein the non-aqueous a-cyclodextrin complexes with one or more
cannabinoid.
The cannabinoids may be a phytocannabinoids, i.e., naturally-occurring
cannabinoids, or
synthetically produced cannabinoids referred to hereinafter as "synthetic
cannabinoids." An
embodiment of this invention is a method for preparing a cannabis plant
extract-derived
composition, by treating a cannabis plant extract with an aqueous a-
cyclodextrin-containing
composition under conditions wherein the a-cyclodextrin forms complexes with
the
cannabinoids and terpenes in the plant extract thereby producing the cannabis
plant extract-
derived composition. Another embodiment of this invention is a method for
preparing a cannabis
plant extract-derived composition, by treating a cannabis plant extract with a
non-aqueous a-
cyclodextrin-containing composition under conditions wherein the non-aqueous a-
cyclodextrin
forms complexes with the cannabinoids and terpenes in the plant extract
thereby producing the
cannabis plant extract-derived composition.
A further embodiment of this invention is a method for preparing a synthetic
cannabinoid-derived composition comprising water soluble complexes of a-
cyclodextrin and
synthetic cannabinoids, by mixing a composition comprising synthetic
cannabinoids with an
aqueous a-cyclodextrin-containing composition under conditions wherein the a-
cyclodextrin
Date Recue/Date Received 2022-06-17
forms complexes with the synthetic cannabinoids thereby producing the
synthetic cannabinoid-
derived composition. Another embodiment of this invention is a method for
preparing a synthetic
cannabinoid-derived composition comprising complexes of a-cyclodextrin and
synthetic
cannabinoids, by mixing a composition comprising synthetic cannabinoids with a
non-aqueous
a-cyclodextrin-containing composition under conditions wherein the non-aqueous
a-cyclodextrin
forms complexes with the synthetic cannabinoids thereby producing the
synthetic cannabinoid-
derived composition.
Also described herein is a cannabis plant extract-derived composition
comprising
complexes of a-cyclodextrin and at least one cannabinoid, or complexes of a-
cyclodextrin and at
least one terpene, or both complexes of a-cyclodextrin and at least one
cannabinoid and
complexes of a-cyclodextrin and at least one terpene. The cannabinoids may be,
e.g., THC,
CBD, cannabinol, or mixtures thereof. The a-cyclodextrin may be in aqueous or
non-aqueous
form.
Also described herein is a composition comprising complexes of a-cyclodextrin
and at
least one synthetic cannabinoid. Synthetic cannabinoids are well known in the
art and include,
e.g., 1-penty1-3-(1-naphthoyl)indole (JWH-018), 1-buty1-3-(1-naphthoyl)indole
(JWH-073), 1-
[2-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200), 5-(1,1-
dimethylhepty1)-2-[(1 R, 3
S)-3-hydroxycyclohexyl]-phenol (CP-47,497), and 5-(1,1-dimethylocty1)-2-[(1 R,
3 S)-3-
hydroxycyclohexyl]-phenol (cannabicyclohexanol; CP-47,497 C8 homologue) and
other CBD
analogs (see e.g., Morales et al. Frontiers in Pharmacology 28 June 2017 Vol
8, Article 422 p. 1-
18). Synthetic cannabinoids also include the FDA-approved compounds
dronabinol, a synthetic
delta-9- tetrahydrocannabinol (THC), and nabilone, which has a chemical
structure similar to
THC and is synthetically derived.
The compositions of this invention, e.g., the cannabis plant extract-derived
composition
and synthetic cannabinoid-derived compositions comprising complexes of a-
cyclodextrin and
cannabinoids and/or complexes of a-cyclodextrin and terpenes, exhibit reduced
or no odor and/or
taste associated with cannabinoids or terpenes, as compared to the starting
material, e.g. a
cannabis plant extract or a synthetic cannabinoid. Moreover, the compositions
of this invention
achieve the effects associated with administration of cannabinoids, e.g.,
reduction in symptoms
of pain or anxiety or both, and/or an increase in feelings of well-being, more
rapidly than
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Date Recue/Date Received 2022-06-17
achieved with the starting material, e.g., the untreated cannabis plant
extract or synthetic
cannabinoid. These effects are also prolonged as compared to the effects
achieved with the
untreated material.
Without wishing to be bound by theory it is contemplated that the a-
cyclodextrin and
cannabinoid complexes are amphiphilic complexes, having a hydrophilic or polar
end and a
hydrophobic or nonpolar end, that are absorbed quickly through mucosal
membranes such that
the cannabinoids are absorbed into the blood stream of the subject more
quickly as compared to
uncomplexed cannabinoids. The compositions of this invention comprising
complexes of a-
cyclodextrin and cannabinoids, and/or complexes of a-cyclodextrin and terpenes
may be in the
form of, e.g., a powder, crystals, granules, an aqueous solution, an aqueous
slurry, or an aqueous
suspension. The powder, crystals, granules, aqueous solution, uniform aqueous
slurry and
uniform aqueous suspension offer the added benefit of controlled and
consistent dosing of the
cannabinoids contained therein.
It has been discovered that a-cyclodextrin renders phytocannabinoids and
terpenes in
cannabis plant extracts, and synthetic cannabinoids having aliphatic chains
long enough to
complex with a-cyclodextrin, soluble in aqueous medium. Without wishing to be
bound by
theory, it is contemplated that the terpenes form complexes with the a-
cyclodextrin and the
aliphatic chains of cannabinoids are long enough to form a complex with a-
cyclodextrin. Thus,
a-cyclodextrin eliminates the terpene taste and odor characteristic of
cannabis plant extracts, e.g.,
cannabis oil or cannabis tar, and renders the cannabinoids and terpenes in the
compositions of
this invention soluble in an aqueous medium.
The cannabis plant that serves as the source of the plant extract from which
the inventive
compositions are derived may be any cannabis plant, including, e.g., a
Cannabis saliva,
Cannabis indica, or Cannabis ruderalis, hemp, and strains and hybrid
varieties, including
crossbred varieties, of such cannabis plants. In an embodiment, the cannabis
plant is not hemp,
e.g., a cannabis plant having a THC content of less than or equal to 0.2% or
less than or equal to
0.3% of the dried flowering portion of the plant. In some embodiments, the
extract is from a
cannabis plants having a THC content of the dried flowering portion of the
plant of less than or
equal to 0.3%. In various embodiments, the cannabis plant is marijuana. In
some embodiments,
the extract is from a cannabis plants having a THC content of the dried
flowering portion of the
12
Date Recue/Date Received 2022-06-17
plant of greater than 0.3%. In some embodiments of this invention, the extract
is prepared from a
cannabis plant having greater than 0.3% to about 30% THC content of dried
flowering portion,
and in other embodiments, the THC content of the dried flowering portion of
the plant is about
5% to about 30%, or about 5% to about 20%, of the dried flowering portion of
the plant.
In addition to the commercially-available cannabis plant extracts comprising
cannabinoids that are suitable for use in the methods of this invention, those
of skill in the art
recognize that there are a variety of extraction methods, e.g., solvent
extraction, and CO2
extraction, known in the art for producing a cannabis plant extract comprising
cannabinoids, or
an extract comprising cannabinoids and terpenes, that are suitable for use in
the methods of this
invention. Some of the known methods produce cannabis plant extracts
containing high levels of
THC, in some instances as high as 80%, 90%, or more (see e.g., Romano and
Hazekamp
Cannabinoids 2013:1(1):1-11, U.S. Patent No. 8895078, and WO 00/25127,
incorporated herein
by reference in their entireties). In some embodiments, the cannabis plant
extract is treated to
increase the ratio of cannabinoids to terpenes, e.g. by reducing the amount of
terpenes and/or
increasing the concentration of cannabinoids. For example, the cannabis plant
extract may be
subjected to purification techniques known in the art, such as distillation,
chromatography, or
crystallization to obtain a composition high in cannabinoid content with a
reduced level of
terpenes. A benefit of using an unpurified cannabis plant extract to produce
the composition of
this invention is that the resulting composition contains a broad spectrum, if
not all, of the
medicinally-beneficial cannabinoids of the starting cannabis plant extract.
One embodiment of the invention is a method for making a cannabis plant-
extract
derived composition comprising a-cyclodextrin and a compound selected from
cannabinoids,
terpenes, or mixtures thereof, the method comprising the steps of: (a)
combining a cannabis plant
extract comprising at least one cannabinoid and/or at least one terpene with
an aqueous a-
cyclodextrin-containing composition, e.g., an aqueous a-cyclodextrin solution,
an aqueous a-
cyclodextrin slurry, or an aqueous a-cyclodextrin suspension; and (b) mixing
the cannabis plant
extract and the aqueous a-cyclodextrin composition for a sufficient time to
form a complex
between the aqueous a-cyclodextrin and the cannabinoid(s) and/or terpene(s),
thereby producing
an aqueous mixture comprising complexes of a-cyclodextrin and a compound
selected from
cannabinoids, terpenes, and/or mixtures thereof. The method may further
comprise the step of (c)
13
Date Recue/Date Received 2022-06-17
drying the mixture from step (b), thereby producing a cannabis plant extract-
derived composition
comprising complexes of a-cyclodextrin and at least one cannabinoid, or
complexes of a-
cyclodextrin and at least one terpene, or mixtures of complexes of a-
cyclodextrin and at least one
cannabinoid and complexes of a-cyclodextrin and at least one terpene, in the
form of an odorless
and/or tasteless water-soluble powder.
Suitable methods for drying the mixture include evaporating the mixture in
dishes or
pans, evaporating under reduced pressure and/or ambient temperatures and/or
moderately
elevated temperatures (e.g., temperatures ranging from 40-150 C), evaporating
in a rotary
evaporator, freeze drying or lyophilization, spray drying, or by any other
drying method known
to a person of skill in the art. This method may also be applied to a
synthetic cannabinoid
containing composition rather than a cannabis plant extract to produce a
synthetic cannabinoid-
derived composition comprising complexes of a-cyclodextrin and one or more
synthetic
cannabinoids.
Another embodiment of the invention is a method for making a cannabis plant-
extract
derived composition comprising a-cyclodextrin and a compound selected from
cannabinoids,
terpenes, or mixtures thereof, the method comprising the steps of: (a)
combining a cannabis plant
extract comprising at least one cannabinoid and/or at least one terpene with a
non-aqueous a-
cyclodextrin-containing composition, e.g., a non-aqueous a-cyclodextrin
powder, crystals, or
granules; and (b) mixing the cannabis plant extract and the non-aqueous a-
cyclodextrin
composition for a sufficient time to form a complex between the non-aqueous a-
cyclodextrin and
the cannabinoid(s) and/or terpene(s), thereby producing a non-aqueous mixture
comprising
complexes of a-cyclodextrin and a compound selected from cannabinoids,
terpenes, and/or
mixtures thereof. The method may further comprise the step of (c) removing
diluents from the
mixture of step (b), thereby producing a cannabis plant extract-derived
composition comprising
complexes of a-cyclodextrin and at least one cannabinoid, or complexes of a-
cyclodextrin and at
least one terpene, or mixtures of complexes of a-cyclodextrin and at least one
cannabinoid and
complexes of a-cyclodextrin and at least one terpene, in the form of an
odorless and/or tasteless
water-soluble powder. Suitable methods for removing diluents from the mixture
include
evaporating diluents from the mixture in dishes or pans, evaporating under
reduced pressure
and/or ambient temperatures and/or moderately elevated temperatures (e.g.,
temperatures ranging
14
Date Recue/Date Received 2022-06-17
from 40-150 C), evaporating in a rotary evaporator, freeze drying or
lyophilization, spray
drying, or by any other drying method known to a person of skill in the art.
This method may
also be applied to a synthetic cannabinoid containing composition rather than
a cannabis plant
extract to produce a synthetic cannabinoid-derived composition comprising
complexes of a-
cyclodextrin and one or more synthetic cannabinoids.
In an embodiment, the method of (a) combining a cannabis plant extract
comprising at
least one cannabinoid and/or at least one terpene with a non-aqueous a-
cyclodextrin-containing
composition, e.g., a non-aqueous a-cyclodextrin powder, crystals, or granules;
and (b) mixing
the cannabis plant extract and the non-aqueous a-cyclodextrin composition for
a sufficient time
to form a complex between the non-aqueous a-cyclodextrin and the
cannabinoid(s) and/or
terpene(s) may not require a step of (c) drying the mixture from step (b).
Step (c) of removing
diluents from the mixture of step (b) may optionally be performed in the non-
aqueous
embodiment. Advantageously, by using non-aqueous cyclodextrin, step (c) of
removing one or
more diluents may be advantageously shorter, as compared with the drying of
step (c) when
aqueous cyclodextrin is used.
The non-aqueous methods may also be applied to a synthetic cannabinoid
containing
composition rather than a cannabis plant extract to produce a synthetic
cannabinoid-derived
composition comprising complexes of a-cyclodextrin and one or more synthetic
cannabinoids.
The cannabis plant extract or synthetic cannabinoids and the aqueous a-
cyclodextrin-
containing composition are mixed together for a length of time sufficient to
form complexes
between the a-cyclodextrin and the cannabinoid(s) and/or terpene(s), e.g., at
least 5 minutes, at
least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour,
at least 3 hours, at least
6 hours, or at least 12 hours. The cannabis plant extract or synthetic
cannabinoids and the
aqueous a-cyclodextrin containing composition are mixed together under
conditions wherein an
emulsion is not formed. In one embodiment, the synthetic cannabinoid-derived
composition of
this invention comprising complexes of a-cyclodextrin and the synthetic
cannabinoids is not an
emulsion.
The cannabis plant extract or synthetic cannabinoids and the non-aqueous a-
cyclodextrin-
containing composition are mixed together vigorously for a length of time
sufficient to form
complexes between the non-aqueous a-cyclodextrin and the cannabinoid(s) and/or
terpene(s),
Date Recue/Date Received 2022-06-17
e.g., until the material appears uniform and homogeneous. The cannabis plant
extract or
synthetic cannabinoids and the non-aqueous a-cyclodextrin containing
composition are mixed
together under conditions wherein a complex is formed. By way of non-limiting
example, the
cannabinoid is diluted in alcohol (e.g., ethyl or isopropyl), followed by
adding the diluted
cannabinoid to dry a-CD, followed by vigorous blending in a food processor or
blender. In an
embodiment, the blended materials are incubated in a sealed container at about
ambient
temperature, about 50 C, about 60 C, or about 70 C for about 5 minutes, about
15 minutes, about
30 minutes, about 45 minutes, about 1 hour, about 90 minutes, about 2 hours,
about 2.5 hours,
about 3 hours, about 3.5 hours, about 4 hours before the seal is removed. In
another preferred
embodiment, the blended materials do not require incubation after blending.
Following blending and any incubation, the alcohol diluent is allowed to
evaporate at any
time and temperature sufficient to achieve evaporation of the diluent without
alteration of the
chemical composition of the blended materials. In an embodiment, evaporation
is conducted at
about 50 C, about 60 C, or about 70 C for about 2-4 hours, about 1-2 hours, or
about 30 minutes
-1 hour. In a preferred embodiment, evaporation is conducted at about 60 C for
about 1-2 hours.
Suitable aqueous a-cyclodextrin-containing compositions for mixing with the
cannabis
plant extract or synthetic cannabinoids in the methods described herein
comprise at least
15% w/v a-cyclodextrin. Preferable a-cyclodextrin slurries or suspensions
comprise at least
20% w/v a-cyclodextrin. Preferable a-cyclodextrin slurries or suspensions
comprise at least
25% w/v a-cyclodextrin. Suitable aqueous a-cyclodextrin slurries or
suspensions comprise an
amount of a-cyclodextrin that exceeds the solubility of a-cyclodextrin in the
solution such that
non-solubilized a-cyclodextrin is present in the slurry or suspension. In an
embodiment of this
invention, the aqueous a-cyclodextrin compositions for mixing with the
cannabis plant extract or
synthetic cannabinoids comprise about 15% w/v to about 40% w/v a-cyclodextrin,
about
20% w/v to about 35% w/v a-cyclodextrin or about 20% to about 30% w/v a-
cyclodextrin.
Suitable non-aqueous a-cyclodextrin-containing compositions for mixing with
the
cannabis plant extract or synthetic cannabinoids in the methods described
herein comprise a
concentration of at least about 2000 grams of a-cyclodextrin per liter of
cannabis
extract/synthetic cannabinoid mixture. Other non-aqueous a-cyclodextrin
powders, crystals, or
granules comprise a concentration of at least about 2250 grams of a-
cyclodextrin per liter of
16
Date Recue/Date Received 2022-06-17
cannabis extract/synthetic cannabinoid mixture. Preferable a-cyclodextrin
powders, crystals, or
granules may also comprise at least about 2500 grams of non-aqueous a-
cyclodextrin per liter of
cannabis extract/synthetic cannabinoid mixture. In other embodiments of this
invention, the non-
aqueous a-cyclodextrin compositions for mixing with the cannabis plant extract
or synthetic
cannabinoids comprise at least about 2750 grams, at least about 3000 grams, at
least about 3500
grams, at least about 4000 grams, at least about 5000 grams, at least about
7500 grams, or at least
about 10,000 grams of a-cyclodextrin per liter of other components. In a
further embodiment, the
non-aqueous a-cyclodextrin compositions for mixing with the cannabis plant
extract or synthetic
cannabinoids comprise more than 10,000 grams of a-cyclodextrin to a liter of
other components.
It is recognized that the amount of a-cyclodextrin to be mixed with the
cannabis plant
extract or synthetic cannabinoids to complex with the cannabinoids and
terpenes may be varied
depending on the characteristics of the starting material, e.g., its
viscosity, its solid content,
characteristics of its other solid components, its cannabinoid content, or its
terpene content, and
the desired characteristics of the composition produced by the methods
described herein, e.g., a
solution, suspension, slurry, powder, crystals, or granules.
In an embodiment of the invention the ratio of aqueous a-cyclodextrin to the
cannabis
plant extract is at least about 70:1 weight/weight (w/w), at least about 80:1
w/w, at least about
85:1 w/w, at least about 95:1 w/w, or at least about 100:1 w/w, at least about
120:1, and any and
all ranges therebetween.
In another embodiment of the invention the ratio of non-aqueous a-cyclodextrin
to the
cannabis plant extract is at least about 2:1 weight/weight (w/w), at least
about 10:1 w/w, at least
about 20:1 w/w, at least about 50:1 w/w, at least about 100:1 w/w or at least
about 200:1 w/w, at
least about 300:1, at least about 500:1, at least about 750:1, at least about
1000:1, at least about
1500:1, at least about 2000:1, at least about 2500:1, at least about 3000:1,
at least about 4000:1,
at least about 5000:1, at least about 7500:1, at least about 10,000:1, and any
and all ranges
therebetween. In a further embodiment, the ratio of non-aqueous a-cyclodextrin
to the cannabis
plant extract is greater than 10,000:1 weight/weight.
In one embodiment of the invention, the aqueous a-cyclodextrin-containing
composition,
e.g. a solution, slurry, or suspension, is combined with the cannabis plant
extract or synthetic
cannabinoids in an amount and mixed for a time and at a temperature such that
at least 80%, at
17
Date Recue/Date Received 2022-06-17
least 85%, at least 90%, at least 95%, at least 99%, or at least 100% of the
cannabinoids are
complexed with the a-cyclodextrin. In another embodiment, a non-aqueous a-
cyclodextrin-
containing composition, e.g., a solid cyclodextrin compound, is combined with
the cannabis
plant extract or synthetic cannabinoids in an amount and mixed for a time and
at a temperature
such that at least 80%, at least 85%, at least 90%, at least 95%, at least
99%, or at least 100% of
the cannabinoids are complexed with the non-aqueous a-cyclodextrin.
In one embodiment of the invention, the aqueous a-cyclodextrin-containing
composition,
e.g., a solution, slurry, or suspension, is combined with the cannabis plant
extract in an amount
such that at least 80%, at least 85%, at least 90%, at least 95%, at least
99%, or at least 100% of
the terpenes are complexed with the a-cyclodextrin. In another embodiment, a
non-aqueous a-
cyclodextrin-containing solid composition, e.g., powder, crystalline or
granule cyclodextrin
compound, is combined with the cannabis plant extract in an amount such that
at least 80%, at
least 85%, at least 90%, at least 95%, at least 99%, or at least 100% of the
terpenes are
complexed with the solid a-cyclodextrin.
In one embodiment of the invention, the aqueous a-cyclodextrin-containing
composition,
e.g., solution, slurry, or suspension, is combined with the cannabis plant
extract or synthetic
cannabinoids in an amount such that at least 80%, at least 85%, at least 90%,
at least 95%, at
least 99%, or at least 100% of the cannabinoids and terpenes are complexed
with the cc-
cyclodextrin. In another embodiment, a non-aqueous a-cyclodextrin-containing
composition,
e.g., a solid cyclodextrin compound (e.g., powder, crystal, or granule), is
combined with the
cannabis plant extract or synthetic cannabinoids in an amount such that at
least 80%, at least
85%, at least 90%, at least 95%, at least 99%, or at least 100% of the
cannabinoids and terpenes
are complexed with the solid a-cyclodextrin.
In an embodiment of this invention, to achieve the cannabis plant extract-
derived
composition or synthetic cannabinoid-derived composition of this invention
having essentially
no odor or taste typically associated with a cannabinoid, the ratio of aqueous
a-cyclodextrin to
cannabinoids in the extract or synthetic cannabinoid is greater than about
70:1 w/w, greater than
85:1 w/w, greater than 90:1 w/w, greater than 95:1 w/w, greater than about
100:1 w/w and
greater than about 120:1 w/w and ranges there between.
18
Date Recue/Date Received 2022-06-17
In another embodiment of the invention, to achieve the cannabis plant extract-
derived
composition or synthetic cannabinoid-derived composition of this invention
having essentially
no odor or taste typically associated with a cannabinoid, the ratio of non-
aqueous a-cyclodextrin
to cannabinoids in the extract or synthetic cannabinoid is greater than about
10:1 weight/weight
(w/w), greater than about 20:1 w/w, greater than about 50:1 w/w, greater than
about 100:1 w/w,
or greater than about 200:1 w/w, greater than about 300:1, greater than about
500:1, greater than
about 750:1, greater than about 1000:1, greater than about 1500:1, greater
than about 2000:1,
greater than about 2500:1, greater than about 3000:1, greater than about
4000:1, greater than
about 5000:1, greater than about 7500:1, greater than about 10,000:1, and any
and all ranges
therebetween. In a further embodiment, the ratio of non-aqueous a-cyclodextrin
to the cannabis
plant extract is greater than 10,000:1 weight/weight.
U.S. Patent No. 2017/0224842 (Czap) describes mixing cyclodextrin with
cannabinoids
from partially purified, low terpene containing, hemp oil. Unlike the Czap
formulations, which
are formulated with amylase-like enzymes that hydrolyze the cyclodextrins, the
cannabis plant
extract-derived compositions and synthetic cannabinoid-derived composition of
this invention do
not require an amylase-like enzyme to be effective or to achieve their desired
results. Thus, an
aspect of this invention is a cannabis plant extract-derived compositions or
synthetic
cannabinoid-derived composition comprising complexes of a-cyclodextrin and a
compound
selected from cannabinoids, terpenes, or mixtures thereof, wherein the
compositions do not
comprise an amylase or an amylase-like enzyme, e.g., a cyclodextrinase,
maltogenic amylase, or
neopullulanase, that is formulated so that the cyclodextrin-degrading activity
of the enzyme is
activated on delivery of the composition to a subject.
In one embodiment, the plant extract-derived compositions of this invention
comprise a-
cyclodextrin complexes comprising THC, CBD, cannabinol, or mixtures thereof.
In an
embodiment of the invention, the cannabinoids in complex with a-cyclodextrin
are selected from
the group consisting of THC, CBD, cannabinol, and mixtures thereof.
Preferably, the cannabis plant extract and synthetic cannabinoids (or
compositions
comprising synthetic cannabinoids) have a consistency that facilitates mixing
with the aqueous
or non-aqueous a-cyclodextrin-containing composition. For example, the
cannabis plant extract
and synthetic cannabinoids may have the consistency of a free-flowing oil.
Thus, in an
19
Date Recue/Date Received 2022-06-17
embodiment of this invention, the cannabis plant extract or synthetic
cannabinoid is mixed with a
solvent to facilitate its mixing with an aqueous a-cyclodextrin¨containing
composition. The
solvent may be for example water, an oil, or an alcohol.
In the case of mixing with a non-aqueous, a-cyclodextrin-containing
composition, the
cannabis plant extract (or compositions comprising synthetic cannabinoids) may
be in a solid
form, without solvent. Alternatively, the cannabis plant extract (or
compositions comprising
synthetic cannabinoids) may be contained in any non-aqueous solvent, including
for example,
ethyl alcohol, propyl alcohol, isopropyl alcohol, or butyl alcohol.
In an embodiment, the amount of solvent added to the cannabis plant extract or
synthetic
cannabinoid is sufficient such that the cannabis plant extract or synthetic
cannabinoid is free-
flowing. The amount of solvent added to the cannabis plant extract or
synthetic cannabinoid may
be up to 95% v/v of the total volume of the solvent and cannabis plant extract
mixture. The
amount of solvent added to the cannabis plant extract or synthetic cannabinoid
is preferably up to
75% v/v. The amount of solvent added to the cannabis plant extract or
synthetic cannabinoid is
more preferably up to 50% v/v. The extract or synthetic cannabinoid may be
mixed with the
solvent before or after, preferably before, combining the extract or synthetic
cannabinoid with an
aqueous a-cyclodextrin¨containing composition. Preferably, the solvent is
mixed with the
extract or synthetic cannabinoid before combining the extract or synthetic
cannabinoid with the
aqueous cyclodextrin¨containing composition and then mixing the cannabis plant
extract or
synthetic cannabinoid and the aqueous cyclodextrin¨containing composition for
a sufficient time
to form complexes between the a-cyclodextrin and the cannabinoid(s) and/or
terpene(s). The
aqueous a-cyclodextrin¨containing composition for use in the method may be an
aqueous a-
cyclodextrin¨containing solution, slurry, or suspension. The non-aqueous a-
cyclodextrin¨
containing composition for use in the method may be in the form of a powder,
crystals, granules,
or any other solid form.
Suitable oils for mixing with the cannabis plant extract or synthetic
cannabinoid include
non-toxic oils, such as edible oils, macerated oils, essential oils, and
pharmaceutically acceptable
oils. Examples of suitable edible oils include coconut oil, corn oil, olive
oil, palm oil, cottonseed
oil, peanut oil, rapeseed oil, safflower oil, sunflower oil, sesame oil,
soybean oil, almond oil,
pumpkin or squash seed oil, Brazil nut oil, cashew oil, hazelnut oil,
macadamia nut oil, pecan oil,
Date Recue/Date Received 2022-06-17
pine nut oil, pistachio oil, walnut oil, citrus oils, carob oil, cocoa butter,
shea butter, hemp oil,
flaxseed oil, grapeseed oil, other seed oils. Examples of suitable macerated
oils include arnica
oil, calendula oil, carrot oil, chickweed oil, comfrey oil, galangal oil,
horse chestnut oil, linden
blossom oil, marigold oil, meadowsweet oil, mullein oil, sea weed oil, and St.
John's Wort oil.
Examples of suitable essential oils include bergamot oil, camphor oil,
peppermint oil, cannabis
flower essential oil, cardamom seed oil, cinnamon oil, citronella oil, coffee
oil, eucalyptus oil,
garlic oil, fennel seed oil, fenugreek oil, ginger oil, henna oil, jasmine
oil, rose oil, rosehip oil,
lavender oil, ylang-ylang oil, wintergreen oil, turmeric oil, thyme oil.
Examples of
pharmaceutically acceptable oils include ethyl butyrate, ethyl caprylate,
ethyl oleate,
triglycerides, and soybean oil.
Suitable alcohols for mixing with the cannabis plant extract or synthetic
cannabinoid
include alcohols that are suitable for food and/or natural products and/or
pharmaceutical
production. Examples of suitable alcohols are ethanol and isopropanol. The
amount of alcohol
added to the cannabis plant extract or synthetic cannabinoid is sufficient to
make the cannabis
plant extract or synthetic cannabinoid free flowing. The amount of alcohol
added to the cannabis
plant extract or synthetic cannabinoid may be up to 95% v/v, 90% v/v, 85% v/v,
80% v/v,
75% v/v, 70% v/v, 65% v/v, 60% v/v, 55% v/v, 50% v/v, or 45% v/v of the total
volume of the
alcohol and cannabis plant extract mixture. The cannabis plant extract or
synthetic cannabinoid
may be mixed with the alcohol before or after combining the extract or
synthetic cannabinoid
with an aqueous or non-aqueous a-cyclodextrin-containing composition.
Preferably, the alcohol
is mixed with the extract or synthetic cannabinoid before mixing the extract
or synthetic
cannabinoid with the aqueous a-cyclodextrin-containing composition, e.g., an
aqueous solution,
slurry, or suspension or the non-aqueous a-cyclodextrin-containing
composition, e.g., powder,
crystals, or granules. The cannabis plant extract or synthetic cannabinoid may
be mixed with an
alcohol in a 1:15 w/v, 1:10 w/v, 1:5 w/v, 1:2 w/v ratio of extract to alcohol,
and ranges there
between.
The effects of the consistency and/or viscosity of the plant extract in the
methods of this
invention are shown in Figures 1-3. As shown in Fig. 1, adding an overly
concentrated tar-like
cannabinoid-containing extract to an a-cyclodextrin slurry results in the tar-
like material not
being suspended in an aqueous a-cyclodextrin slurry. Instead, the tar-like
material congeals into
21
Date Recue/Date Received 2022-06-17
clumps of material that stick to the walls of the container (e.g., a tube).
The clumps of material
remain unchanged even after extensive mixing. In contrast, Fig. 2 shows a tube
containing a
commercially-available cannabinoid-containing oil diluted with vegetable oil
when it is first
mixed with an aqueous a-cyclodextrin containing slurry. As can be seen,
undissolved a-
cyclodextrin rests at the bottom of the tube while the middle portion of the
tube contains an
aqueous layer comprising both dissolved a-cyclodextrin and suspended
undissolved a-
cyclodextrin. The cannabinoid-containing oil appears to be distributed between
the undissolved
a-cyclodextrin layer and the top of the aqueous layer. Gentle mixing is used
in order to avoid the
formation of froth, as seen at the top of the container, and to avoid the
formation of an emulsion.
After gently mixing the tube for several hours, the a-cyclodextrin/oil slurry
mixture appears
homogeneous and has a uniform off-white color (Fig. 3). Due to the gentle
mixing, an emulsion
is not formed and there is no froth at the top of the container. The aqueous
mixture in the
container is ready for using as a slurry in an edible product, e.g., a
cupcake, and/or for drying,
e.g., into a powder.
An embodiment of this invention is a cannabis plant extract-derived
composition or
synthetic cannabinoid-derived composition comprising complexes of cannabinoids
and aqueous
or non-aqueous a-cyclodextrin, where the complexes are water soluble. Fig 4A
depicts a
graduated cylinder containing a mixture of 100 mL water and 863 mg of a dried
cannabis plant
extract-derived composition of this invention comprising lmg THC in complexes
with a-
cyclodextrin and Fig 4B depicts a graduated cylinder with just 100 ml water.
The mixture in Fig.
4A and the water in Fig. 4B are indistinguishable. The cannabis plant extract
composition
combined with water depicted in Fig. 4A was prepared from cannabis plant
distillate.
An aspect of this invention is a cannabis plant extract-derived composition
comprising
water soluble complexes of a-cyclodextrin and terpenes; a-cyclodextrin and
THC; a-
cyclodextrin and CBD, or a-cyclodextrin and cannabinol, or mixtures of such
complexes.
Another aspect of the invention is a cannabis plant extract-derived
composition comprising
complexes selected from the group consisting of a-cyclodextrin and terpenes, a-
cyclodextrin and
THC, a-cyclodextrin and CBD, a-cyclodextrin and cannabinol, and mixtures of
such complexes
that are water soluble. An aspect of this invention is a synthetic cannabinoid-
derived composition
comprising water soluble complexes of a-cyclodextrin and one or more synthetic
cannabinoids.
22
Date Recue/Date Received 2022-06-17
Complexes of a-cyclodextrin and terpenes; a-cyclodextrin and THC; a-
cyclodextrin and CBD,
or a-cyclodextrin and cannabinol, or mixtures of such complexes may themselves
be water
soluble or may be soluble in alcohol, oil, or any other liquids, or
combination of liquids,
regardless of whether aqueous a-cyclodextrin or non-aqueous a-cyclodextrin is
used to form the
complex.
In one embodiment of the invention, the cannabis plant-derived composition or
synthetic
cannabinoid-derived composition of this invention is an aqueous solution, an
aqueous slurry, or
an aqueous suspension comprising complexes of a-cyclodextrin and
cannabinoid(s) and/or
complexes of a-cyclodextrin and terpene(s) or mixtures of such complexes. In
another
embodiment of the invention, the cannabis plant-derived composition or
synthetic cannabinoid-
derived composition of this invention is a solution, slurry, or suspension
comprising complexes
of a-cyclodextrin and cannabinoid(s) and/or complexes of a-cyclodextrin and
terpene(s) or
mixtures of such complexes in a non-aqueous solvent.
In a further embodiment, the cannabis plant-derived composition or synthetic
cannabinoid-derived composition of this invention is a non-aqueous solid
comprising complexes
of a-cyclodextrin and cannabinoid(s) and/or complexes of a-cyclodextrin and
terpene(s) or
mixtures of such complexes.
In one embodiment of the invention, the cannabis plant-derived composition or
synthetic
cannabinoid-derived composition of this invention is a water-soluble powder,
crystals, or
granules comprising complexes of a-cyclodextrin and cannabinoid(s) and/or
complexes of a-
cyclodextrin and terpene(s) or mixtures of such complexes.
An embodiment of the invention is a liquid comprising the cannabis plant
extract-derived
composition or synthetic cannabinoid-derived composition described herein
comprising
complexes of a-cyclodextrin and cannabinoid(s) and/or complexes of a-
cyclodextrin and
terpene(s) or mixtures of such complexes. The liquid may be, for example, a
water (including
flavored water), a tea, a coffee, a juice, a smoothie, any carbonated beverage
(e.g., a carbonated
water or soft drink), a sports or other rehydration drink, a mocktail, or an
alcoholic beverage
(e.g., beer, wine, wine cooler, cocktail, or liquor).
23
Date Recue/Date Received 2022-06-17
Another aspect of the invention is a food product comprising a cannabis plant
extract-
derived composition or synthetic cannabinoid-derived composition of this
invention such that the
food comprises complexes of a-cyclodextrin and at least one cannabinoid and/or
complexes of a-
cyclodextrin and at least one terpene, or mixtures of such complexes. In one
embodiment, the
food product of the invention may comprise a sweetening agent, a coloring
agent and/or a
flavoring agent known in the art.
In one embodiment, the food product is a farinaceous food product or a
confection.
Examples of a farinaceous food products include, e.g., cake, muffin, brownie,
cookie, cracker,
doughnut, or biscuit. Examples of a confection include e.g., caramel,
chocolate, nougat, chewing
gum, toffee, lozenge, fondant, halvah, jelly, gelatin, candies, e.g., gummies
(e.g., gummy bears),
suckers or lollipops, licorice, marshmallow, taffy, or marzipan.
In another embodiment, the food product is a non-farinaceous food product.
Examples of
a non-farinaceous food product include e.g., a dairy product, a meat product,
a fruit product, or a
vegetable product. Preferred examples of a non-farinaceous food product
include beverages,
such as tea, herbal tea, coffee, juice, bottled water, carbonated beverages,
smoothies, sports or
other rehydration drinks, mocktails or alcoholic beverages.
While cannabis plant-derived compositions and synthetic cannabinoid-derived
compositions of this invention can be added to the food products in any
amount, it is understood
that a preferred amount would be such that the organoleptic properties between
the food product
with and without the cannabis plant-derived compositions or synthetic
cannabinoid-derived
compositions are not significantly different.
The cannabis plant extract-derived composition or synthetic cannabinoid-
derived
composition of this invention may be mixed with an edible oil, e.g., include
coconut oil, corn oil,
olive oil, palm oil, cottonseed oil, peanut oil, rapeseed oil, safflower oil,
sunflower oil, sesame
.. oil, soybean oil, almond oil, pumpkin or squash seed oil, Brazil nut oil,
cashew oil, hazelnut oil,
macadamia nut oil, pecan oil, pine nut oil, pistachio oil, walnut oil, citrus
oils, carob oil, cocoa
butter, shea butter, hemp oil, flaxseed oil, grapeseed oil, other seed oils.
Another aspect of this invention is a method for increasing the content of THC
and/or
CBD and/or synthetic cannabinoid in a food product by adding the cannabis
plant-derived
24
Date Recue/Date Received 2022-06-17
composition or synthetic cannabinoid-derived composition of this invention to
a food product in
an amount sufficient to increase the THC and/or CBD and/or synthetic
cannabinoid content of
the food product.
The cannabis plant-derived composition or synthetic cannabinoid-derived
composition of
this invention may be added to the food product at any stage of its
preparation. For example, a
cannabis plant extract-derived composition or synthetic cannabinoid-derived
composition
described herein may be mixed with the food product's ingredients so that it
is distributed
throughout the food product and the product may then be cooked, baked,
grilled, or fried, or the
composition may be mixed or added to the final food product after cooking,
baking, grilling or
frying. In some instances, a cannabis plant extract-derived composition and
synthetic
cannabinoid-derived composition of this invention may be applied to the
surface of the food
product, e.g., as a glaze, icing, sprinkling, or coating, or the composition
may be simply
sprinkled on or mixed with the food product, e.g., stirred into a beverage,
e.g., a tea, cocoa,
coffee, juice, smoothie, or alcoholic beverage.
Another embodiment of the invention is a topical formulation comprising a
cannabis
plant extract-derived composition of this invention. An embodiment of this
invention is a topical
formulation comprising a synthetic, cannabinoid-derived composition of the
invention. The
topical formulation may be, for example, a lotion, an oil, a topical gel, a
spray, an ointment, or a
cream comprising the cannabis plant extract-derived composition or synthetic
cannabinoid-
derived composition of this invention comprising complexes of a-cyclodextrin
and at least one
cannabinoid or complexes of a-cyclodextrin and at least one terpene, or
comprising mixtures of
such complexes.
The topical formulation may include a compound which enhances absorption or
penetration of the a-cyclodextrin complexes through the skin. Typical carriers
include alcohol,
water, mineral oil, liquid petrolatum, white petrolatum, glycerin,
dimethylsulfoxide,
polyethylene glycol and propylene glycol.
The cannabis plant extract-derived composition or synthetic cannabinoid-
derived
composition of this invention may be added to the topical formulation at any
stage of its
preparation, e.g., the cannabis plant extract-derived composition or synthetic
cannabinoid-
derived composition may be mixed with the topical formulation's ingredients
and then mixed
Date Recue/Date Received 2022-06-17
together or the cannabis plant extract-derived composition or synthetic
cannabinoid-derived
composition may be mixed or added to the final topical formulation. The
cannabis plant extract-
derived composition or synthetic cannabinoid-derived composition of this
invention may be
mixed with an oil suitable for topical application, e.g., an essential oil,
e.g., bergamot oil,
camphor oil, peppermint oil, cannabis flower essential oil, cardamom seed oil,
cinnamon oil,
citronella oil, coffee oil, eucalyptus oil, garlic oil, fennel seed oil,
fenugreek oil, ginger oil, henna
oil, jasmine oil, rose oil, rosehip oil, lavender oil, ylang-ylang oil,
wintergreen oil, turmeric oil,
or thyme oil.
In one embodiment, the topical formulation of this invention comprises
complexes of
terpenes. In another embodiment, the topical formulation of this invention
comprises complexes
of a-cyclodextrin and cannabinoids, e.g., a-cyclodextrin and THC, a-
cyclodextrin and CBD, a-
cyclodextrin and cannabinol, or a-cyclodextrin and one or more synthetic
cannabinoids, or
mixtures thereof, where any of the complexes of cannabinoids may also
optionally comprise
complexes of terpenes. In one embodiment, the topical formulation comprises
complexes
selected from the group consisting of THC-a-cyclodextrin complexes, CBD-a-
cyclodextrin
complexes, or cannabinol-a-cyclodextrin complexes, and mixtures thereof. In
one embodiment,
the topical formulation comprises complexes of-a-cyclodextrin in complex with
one or more of
1-penty1-3-(1-naphthoyl)indole (JWH-018), 1-buty1-3-(1-naphthoyl)indole (JWH-
073), 14244-
morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200), 5-(1,1-dimethylhepty1)-2-
[(1 R, 3 S)-3-
hydroxycyclohexyl]-phenol (CP-47,497), and 5-(1,1-dimethylocty1)-2-[(1 R, 3 S)-
3-
hydroxycyclohexyl]-phenol (cannabicyclohexanol; CP-47,497 C8 homologue) and
other CBD
analogs (see e.g., Morales et al. Frontiers in Pharmacology 28 June 2017 Vol
8, Article 422 p. 1-
18), dronabinol, or nabilone. In one embodiment, the topical formulation
comprises complexes
of-a-cyclodextrin in complex with one or more synthetic cannabinoids selected
from the group
consisting of 1-penty1-3-(1-naphthoyl)indole (JWH-018), 1-butyl-3-(1-
naphthoyl)indole (JWH-
073), 142-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200), 5-(1,1-
dimethylhepty1)-2-
[(1 R, 3 S)-3-hydroxycyclohexyl]-phenol (CP-47,497), and 5-(1,1-dimethylocty1)-
2-[(1 R, 3 S)-
3-hydroxycyclohexyl]-phenol (cannabicyclohexanol; CP-47,497 C8 homologue),
dronabinol,
and nabilone.
26
Date Recue/Date Received 2022-06-17
An aspect of the invention is a method of alleviating pain in a subject in
need thereof,
comprising administering to the subject a therapeutically effective amount of
a cannabis plant-
derived composition or synthetic cannabinoid-derived composition of the
invention described
herein, comprising complexes of a-cyclodextrin and at least one cannabinoid
(e.g., THC, CBD,
and/or cannabinol or a synthetic cannabinoid). The cannabis plant-derived
composition
administered may also comprise complexes of a-cyclodextrin and at least one
terpene. A
therapeutically effective amount of the cannabis plant-derived composition or
the synthetic
cannabinoid-derived composition in this embodiment is an amount sufficient to
alleviate (e.g.,
reduce or eliminate) pain in the subject in need thereof. The subject in need
thereof is a subject,
e.g. a human, non-human primate, horse, cow, sheep, pig, goat, dog, cat, rat,
or mouse, suffering
from pain.
An aspect of the invention is a method of alleviating anxiety in a subject in
need thereof,
comprising administering a therapeutically effective amount of a cannabis
plant-derived
composition or synthetic cannabinoid-derived composition of the invention
described herein
comprising complexes of a-cyclodextrin and at least one terpene and/or a-
cyclodextrin and at
least one cannabinoid (e.g., THC, CBD, and/or cannabinol, or synthetic
cannabinoid) to the
subject. A therapeutically effective amount of the composition of this
invention is an amount
sufficient to alleviate (e.g., reduce or eliminate) anxiety in the subject in
need thereof. The
subject in need thereof is a subject, e.g. a human, non-human primate, horse,
cow, sheep, pig,
.. goat, dog, cat, rat, or mouse, suffering from anxiety.
An aspect of the invention is a method of increasing feelings of well-being
and relaxation
in a subject comprising administering a sufficient amount of a cannabis plant-
derived
composition or synthetic cannabinoid-derived composition of the invention
comprising
complexes of a-cyclodextrin and at least one terpene and/or a-cyclodextrin and
at least one
cannabinoid (e.g., THC, CBD, and/or cannabinol, or synthetic cannabinoid) to
the subject. A
sufficient amount of the compositions of this invention is an amount
sufficient to increase
feelings of well-being and relaxation in the subject.
Another aspect of the invention is a method of treating a subject, e.g. a
human, a non-
human primate, a horse, cow, sheep, pig, goat, dog, cat, rat, or mouse, having
a disorder having
symptoms that are alleviated (e.g., reduced or eliminated) by treatment with a
cannabinoid. The
27
Date Recue/Date Received 2022-06-17
method comprises administering a therapeutically effective amount of a
cannabis plant-derived
composition or synthetic cannabinoid-derived composition of the invention
comprising
complexes of a-cyclodextrin and at least one terpene and/or a-cyclodextrin and
at least one
cannabinoid (e.g., THC, CBD, and/or cannabinol and/or a synthetic cannabinoid)
to the subject
having the disorder. In an aspect of the invention, the composition of this
invention administered
to the subject comprises complexes of a-cyclodextrin and cannabinoids (e.g.,
THC, CBD,
cannabinol, and synthetic cannabinoids).
Examples of disorders that can be treated with the compositions described
herein include
trigeminal neuralgia, agitation, Alzheimer's dementia, anxiety disorders, jet
lag, depression,
anorexia, Attention Deficit Disorder (ADD) with or without hyperactivity,
Autism Spectrum
Disorder (ASD), cachexia, cancer, chronic cluster headaches, Crohn's disease,
convulsions,
epilepsy, gastrointestinal tract distress (e.g., heartburn indigestion,
stomach ache), glaucoma,
HIV/AIDS, Huntington's disease, inflammation (chronic or acute), inflammatory
bowel disease,
irritable bowel syndrome (IBS) with or without diarrhea or constipation,
migraine headaches
whether hormone mediated or not, muscle spasms, nausea, neurodegenerative
diseases including
Lou Gehrig's disease, all forms of pain (e.g., acute, chronic, neuropathic,
trigeminal nerve pain,
pain associated with or accompanying migraine headaches and cancer),
Parkinson's disease and
Parkinsonian-type symptoms, spinal-cord injuries, postmenstrual syndrome
(PMS), Post-
Traumatic Stress Disorder (PTSD), seasonal affective disorder (SAD), seizures,
seizures
associated with Lennox-Gastaut syndrome or Dravet syndrome, sleep disorders
such as
insomnia, spasticity from multiple sclerosis, ulcerative colitis, and
vomiting. An embodiment of
this invention is a method for treating a subject, e.g. a human, having
cancer, chronic cluster
headaches, Crohn's disease, convulsions, epilepsy, glaucoma, migraine
headaches whether
hormone mediated or not, nausea, or trigeminal nerve pain by administering to
the subject a
therapeutically effective amount of a cannabis plant extract-derived
composition or synthetic
cannabinoid-derived composition of this invention.
Treatment of a disorder as described herein refers to reducing or eliminating
one or more
symptoms of the disorder. A therapeutically effective amount of a composition
of this invention
as described herein for treating a disorder is an amount sufficient to reduce
or eliminate one or
more symptoms of the disorder. For example, if a subject has a disorder that
is associated with
28
Date Recue/Date Received 2022-06-17
pain, a therapeutically effective amount is an amount sufficient to reduce or
eliminate the pain.
For example, if the disorder is an anxiety disorder a therapeutically
effective amount is an
amount sufficient to reduce or eliminate anxiety.
A therapeutically effective amount of a cannabis plant-derived composition or
synthetic
.. cannabinoid-derived composition of the invention described herein,
comprising complexes of a-
cyclodextrin and at least one cannabinoid (e.g., THC, CBD, and/or cannabinol
or a synthetic
cannabinoid) administered to a subject, e.g. a subject having anxiety, pain or
another disorder
having symptoms that are alleviated by treatment with a cannabinoid, may be
administered to the
subject in any suitable form, e.g., a tablet, capsule, pill, elixir, wafer,
beverage, or a food product.
The compositions of this invention may be administered to the subject by any
suitable
method, e.g., orally (swallowed), sublingually (under the tongue),
transdermally, transmucosally,
intranasally, topically, or rectally, in an amount suitable to achieve the
desired effects.
It has been found that the cannabinoids and/or terpenes complexed with a-
cyclodextrin in
the compositions of this invention are absorbed more rapidly through the
mucosal membranes of
a subject than are cannabinoids and/or terpenes that are not complexed with a-
cyclodextrin.
Moreover, the effects of the cannabinoids in the a-cyclodextrin complexes in
the cannabis plant
extract-derived compositions and synthetic cannabinoid-derived compositions of
this invention
are prolonged as compared to the effects of the cannabinoids in the untreated
cannabis plant
extracts or synthetic cannabinoids. Without wishing to be bound by theory, it
is contemplated
.. that the a-cyclodextrin and cannabinoid complexes are amphiphilic and are
thereby absorbed
more readily through a mucosal membrane. It is also contemplated that at least
a portion of the
complexes are delivered to the subject's stomach and intestines where the
cannabinoids are
released, thereby prolonging their effect on the subject. An embodiment of
this invention is a
composition comprising cannabinoids formulated to enhance absorption of the
cannabinoids
through mucosal membranes of a subject, and/or to prolong the effect of the
cannabinoids on the
subject, wherein the cannabinoids are in the form of complexes with a-
cyclodextrin.
An embodiment of this invention is a method for enhancing the absorption of
cannabinoids and/or terpenes in a cannabis plant extract or absorption of
synthetic cannabinoids
through mucosal membrane of a subject by mixing the cannabis plant extract or
synthetic
cannabinoids with an aqueous or a non-aqueous a-cyclodextrin-containing
composition under
29
Date Recue/Date Received 2022-06-17
conditions suitable to form complexes of a-cyclodextrin and the cannabinoids
and/or terpenes, or
both. The resulting composition comprising the complexes of a-cyclodextrin and
the
cannabinoids and/or terpenes, or both may be administered to the subject or
the complexes in the
mixture may then be collected, e.g., by filtering the mixture, or drying the
mixture, or in the case
of a non-aqueous a-cyclodextrin-containing composition simply collecting the
mixture by spoon,
spatula, or other device or tool. The resulting composition comprising the
complexes may be
diluted, mixed, or added directly to a food or beverage product and may be
administered to the
subject.
EXAMPLES
Example 1 ¨ THC-Containing Cannabis Powders
THC-containing cannabis powders were prepared by mixing various ratios of THC
distillate, commercially available from, e.g., https://www.thconcentrates.ca,
and a-cyclodextrin.
The THC distillate (300 mg) was diluted with isopropyl alcohol (4.2 mL) and
then added to an a-
cyclodextrin aqueous solution to generate suspensions having a ratio of a-
cyclodextrin to THC
.. distillate of 70:1, 87:1, 105:1 and 122:1. The resulting suspensions were
shaken vigorously by
hand in order to evenly distribute the diluted distillate throughout the
suspensions. The
suspensions were then rocked gently for 3 hours before being transferred to a
drying dish. The
suspensions were dried at ambient temperature for 48-72 hours or at 90-120 C
for 1-3 hours.
Sufficient amounts of each resulting powder were added to water to produce
solutions having a
.. THC concentration of 10mg/L. The solutions were then tasted by volunteers.
The results are
presented in Table 1. Table 1 recites the ratios of a-cyclodextrin (a-CD) to
THC distillate and the
taste characteristics of THC-containing solutions. All the solutions showed
opalescence that
decreased as the percent a-cyclodextrin increased and the ratio of a-
cyclodextrin to distillate
increased.
Date Recue/Date Received 2022-06-17
Table 1
% a-CD a-CD : a-CD : THC Solution
Characteristics
Isopropanol Distillate
20 0.20 70:1 Slight "off' taste, like stale water,
with a thin and
sparse layer on top of water
25 0.16 87:1 No taste, small film on surface of
water
30 0.13 105:1 No taste, all solid material dissolved
35 0.11 122:1 No taste, all solid material dissolved
The following Table 2 provides examples of cannabis plant extract-derived
compositions
prepared from different cannabis plant extracts, i.e., a tar, a distillate or
an oil according to
methods of the invention. "% Starting Material" in Table 2 refers to the
approximate % mass
(tar) or volume (distillate or oil) of the original tar, distillate, or oil
mixed with an aqueous a-
cyclodextrin composition. "% a-CD" is the % of a-cyclodextrin by weight in the
aqueous
cyclodextrin-containing composition mixed with the cannabis plant extract.
"End Product"
means the cannabis plant extract-derived composition produced by treating the
plant extract with
the aqueous a-cyclodextrin composition as described herein and dried to a
powder form or not
dried such that the end-product is in the form of a slurry.
Table 2
Staring Material End Product % a-CD % Starting
Material
1 Tar Powder 30 0.3
2 Distillate Powder 25 0.3
3 Commercial Oil Slurry 21 6.7
Example 2 - Tasteless, Odorless Cannabis Powder
A high CBD-containing cannabis viscous oil was diluted 1:15 (w/v) with either
ethyl or
isopropyl alcohol and gently mixed using a tube rocking apparatus, for up to 3
hours to make the
viscous oil less viscous. An a-cyclodextrin slurry was prepared by adding 900
mg of a-
31
Date Recue/Date Received 2022-06-17
cyclodextrin to 10 mL of a 10% (w/v) aqueous a-cyclodextrin solution. 600 [IL
of the above-
mentioned alcohol diluted cannabis viscous oils was added to the aqueous a-
cyclodextrin slurry
to form a suspension. The suspension was shaken vigorously by hand for 30
seconds and then
gently mixed at ambient temperature for at least 1 hour or until all visible
signs of the deep green
diluted viscous oil disappear. The suspension was shaken vigorously by hand
for a few seconds
and then poured into an evaporating dish. The suspension was dried at ambient
temperatures for
at least 48 hours or at 90-120 C for 1-3 hours, scraped into a mortar, and
ground to a fine
greenish-tinged off-white powder. The powder was odorless, tasteless, and
water soluble.
Recovery based upon the quantity of solids in the initial mix of oil and a-
cyclodextrin slurry was
near 100%.
Example 3 ¨ Tasteless, Odorless Cannabis Powder
A commercially-available cannabinoid oil [Tweed https: // www.tweed.com] that
had
been diluted with vegetable oil by the supplier to contain 5.16 mg/mL THC and
4.77 mg/mL
CBD was made into an off-white tasteless and odorless powder as follows. 600
mg of a-
.. cyclodextrin was suspended in 7 mL of 10% (w/v) a-cyclodextrin in water. To
this a-
cyclodextrin suspension, 420 [IL of the commercially available cannabinoid oil
was added and
briefly shaken by hand. The suspension was then mixed gently overnight or
until all signs of the
oil disappeared and the suspension appeared homogenous. The homogenous
suspension was
transferred to an evaporating dish and dried at ambient temperature for 48-72
hours. The dried
material was transferred to a mortar and ground to an off-white waxy powder.
At least a portion
of this material was not soluble in cold water and formed small oil droplets
in hot water.
However, this material was tasteless and odorless. Analysis of the
commercially available
cannabinoid oil demonstrated that 2.0 mg of CBD and 2.17 mg of THC were added
to the a-
cyclodextrin suspension. Analysis of the off-white waxy powder generated by
the method
demonstrated 0.12% (w/w) THC and 0.13% (w/w) CBD. Recovery based upon total
solids was
near 100%.
Example 4 ¨ Tasteless, Odorless Cannabis Suspension for Baking
3.0 mL of a commercially-available cannabis oil (Spectrum Cannabis,
https://spectrum
Cannabis. com) containing 25 mg/mL THC was added to 45 mL of water containing
9.5 g a-
cyclodextrin powder to make a suspension. The suspension was shaken vigorously
by hand for
32
Date Recue/Date Received 2022-06-17
one minute and then gently rocked for 3 hours. The resulting slurry was then
added to a
commercially available cupcake mix (e.g., Betty Crocker Vanilla Butter Cream)
as a direct
substitute for the same amount of water required by the manufacturer's cupcake
recipe. As
instructed by the cupcake recipe, the batter was divided into 12 equal
portions and baked as
indicated by the cupcake recipe. The olfactory and organoleptic properties of
the resulting
cupcakes were indiscernible from those of cupcakes prepared according to the
unaltered cupcake
recipe.
Example 5 ¨ Tasteless, Odorless, High CBD-Containing Beverage
High CBD cannabis containing viscous oil (50.9 mg CBD/100 mg oil) was diluted
1:15
(w/v) with isopropyl alcohol with gentle rocking until the oil was totally
dissolved. The diluted
oil (1.6 mL) was added to 10% (w/v) a-cyclodextrin aqueous solution (40 mL)
containing
additional solid a-cyclodextrin (8 g). The suspension was briefly mixed
vigorously by hand
before being rocked gently for 3-4 hours. The resulting homogeneous-appearing
slurry was
poured into a drying dish, and the solvents in the slurry were evaporated over
several hours at
approximately 110 C. Off-white crystalline material was recovered, and the
yield (based on the
measured amount of cannabinoid in the diluted oil) based on total mass of
solids was 97%. The
off-white crystalline material was transferred to a mortar and ground to a
fine off-white powder.
Analysis of the powder indicated that the powder contained 0.46% (w/w) CBD.
The off-white
powder (1.3 g of powder, the equivalent of 6 mg CBD) was dissolved in water
(500 mL). The
resulting solution was filtered through filter paper to remove traces of green
material, believed to
be vegetable matter. Although the resulting solution had a slight opalescence,
the solution was
transparent and tasteless. A volunteer suffering from chronic trigeminal nerve
facial pain
consumed approximately one-third of the CBD-containing solution. The volunteer
reported pain
relief within 10-15 minutes and reported that the relief lasted for over 4
hours after consuming
the CBD-containing solution.
Example 6 ¨ Tasteless, Odorless, High THC-Containing Iced Tea Beverage
The procedure used to make a high THC iced tea beverage was similar to the
procedure
used in Example 5. A THC-containing powder was prepared from a high THC-
containing
distillate as set forth in Example 4 and a sufficient amount of the powder was
mixed with an iced
tea beverage such that the resulting iced tea beverage contained 2.5 mg THC in
341 ml. Eight
33
Date Recue/Date Received 2022-06-17
volunteers, two suffering from anxiety (group 1), three suffering from
headaches (group 2) and
three having neither headaches or anxiety (group 3), consumed 341 ml of the
iced tea beverage
and reported rapid onset of the desired effects, i.e., reduction of anxiety
(group 1), reduction of
headache (group 2) and an enhanced relaxation, happiness, and heightened
sensory perception
(groups 1, 2 and 3) that persisted for more than 2.5 hours.
None of the eight volunteers reported detecting any cannabis and/or terpene
taste or odor
typically associated with cannabis extract in the iced tea beverage. The
volunteers reported that
they only detected the flavor and odor of the tea in the iced tea beverage.
Example 7 ¨Preparing Tasteless, Odorless Cannabis Powder from a Cannabis Oil
High CBD containing cannabis extract with the consistency of a tar was diluted
1:15 (w/v), with isopropyl alcohol and gently mixed by rocking the tube on a
rocking apparatus
for up to 3 hours to make the tar less viscous. An a-cyclodextrin slurry was
prepared by adding
12g of a-cyclodextrin to 40 mL of water followed by vigorous shaking by hand
for 2 minutes.
1.6 mL of the above-mentioned alcohol diluted cannabis tar was added to the
aqueous a-
cyclodextrin slurry to form a suspension. This suspension was shaken
vigorously by hand for 30
seconds and then gently mixed for at least 1 hour or until all visible signs
of the deep green
diluted tar disappear. The suspension was shaken vigorously by hand for a few
seconds and then
poured into an evaporating dish. The suspension was dried at ambient
temperature for at least 48
hours, scraped into a mortar, and ground to a fine off-white powder. The
yield, based upon solids
added, was near 100%.
Example 8¨ Tasteless, Odorless, Water-Soluble THC-Containing Cannabis Powder
A commercially available THC distillate (300 mg)
(https://www.thconcentrates.ca) was
diluted with isopropyl alcohol (4.2 mL). The diluted distillate (1.6 mL) was
added to 40 mL of
water containing 10 g of a-cyclodextrin. The resulting suspension was shaken
vigorously by
hand in order to evenly distribute the diluted distillate throughout the
suspension. The suspension
was then rocked gently for 3 hours before being transferred to a drying dish.
The suspension was
dried at ambient temperature for at least 48 hours to yield a powder
containing 11.6 mg THC per
1 g powder.
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Date Recue/Date Received 2022-06-17
Example 9 ¨ Tasteless, Odorless, THC Water Beverage
The powder of Example 8(435 mg) was dissolved in 500m1 water. Brief mixing
produced
a tasteless, odorless THC-containing water beverage containing 5 mg THC.
Example 10 ¨ Tasteless, Odorless, THC-Containing Tea Beverage
The powder of Example 8 (174 mg) was added to a teacup containing one tea bag
of
commercially available herbal tea (Stress Buster, www.tealish.com). The powder
was dissolved
completely upon addition of boiling water (250 mL). After steeping the tea bag
for 5 minutes, an
herbal tea beverage containing 2 mg THC was produced.
As described in the following examples, surprisingly, water-soluble, odorless,
and
tasteless cannabinoids were prepared without using water as a cosolvent.
Example 11 - Preparation of 10mg THC per gram of alp ha-cyclodextrin
Sixty-seven milligrams of (about 95%) THC Distillate was diluted in 500jiL of
isopropyl
alcohol. Five grams of a-cyclodextrin was added to a large-mouth jar with a
nonreactive solid
object to facilitate mixing. Four hundred eighty-five microliters of the
diluted distillate was
added to the a-cyclodextrin and the container was sealed. Mixing was conducted
by inversion
until the distillate was evenly dispersed in the a-cyclodextrin, for about 4-
14 hours. Alcohol was
removed by evaporation at 60 C to produce a final product. The concentration
of THC
(cannabinoid) achieved in the final product was about 10mg of cannabinoid per
gram of
cyclodextrin. One gram of the final product was dissolved in 500mL of
refrigerated bottled water
(e.g., Walmart, Natural Spring Water). The resulting beverage was odorless,
tasteless, slightly
opalescent, very refreshing and contained 10mg/500mL THC.
Date Recue/Date Received 2022-06-17
Example 12 - Preparation of 20mg THC per gram of alpha-cyclodextrin
THC Distillate (about 95%) at a weight of 133mg was diluted in 500 L of
isopropyl
alcohol. Five grams of a-cyclodextrin was added to a large-mouth jar with a
nonreactive solid
object to facilitate mixing. Four hundred eighty-five microliters of the
diluted distillate was
added to the a-cyclodextrin and the container was sealed. The container was
mixed by inversion
until the distillate was evenly dispersed in the a-cyclodextrin, for about 4-
14 hours. The alcohol
was removed by evaporation at 60 C to produce a final product. The
concentration of THC
(cannabinoid) obtained in the final product was about 20mg/g of cyclodextrin.
One-half gram of
the final product was dissolved in 500mL of refrigerated bottled water (e.g.,
Walmart, Natural
Spring Water). The resulting beverage was odorless, tasteless, slightly
opalescent, very
refreshing and contained 10mg/500mL THC.
Example 13 - Preparation of 50mg THC per gram of alpha-cyclodextrin
Two hundred seventy milligrams of (about 95%) THC Distillate was dissolved in
2.0mL
of isopropyl alcohol. To a large-mouth jar, 5g a-cyclodextrin was added, and a
nonreactive solid
object was also added to facilitate mixing. Then, 1.852mL of the diluted
distillate was added to
the a-cyclodextrin, and the container was sealed. The contents of the
container were mixed by
inversion until the distillate was evenly dispersed in the a-cyclodextrin, for
about 4-14 hours.
The alcohol was removed by evaporation at 60 C to produce a final product. The
obtained
concentration of THC (cannabinoid) in the final product was about 50mg/g of
cyclodextrin. Two
hundred milligrams of the final product was dissolved in 500mL of refrigerated
bottled water
(e.g., Walmart, Natural Spring Water). The resulting beverage was odorless,
tasteless, slightly
opalescent, very refreshing and contained 10mg/500mL THC.
Example 14 - Preparation of 20mg CBD per gram of alpha-cyclodextrin
CBD Distillate (Veridesco, Full Spectrum CBD Distillate, 78% CBD) at a weight
of
540mg was diluted in 4.02mL of ethyl alcohol. 3.712 L of the diluted
distillate was added to 20
grams of a-cyclodextrin in a small blender (NutriBullet, www.nutribullet.com).
The CBD/a-
cyclodextrin mixture was blended for 10 seconds at which time the sides and
the bottom of the
blender were scraped down. This blending process was repeated 3-4 times until
a very fine and
homogeneous in appearance, damp powder was obtained. This damp powder was
transferred to a
drying dish and dried to a fine white powder at 60 C for one hour.
Surprisingly, a timed study
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Date Recue/Date Received 2022-06-17
demonstrated that the CBD/a-cyclodextrin complex formation was complete
without further
incubation or mixing.
Example 15 ¨ Preparation of a CBD-Containing Citrus-Flavored Beverage
As described above in Example 14 prepare dry powder to contain 20mg CBD per
gram of
a-CD. Add 500mg of this powder (10mg CBD) to a sufficient quantity of
commercially available
powdered citrus beverage (Crystal Light, Kraft Heinz, Canada) to prepare 500mL
of beverage.
Dissolve the combined powders in 500mL of cold water, and add ice to taste, if
desired.
Example 16- Preparation of a CBD-Containing Iced Tea Beverage
As described above in Example 14 prepare dry powder to contain 20mg CBD per
gram of
a-CD. Add 500mg of powder (10mg CBD) to a sufficient quantity of commercially
available
powdered iced tea beverage (Nestea, Nestle, Canada) to prepare 500mL of
beverage. Dissolve
the combined powders in 500mL of cold water. Add ice if desired.
Example 17- Preparation of a CBD-Containing Sports Recovery Drink
As described above in Example 14 prepare dry powder to contain 20mg CBD per
gram of
a-CD. Add 500mg of powder (10mg CBD) to a sufficient quantity of commercially
available
powdered citrus beverage (Crystal Light, Kraft Heinz, Canada) to prepare 500mL
of beverage.
Add 800mg of trisodium citrate and 104 mg of potassium chloride. Dissolve the
combined
powders in 500mL of cold water. Add ice as desired.
Example 18- Preparation of 15mg CBD per gram of alp ha-cyclodextrin Full
Spectrum
Powder
CBD Full Spectrum Organic CBD Distillate (Veridesco, Full Spectrum CBD
Distillate,
58% CBD, 2.8% THC, 2.4% CannaBiChromene, 0.8% CannaBiGerol, 0.3%
CannaBiDiVarin
and 0.2% Other Cannabinoids) at a weight of 675mg was diluted in 4.02mL of
ethyl alcohol. The
diluted distillate, at a volume of 3.712 L, was added to 20 grams of a-
cyclodextrin in a small
blender (NutriBullet, www.nutribullet.com).
The alpha-cyclodextrin starting material that was used is a pure, white free-
flowing
powder as illustrated in Figure 5. The undiluted full spectrum distillate (58%
CBD, 2.8% THC,
2.4% CannaBiChromene, 0.8% CannaBiGerol, 0.3% CannaBiDiVarin and 0.2% Other
37
Date Recue/Date Received 2022-06-17
Cannabinoids) that was used is very viscous and dark green, tending to black,
in appearance as
illustrated in Figure 6. When the distillate was diluted with ethyl alcohol,
the diluted distillate is
less viscous (and thus easier to work with) but is still very dark in color as
illustrated in Figure 7.
The cannabinoid/terpene/a-cyclodextrin mixture was blended for 10 seconds at
which
time the sides and the bottom of the blender were scraped down. This blending
process was
repeated 3-4 times until a very fine and homogeneous in appearance, damp
powder was obtained.
The obtained damp powder is illustrated in Figure 8.
This obtained damp powder was transferred to a drying dish and dried to a fine
light
yellow powder at 60 C for one hour. The dried cannabinoid-containing powder is
illustrated in
Figure 9. This cannabinoid-containing powder after evaporation of ethyl
alcohol is fine and free-
flowing. As can be observed in Figure 9, a slight yellowish tinge remains in
the distillate. This
yellowish color decreases to an off-white as the purity of the distillate
increases.
The dried cannabinoid-containing powder of Figure 9 is dissolved in water at a
concentration of 15mg/L of CBD. The resulting solution can be seen in Figure
10. As can be
observed from Figure 10, there is a slight yellowish tinge to the water as a
result of impurities in
the distillate; nonetheless, the water is odorless and tasteless with a slight
opalescence.
Example 19¨ Improved Absorption of Cannabinoid Complexed with a-CD
Hydrophobic molecules tend to be absorbed very poorly. Cannabinoids that are
complexed by a-CD are water soluble and are absorbed (beginning in the mouth)
much more
efficiently than cannabinoids not complexed by a-CD. As a result,
substantially less a-CD-
complexed cannabinoid needs to be consumed in order to elicit similar effects
to products where
cannabinoid is not complexed with a-CD. As evident from Figure 11, the onset
of effects took
between 10 and 30 minutes, which is consistent with oral (as opposed to
intestinal) absorption.
Peak absorption is in the range of 90-120 minutes and is consistent with
additional intestinal
absorption. It is also of note that the desired effects of the a-CD complexed
cannabinoid are
experienced for a duration of four to five hours.
The foregoing description and examples have been set forth merely to
illustrate the
invention and are not meant to be limiting. Since modifications of the
described embodiments
incorporating the spirit and the substance of the invention may occur to
persons skilled in the art,
38
Date Recue/Date Received 2022-06-17
the invention should be construed broadly to include all variations within the
scope of the claims
and equivalents thereof.
39
Date Recue/Date Received 2022-06-17
