U.S. patent application number 15/998484 was filed with the patent office on 2018-12-13 for cannabinoid formulations.
This patent application is currently assigned to TEEWINOT TECHNOLOGIES LIMITED. The applicant listed for this patent is TEEWINOT TECHNOLOGIES LIMITED. Invention is credited to Robert Winnicki.
Application Number | 20180353463 15/998484 |
Document ID | / |
Family ID | 47506517 |
Filed Date | 2018-12-13 |
United States Patent
Application |
20180353463 |
Kind Code |
A1 |
Winnicki; Robert |
December 13, 2018 |
Cannabinoid Formulations
Abstract
The present invention provides stable, fast-acting liposomal and
micelle formulations of cannabinoids that are suitable for
pharmaceutical and nutraceutical applications.
Inventors: |
Winnicki; Robert; (Denver,
CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TEEWINOT TECHNOLOGIES LIMITED |
Dublin 2 |
|
IE |
|
|
Assignee: |
TEEWINOT TECHNOLOGIES
LIMITED
Dublin 2
IE
|
Family ID: |
47506517 |
Appl. No.: |
15/998484 |
Filed: |
August 16, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14816959 |
Aug 3, 2015 |
10052303 |
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15998484 |
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14312570 |
Jun 23, 2014 |
9095555 |
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14816959 |
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13547039 |
Jul 11, 2012 |
8808734 |
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14312570 |
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61506331 |
Jul 11, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/1075 20130101;
A61K 36/185 20130101; A23L 33/105 20160801; A61K 31/05 20130101;
A61K 31/352 20130101; A61K 47/10 20130101; A61K 9/107 20130101;
A61K 9/127 20130101; A61K 45/06 20130101; A61K 47/36 20130101; A61K
47/24 20130101; A23V 2002/00 20130101 |
International
Class: |
A61K 31/352 20060101
A61K031/352; A61K 45/06 20060101 A61K045/06; A61K 9/107 20060101
A61K009/107; A23L 33/105 20060101 A23L033/105; A61K 36/185 20060101
A61K036/185; A61K 9/127 20060101 A61K009/127; A61K 47/36 20060101
A61K047/36; A61K 47/24 20060101 A61K047/24; A61K 47/10 20060101
A61K047/10; A61K 31/05 20060101 A61K031/05 |
Claims
1.-27. (canceled)
28. A formulation comprising a unilamellar micelle suspension of
one or more cannabinoids or cannabinoid analogues, wherein the
unilamellar micelle suspension is thermostable at temperatures
greater than 50.degree. C.
29. The formulation of claim 28, wherein the one or more
cannabinoids or cannabinoid analogues are one or more of a natural
compound, a synthetic compound, a semi-synthetic compound, or
mixtures thereof.
30. The formulation of claim 29, wherein the cannabinoid or
cannabinoid analogue comprises one or more of cannabinol,
cannabidiol, .DELTA.9-tetrahydrocannabinol,
.DELTA.8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol,
11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol,
.DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,
amandamide, nabilone, a combination thereof, a natural or synthetic
analogue thereof, or a natural or synthetic molecule with a basic
cannabinoid structure.
31. The formulation of claim 28, wherein the formulation is a
composition for parenteral injection, a dietary composition for
oral delivery, or a composition dosage form for topical
administration.
32. The formulation of claim 31, wherein the formulation is a
liquid dosage form, wherein the liquid dosage form is an emulsion,
a solution, a suspension, a syrup, or an elixir.
33. The formulation of claim 31, wherein the formulation is a solid
dosage form comprising an extract, a capsule, a tablet, a pill, a
dragee, a powder or a granule, and wherein the formulation further
comprises one or more of a pharmaceutically acceptable excipient, a
carrier, a filler, a binder, a disintegrating agent, a humectant,
an absorption accelerator, a wetting agent, an absorber, a
lubricant and a buffering agent.
34. The formulation of claim 33, wherein the solid dosage form
comprises a coating, and wherein the coating is an enteric coating,
an extended-release coating, a sustained-release coating, a delayed
release coating, or an immediate release coating.
35. The formulation of claim 31, wherein the formulation is a
dosage form for topical administration comprising an ointment, a
cream, an emulsion, a lotion, a gel, a sunscreen or an agent that
favors penetration into the skin.
36. The formulation of claim 31, wherein the formulation is a
composition for parenteral injection, wherein the composition
comprises a pharmaceutically acceptable sterile aqueous or
non-aqueous solution, a dispersion, a suspension, an emulsion, a
powder or a depot injectable formulation.
37. The formulation of claim 31, wherein the dietary composition is
nutraceutical, a soup, a baking good, a dairy product, a meat
product, a fish product, a vegetable product or a fruit
product.
38. The formulation of claim 28, further comprising a stabilizer
selected from the group consisting of guar gum, xanthan gum
cellulose hyaluronic acid, polyvinyl pyrrolidone (PVP), alginate,
chondritin sulfate, poly gamma glutamic acid, gelatin, chitisin,
corn starch and flour, in an amount from about 0.25% to about 2%
(w/v).
39. The formulation of claim 28, wherein the average micelle
diameter size is in a range between 50 and 1000 nm.
40. The formulation of claim 39, wherein the concentration of
cannabinoids or cannabinoid analogues in the suspension is from
about 1 g/l to about 2 g/liter.
41. A method of producing a formulation comprising a unilamellar
suspension of one or more cannabinoids or cannabinoid analogues
according to claim 28, wherein the method comprises the steps of:
(a) dissolving one or more cannabinoids or cannabinoid analogues in
a solvent; (b) adding a phospholipid to the cannabinoid solution;
(c) injecting the cannabinoid solution from step (b) into distilled
water to obtain a cannabinoid suspension; (d) removing the solvent;
(e) adding an encapsulant to the formulation of step (d) to obtain
an encapsulated cannabinoid formulation; (f) cold-pressing and
air-drying or shell-freezing the encapsulated cannabinoid
formulation to obtain a dry cannabinoid powder; and (h) milling and
re-suspending the dry cannabinoid powder in an aqueous solution;
and wherein the amount of cannabinoids or cannabinoid analogues in
the aqueous cannabinoid solution is greater than 40%.
42. The method of claim 41, wherein the one or more cannabinoids or
cannabinoid analogues are one or more of a natural compound, a
synthetic compound, a semi-synthetic compound, or mixtures
thereof.
43. The method of claim 42, wherein the cannabinoid or cannabinoid
analogue comprises one or more of cannabinol, cannabidiol,
.DELTA.9-tetrahydrocannabinol, .DELTA.8-tetrahydrocannabinol,
11-hydroxy-tetrahydrocannabinol,
11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol,
.DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,
amandamide, nabilone, a combination thereof, a natural or synthetic
analogue thereof, or a natural or synthetic molecule with a basic
cannabinoid structure.
44. The method of claim 41, wherein the encapsulant is calcium
alginate, L-leucine or a sugar.
45. A method of alleviating pain or reducing undesirable side
effects associated with radiation therapy or chemotherapy in a
subject having a compromised immune system, a cancer, a pulmonary
disease or a condition that causes violent tremors comprising
administering to the subject the formulation of claim 28.
Description
[0001] This application claims priority to U.S. Provisional
Application No. 61/506,331, filed on Jul. 11, 2011 The contents of
the provisional applications are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to liposomal and micelle
formulations of cannabinoids suitable for pharmaceutical and
nutraceutical applications.
BACKGROUND OF THE INVENTION
[0003] Cannabinoids are compounds derived from Cannabis sativa, an
annual plant in the Cannabaceae family. The plant contains about 60
cannabinoids. The most active naturally occurring cannabinoid is
tetrahydrocannabinol (THC), which is used for the treatment of a
wide range of medical conditions, including glaucoma, AIDS wasting,
neuropathic pain, treatment of spasticity associated with multiple
sclerosis, fibromyalgia and chemotherapy-induced nausea.
Additionally, THC has been reported to exhibit a therapeutic effect
in the treatment of allergies, inflammation, infection, epilepsy,
depression, migraine, bipolar disorders, anxiety disorder, and drug
dependency and withdrawal syndromes. THC is particularly effective
as an anti-emetic drug and is administered to curb emesis, a common
side effect accompanying the use of opioid analgesics and
anaesthetics, highly active anti-retroviral therapy and cancer
chemotherapy.
[0004] Cannabinoids are lipophilic and potentially acid-labile
compounds. Because of their hydrophobic nature, cannabinoids are
poorly absorbed systemically from oral dosage forms because of the
poor dissolution of cannabinoids in the aqueous environment of
gastrointestinal tract. Oral formulations of cannabinoids,
therefore, exhibit low bioavailability.
[0005] .DELTA..sup.9-tetrahydrocannabinol is prone to oxidation,
Prolonged contact with air results in the gradual oxidation of
.DELTA..sup.9-tetrahydrocannabinol to cannabinol (CBN). There are
currently two oral formulations of
.DELTA..sup.9-tetrahydrocannabinol commercially available by
prescription in the United States: Dronabinol, is available
commercially as Marinol.RTM. soft gelatin capsules and Namisol.RTM.
is available as sublingual tablets, have been approved by the Food
and Drug Administration (FDA) for the control of nausea and
vomiting associated with chemotherapy and for appetite stimulation
in AIDS patients suffering from the wasting syndrome. Marinol.RTM.
is formulated by dissolving .DELTA..sup.9-tetrahydrocannabinol in
sesame oil to manufacture soft gelatin capsules suitable for oral
administration. Marinol.RTM. is expensive and gelatin capsules of
Marinol.RTM. exhibit full therapeutic potency approximately one
hour following their administration.
[0006] Onset of therapeutic potency for Dronabinol is shorter,
approximately 0.5 to 1 hour after oral administration, with a peak
therapeutic effect lasting for a time period of 2-4 hours post
administration. However, the amount of Dronabinol reaching the
blood stream by absorption through the digestive system is only
10-20% of the administered dose. Fasting or food deprivation may
further decrease the rate of absorption of Dronabinol.
[0007] On the other hand, Namisol.RTM. has a rapid uptake through
the sublingual mucosa. However, the tablet, has to be kept under
the tongue for the time it takes to dissolve and stimulates the
flow of saliva. This make it difficult for patients to avoid
swallowing the tablet when substantial amounts of saliva are
produced.
[0008] Oral formulations of synthetic cannabionoids are also
available commercially. For instance, Nabilone is a synthetic
cannabinoid marketed as Cesamet.RTM. in Canada the United States,
the United Kingdom and Mexico. Nabilone is formulated as capsules
suitable for oral administration. Cesamet.RTM. is approved for use
as an antiemetic and analgesic for neuropathic pain. Sativex.RTM.,
is a mouth spray containing tetrahydrocannabinol (THC) and
cannabidiol (CBD). It is approved for the treatment of spasticity
due to multiple sclerosis. Administration of synthetic cannabinoid
formulations show fewer undesirable side effects than THC.
[0009] Because of their poor absorbtion and poor bioavailability,
oral formulations have the additional disadvantage that they
require several administrations a day, making it inconvenient for
patients who have difficulty swallowing.
[0010] Accordingly, there is an urgent need in the art for oral
formulations of cannabinoids with improved dissolution and taste
and enhanced bioavailability and absorption, while at the same time
do not cause gastrointestinal irritation. The present invention
satisfies this need.
SUMMARY OF THE INVENTION
[0011] It is therefore an object of the invention to provide
solutions to the aforementioned deficiencies in the art. To this
end the invention provides a stable, aqueous micelle suspension of
one or more cannabinoids or cannabinoid analogues, wherein the
stable aqueous micelle suspension of one or more cannabinoids or
cannabinoid analogues does not comprise phospholipids and
cholesterol. For the inventive compositions, the average micelle
diameter size is in a range between 50 and 1000 nm.
[0012] According to one embodiment, the final maximum concentration
of cannabinoids or cannabinoid analogues in the aqueous micelle
suspension of one or more cannabinoids or cannabinoid analogues is
2 g/liter. The cannabinoids or cannabinoid analogues are a natural
compound, a synthetic compound, a semi-synthetic compound, or
mixtures thereof. Illustrative of cannabinoids or cannabinoid
analogues are compounds selected from the group consisting of
cannabinol, cannabidiol, .DELTA.9-tetrahydrocannabinol,
.DELTA.8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol,
11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol,
.DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,
amandamide, nabilone, a combination thereof, a natural or synthetic
analogue thereof, and a natural or synthetic molecule with a basic
cannabinoid structure.
[0013] In one embodiment the stable aqueous micelle suspension of
one or more cannabinoids or cannabinoid analogues further comprises
a stabilizer selected from the group consisting of guar gum,
xyanthan gum cellulose hyaluronic acid, polyvinyl pyrrolidone
(PVP), alginate, chondritin sulfate, poly gamma glutamic acid,
gelatin, chitisin, corn starch and flour, in an amount from about
0.25% to about 2% (w/v).
[0014] In yet another embodiment is provided a method of producing
a stable aqueous micelle suspension of one or more cannabinoids or
cannabinoid analogues that is devoid of phospholipids and
cholesterol. The inventive method comprises the steps of (a)
dissolving one or more cannabinoids or cannabinoid analogues in
ethanol to obtain an ethanol cannabinoid solution; (b) injecting
the ethanol cannabinoid solution into distilled water to obtain a
micelle cannabinoid aqueous suspension; and (c) removing the
ethanol from the cannabinoid aqueous suspension thereby producing a
stable aqueous micelle suspension of one or more cannabinoids or
cannabinoid analogues. The aqueous micelle suspension do not
contain phospholipids and cholesterol and are devoid of an aqueous
core under oil immersion microscopy.
[0015] According to one embodiment, the average micelle diameter
size in the aqueous micelle suspension of one or more cannabinoids
or cannabinoid analogues is in a range between 50 and 1000 nm, and
the final maximum concentration of cannabinoids or cannabinoid
analogues in the aqueous micelle suspension of one or more
cannabinoids or cannabinoid analogues is 2 g/liter. The one or more
cannabinoids or cannabinoid analogues of the present invention are
a natural compound, a synthetic compound, a semi-synthetic
compound, or mixtures thereof. Illustrative of such compounds are
cannabinoids or cannabinoid analogues selected from the group
consisting of cannabinol, cannabidiol,
.DELTA.9-tetrahydrocannabinol, .DELTA.8-tetrahydrocannabinol,
11-hydroxy-tetrahydrocannabinol,
11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol,
.DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,
amandamide, nabilone, a combination thereof, a natural or synthetic
analogue thereof, and a natural or synthetic molecule with a basic
cannabinoid structure. The present invention in one of its
embodiments provides a highly concentrated liposomal formulation of
one or more cannabinoids or cannabinoid analogues, with final
maximum concentration of cannabinoids or cannabinoid analogues in
the liposomal suspension being 50 g/liter. The one or more
cannabinoids or cannabinoid analogues in the inventive composition
are a natural compound, a synthetic compound, a semi-synthetic
compound, or mixtures thereof. Illustrative of such compounds are
cannabinoids or cannabinoid analogues selected from the group
consisting of cannabinol, cannabidiol,
.DELTA.9-tetrahydrocannabinol, .DELTA.8-tetrahydrocannabinol,
11-hydroxy-tetrahydrocannabinol,
11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol,
.DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,
amandamide, nabilone, a combination thereof, a natural or synthetic
analogue thereof, and a natural or synthetic molecule with a basic
cannabinoid structure.
[0016] The average diameter size of liposomes in the inventive
composition is from about 200 to about 400 nm. For these
compositions the maximum phospholipid content of the
hydrophobic/lipophilic membrane is 50% of the total composition and
the hydrophobic/lipophilic membrane comprises about 26%
phosphatidylcholine, about 10% phosphatidylethanolamine, about 13%
phosphonophospholipids, and about 1% of other phospholipids.
[0017] Also provided as an embodiment of the present technology is
a method of producing a stable, highly concentrated liposomal
formulation of one or more cannabinoids or cannabinoid analogues by
(a) dissolving one or more cannabinoids or cannabinoid analogues in
ethanol to obtain an ethanol cannabinoid solution; (b) adding a
phospholipid to the ethanol cannabinoid solution to obtain an
ethanol-phospholipid cannabinoid solution; (c) injecting the
ethanol-phospholipid cannabinoid solution into distilled water to
obtain a liposomal cannabinoid suspension; and (d) removing the
ethanol from the liposomal cannabinoid suspension, thereby
producing a stable liposomal suspension of one or more cannabinoids
or cannabinoid analogues;
[0018] The final maximum concentration of cannabinoids or
cannabinoid analogues in the liposomal suspension is 50 g/liter and
the one or more cannabinoids or cannabinoid analogues are a natural
compound, a synthetic compound, a semi-synthetic compound, or
mixtures thereof. Preferably the cannabinoids or cannabinoid
analogues are selected from the group consisting of cannabinol,
cannabidiol, .DELTA.9-tetrahydrocannabinol,
.DELTA.8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol,
11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol,
.DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,
amandamide, nabilone, a combination thereof, a natural or synthetic
analogue thereof, and a natural or synthetic molecule with a basic
cannabinoid structure.
[0019] The inventive method further comprises the step of adding
sodium alginate to the liposomal suspension of one or more
cannabinoids or cannabinoid analogues to obtain an alginate
liposomal cannabinoid suspension that has a final alginate
concentration of 2% w/v, followed by the addition of calcium
chloride to the alginate liposomal cannabinoid suspension to obtain
a calcium alginate-encapsulated liposomal cannabinoid suspension.
This suspension is then cold-pressed and air-dried to remove the
water so as to obtain a dry cannabinoid powder. The dry cannabinoid
powder can be re-suspended in citrate buffer to obtain an aqueous
cannabinoid solution. The amount of cannabinoid or cannabinoid
analogue in the aqueous cannabinoid solution is greater than
40%.
[0020] According to an embodiment of the inventive method, sodium
alginate is added to the liposomal suspension of one or more
cannabinoids or cannabinoid analogues to obtain an alginate
liposomal cannabinoid suspension that has a final alginate
concentration of 4% w/v. Shell-freezing of this solution using dry
ice or in acetone bath and freeze-drying to remove water provides a
dry cannabinoid powder that is milled and can be re-suspended in
water to obtain an aqueous cannabinoid solution. The amount of
cannabinoid or cannabinoid analogue in the aqueous cannabinoid
solution is greater than 40%.
[0021] In one embodiment, L-leucine and a sugar are added to the
liposomal suspension of one or more cannabinoids or cannabinoid
analogues to obtain a sugar liposomal cannabinoid suspension. The
sugar is selected from the group consisting of lactose and sucrose.
Shell-freezing the sugar liposomal cannabinoid suspension over dry
ice acetone bath and freeze-drying the suspension to remove the
water provides a dry cannabinoid powder that is milled and can be
re-suspended in water to obtain an aqueous cannabinoid solution.
The amount of cannabinoids or cannabinoid analogues in the aqueous
solution is 50 g/liter.
[0022] Such an aqueous cannabinoid solution can be in the form of a
fast-acting pharmaceutical composition, a nutraceutical
composition, or a food or beverage for administration to a subject.
Illustrative of food containing the aqueous cannabinoid solution
are foods selected from a soup, a baking good, a dairy product, a
meat product, a fish product, a vegetable product or a fruit
product. The aqueous cannabinoid solution formulated as
pharmaceutical composition, a nutraceutical composition, or a food
or beverage are fast-acting formulations for oral, enteral,
parenteral, intravenous, pulmonary, mucosal, sub-mucosal or topical
administration.
[0023] In yet another embodiment, the invention provides a method
of alleviating pain or reducing undesirable side effects associated
with radiation therapy or chemotherapy in a subject in need thereof
comprising administering to the subject the aqueous cannabinoid
solution as described above. Subjects treated using the inventive
method have a compromised immune system, a cancer, a pulmonary
disease or a condition that causes violent tremors.
[0024] The foregoing general description and following brief
description of the drawings and the detailed description are
exemplary and explanatory and are intended to provide further
explanation of the invention as claimed. Other objects, advantages,
and novel features will be readily apparent to those skilled in the
art from the following detailed description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 provides an oil immersion image of a micelle
suspension stained with fast blue as seen through a red filter.
[0026] FIG. 2 provides an oil immersion image of an unstained
liposomal suspension.
[0027] FIG. 3 provides an oil immersion image of a liposomal
suspension stained with fast blue as seen through a red filter. The
stain condensates on the outer liposome membrane.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0028] The present invention provides stable, fast-acting
formulation of a cannabinoid or a cannabinoid analog. The term
"analog" refers to compound that is structurally related to
naturally occurring cannabinoids, but whose chemical and biological
properties may differ from naturally occurring cannabinoids. In the
present context, analog or analogs refer compounds that may not
exhibit one or more unwanted side effects of a naturally occurring
cannabinoid. Analog also refers to a compound that is derived from
a naturally occurring cannabinoid by chemical, biological or a
semi-synthetic transformation of the naturally occurring
cannabinoid. According to one aspect, therefore, are provided
liquid compositions of cannabinoids and their analogs. The present
invention also provides stable colloidal formulations that are
manufactured by contacting a solution containing a cannabinoid, its
analog, or both into a solvent such as water, with or without
pharmaceutically acceptatable buffers. Any solvent such as
C1-C.sub.6 aliphatic alcohols or mixtures of water and alcohols,
acetone or any water miscible organic solvent can be used to
dissolve the cannabinoids.
[0029] The inventive cannabinoid formulations are in the form of
micelles or liposomes that encapsulate a cannabinoid or its analog
within the membrane of the micelles or liposomes. Within the
context of the present technology, the term "micelle" refers to an
aggregate of surfactant molecules dispersed in a liquid colloid,
while "liposome" refers to a vesicle composed of a mono or bilayer
lipid.
[0030] Other drugs, and pharmaceutically acceptable carriers if
present, may be in the lipophilic membrane or entrapped in the
aqueous fluid that forms the core of the liposome. The entrapped
cannabinoids contribute to the stability of the micelle/liposome
membranes, such that the micelle/liposomes formulations may be used
as an improved, fast, reliable and efficient system for the oral,
enteral, parenteral, intravenous or topical delivery of
cannabinoids and/or additional drugs to subjects in need thereof.
The term "subject" refers to a mammal in need of treatment or
undergoing treatment using the inventive compositions. Mammalian
subjects include without limitation humans, dog, cat, horse or any
other animal in need of treatment.
[0031] Unilamellar micelles or liposomes that are thermostable at
temperatures greater than 50.degree. C. are used in the manufacture
of cannabinoid formulations according to the present invention.
These micelles or liposomes are obtained by contacting a solution
of a cannabinoid, its analog or both (a cannabinoid extract), with
an aqueous solvent or an aqueous solution of a pharmaceutically
active compound or drug. The mixing of the cannabinoid solution
occurs in a manner suitable for the rapid dissolution of the
cannabinoid solution in the aqueous solution. This can be
accomplished through a variety of means including dilution,
injection through a small orifice under pressure, and ultrasonic
atomization.
[0032] For certain embodiments, the inventive composition is in the
form of a concentrated, stable colloidal suspension that is
obtained by infusing a solvent solution containing the cannabinoid
extract or pure cannabinoids into a solvent such as water, with or
without buffer. Stabilizing agent, for instance, a polymer or
compounds selected from cellulose hyaluronic acid, polyvinyl
pyrrolidone (PVP), alginate, chondritin sulfate, poly gamma
glutamic acid, gelatin, chitisin, corn starch and flour can be used
to stabilize the micelle formulations.
[0033] Typically, the size of the inventive micelles is from about
0.01 .mu.m to about 2.0 .mu.m. For certain embodiments, the size of
the spherical micelles is about 0.05 pun, about 0.1 pun, about 0.15
.mu.m, 0.2 .mu.m, 0.25 .mu.m, 0.3 .mu.m, 0.35 .mu.m, 0.4 .mu.m,
0.45 .mu.m, 0.5 .mu.m, 0.55 .mu.m, 0.6 .mu.m, 0.7 .mu.m, 0.75
.mu.m, 0.8 .mu.m, 0.85 .mu.m, 0.9 .mu.m, about 0.95 .mu.m, about
1.0 .mu.m, 1.20 .mu.m, 1.40 .mu.m, 1.50 .mu.m, 1.60 .mu.m, 1.70
.mu.m, 1.80 .mu.m, 1.90 .mu.m and 2.0 .mu.m. For certain
embodiments, micelles that are about 0.04 .mu.m, about 0.05 .mu.m,
about 0.06 .mu.m, about 0.07 .mu.m, about 0.08 .mu.m, or about 0.09
.mu.m are used to formulate the inventive compositions.
[0034] According to one aspect, the maximum final concentration ofa
cannabinoids or an analog of the cannabinoid in the micellar
colloidal suspension is from about 1.0 mg/mL to about 10.0 mg/mL
both values inclusive. For some embodiments, the concentration of a
cannabinoid extract within the inventive micelles is about 1.0
mg/mL, about 2.0 mg/mL, about 3.0 mg/mL, 4.0 mg/mL, about 5.0
mg/mL, about 6.0 mg/mL, about 7.0 mg/mL, about 8.0 mg/mL, or about
9.0 mg/mL.
[0035] Typical concentrations of cannabinoids within a liposomal
suspension according to the present invention are about 50 mg/mL.
For certain embodiments, the maximum final concentration of
cannabinoids or an analog of the cannabinoid in the liposomal
formulation is from about 10.0 mg/mL to about 300.0 mg/mL both
values inclusive, for example, about 15.0 mg/mL, about 20.0 mg/mL,
about 30.0 mg/mL, about 40.0 mg/mL, about 50.0 mg/mL, about 60.0
mg/mL, about 70.0 mg/mL, about 80.0 mg/mL, about 90.0 mg/mL, about
150.0 mg/mL, about 200.0 mg/mL, about 250.0 mg/mL, or about 300.0
mg/mL.
[0036] For liposomal compositions according to this invention, the
size of the unilamellar spherical liposome is from about 0.1 .mu.m
to about 2.0 .mu.m both values inclusive, such as about 0.15 .mu.m,
about 0.2 .mu.m, about 0.22 .mu.m, about 0.25 .mu.m, about 0.3
.mu.m, about 0.32 .mu.m, about 0.35 .mu.m, about 0.4 .mu.m, about
0.42 .mu.m, about 0.45 .mu.m, about 0.5 .mu.m, about 0.52 .mu.m,
about 0.55 .mu.m, about 0.6 .mu.m, about 0.7 .mu.m, about 0.75
.mu.m, about 0.8 .mu.m, about 0.85 .mu.m, about 0.9 .mu.m, about
0.95 .mu.m, about 1.0 .mu.m, about 1.1 .mu.m, about 1.2 .mu.m,
about 1.3 .mu.m, about 1.4 .mu.m, about 1.5 .mu.m, about 1.6 .mu.m,
about 1.7 .mu.m, about 1.8 .mu.m, about 1.9 .mu.m, or about 2.0
.mu.m.
[0037] The formulations of the invention are therefore particularly
suitable for oral administration and may be administered to
subjects with a pre-existing condition or pre-disposed to certain
disease conditions, acute pain, or chronic pain conditions.
Conditions contemplated by the invention include, but are not
limited to, gastrointestinal, metabolic, neurological, circulatory,
soft tissue, musculoskeletal, chronic or acute pain, nausea,
decreased appetite, skin disorders, sexual dysfunction, glaucoma,
AIDS wasting, neuropathic pain, treatment of spasticity associated
with multiple sclerosis, fibromyalgia, chemotherapy-induced nausea,
allergies, inflammation, infection, epilepsy, depression, migraine,
bipolar disorders, anxiety disorder, dependency and withdrawal. In
addition, the methods of the invention may be used to alleviate or
relief symptoms or side effects associated with anti-retroviral
therapy, chemotherapy and radiation therapy.
[0038] Illustrative of cannabinoid compounds include without
limitation cannabinol, cannabidiol, .DELTA.9-tetrahydrocannabinol,
.DELTA.8-tetrahydrocannabinol, l1-hydroxy-tetrahydrocannabinol,
11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol,
.DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,
amandamide, nabilone, any combination thereof, any natural or
synthetic modification thereof, or any natural or synthetic
molecule with a basic cannabinoid structure. In a preferred
embodiment, the cannabinoid is tetrahydrocannabinol (THC).
[0039] Natural cannabinoid compounds used in the inventive
compositions are readily obtained from plant tissue, for example,
trichones of the C. sativa plant, by suspending the tissue in an
appropriate solvent to extract cannabinoid compounds and other
tissue components. Analytical purification of such an extract
provides pharmaceutical grade cannabinoid compounds. Alternatively,
cannabinoid compounds are extracted from plant tissue under
supercritical conditions. Solvents used for supercritical
extraction of cannabinoids include without limitation carbon
dioxide, or other gases in isolation or combination with or without
solvent modifers, selected from ethanol, propanol, butanol, hexane,
chloroform, dichloromethane, acetone, or any organic solvent
capable of extracting cannabinoids, and alcohol-water mixtures, for
instance water-ethanol or water-butanol mixtures.
[0040] In addition to natural cannabinoids, the present technology
encompasses synthetic cannabinoid compounds as well as cannabinoids
and therir analogs that are obtained using semi-synthetic
protocols. The manufacture of cannabinoid compounds and their
analogs using semi-synthetic means involves contacting an
appropriate substrate with one of the cannabinoid synthase enzymes.
For instance, tetrahydrocannabinolic acid (THCA) or its analogs can
be manufactured semi-synthetically by contacting cannabigerolic
acid (CBGA) or an approporiately substituted derivative of CBGA
with THC synthase to obtain the corresponding THCA or THCA analog
respectively. The inventive compositions may also contain natural
or synthetically modified cannabinoids.
[0041] The inventive compositions have unexpected advantageous
properties. For instance, micellar and liposomal compositions
according to the present invention are stable at high temperatures,
exceeding 50.degree. C., are stable to sonication, capable of
carrying large payloads of cannabinoids as well as other drug
suitable for use in combination therapy and can be stored for
extended periods of time, for example greater than 20 weeks at
25.degree. C.
[0042] The inventive compositions also exhibit superior systemic
delivery and release of cannabinoids from the micelle or liposomes
used in the manufacture of the inventive composition. The release
of a cannabinoid from a liposome or micelle of the inventive
composition can be modulated by changing the ratio of the
concentration of lipid to the concentration of cannabinoid present
in the liposome.
[0043] In one embodiment, tissue specific delivery can be achieved
by modifying the surface of the liposomes or micelles with
compounds that bind specifically to biological macromolecules
expressed on cellular surfaces. For instance, the micelle or
liposomal surface can be derivatized to display an antibody
specific to an antigen expressed on cancer cells.
[0044] According to one embodiment, compositions of the present
invention are used in the treatment of disease conditions. For
instance, an inventive composition of the cannabinoid extract,
(cannabinoid, an analog of a cannabinoid, or both), can be
administered to a patient or subject in need of treatment either
alone or in combination with other compounds/drugs having similar
or different biological activities.
[0045] For example, compositions of the invention may be
administered in a combination therapy, i.e., either simultaneously
in single or separate dosage forms or in separate dosage forms
within hours or days of each other. Examples of compounds/drugs
used in such combination therapies include without limitation,
chemotherapeutic agents, immunosuppressive agents,
immunostimulatory, anti pyretic, cytokines, opioids, cytokines,
cytotoxic agents, nucleolytic compounds, radioactive isotopes,
receptors, pro-drug activating enzymes, which may be naturally
occurring or produced by recombinant methods, anti-inflammatory
agents, antibiotics, protease inhibitors, growth factors,
osteo-inductive factors and the like.
[0046] In some embodiments, the composition further contains, in
accordance with accepted practices of pharmaceutical compounding,
one or more pharmaceutically acceptable excipients, diluents,
adjuvants, stabilizers, emulsifiers, preservatives, colorants,
buffers, flavor imparting agents. As stated above, the inventive
compositions may contain a cannabinoid, an analog of a cannabinoid,
or both and may be consumed directly or formulated into
nutraceutical or pharmaceutically acceptable compositions suitable
for oral, enteral, parenteral, intravenous or topical
administration.
[0047] The term parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrasternal injection or
infusion techniques. Such excipients are well known in the art.
Dosage forms for oral administration include food, beverages,
drinks, soups, baked goods, syrups, oral pharmaceutical
compositions, nutraceutical formulations, and the like. Suitable
pharmaceutical carriers include any such materials known in the
art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer,
polymer or the like, which is non-toxic and which does not
significantly interact with other components of the formulations in
a deleterious manner.
[0048] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions, solutions,
suspensions, syrups and elixirs. In addition to the cannabinoid
extract, the liquid dosage forms can contain inert diluents
commonly used in the art. For instance, liquid formulations can
contain water, alcohol, polyethylene glycol ethers, or any other
pharmaceutically acceptable solvents. Solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof may
also be present in the inventive compositions. Additionally, oral
compositions can include adjuvants such as wetting agents,
emulsifying and suspending agents, sweetening, flavoring, and
perfuming agents. When formulated as a suspension, the inventive
compositions contain the cannabinoid extract and suspending agents,
for example, ethoxylated isostearyl alcohols, polyoxyethylene
sorbitol, sorbitan esters, microcrystalline cellulose, aluminum
metahydroxide, bentonite, agar-agar, tragacanth, and mixtures
thereof.
[0049] Solid dosage forms suitable for oral administration include,
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the cannabinoid extract, for instance, a cannabinoid
or a cannabinoid analog can be used alone or in combination with
one or more drugs are mixed with at least one pharmaceutically
acceptable excipient or carrier such as sodium citrate or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose,
sucrose, glucose, mannitol, and silicic acid, b) binders such as,
for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as
glycerol, d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, acetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. For capsules, tablets and pills, the
dosage form can also comprise buffering agents.
[0050] Micellular or liposomal suspensions can be encapsulated with
a variety of polymers, sugars, and chelating agents, to yield
stable solid liposomal cannabinoid preparation. Encapsulation can
take the form of cross linked polymers, trapping of the micells or
liposomes within a non crosslinked polymer network, or dispersed
within the crystalline structer of sugar starches or protein
molecules. These granulas can be further process to yield
sublingual films, suppositories, dispersable powder, tablets, gel
capsules, ect.
[0051] Solid dosages in the form of tablets, dragees, capsules,
pills, and granules can be coated using compounds that accelerate
or decrease the release of cannabinoids. For instance, the
invention encompases solid dosage forms having enteric coatings,
extended-release coatings, sustained-release coatings, delayed
release coatings and immediate-release coatings. Methods used to
coat solid dosage forms as well as the materials used to
manufacture such coatings are well known in the pharmaceutical
formulary art. The solid dosage forms can optionally contain
opacity enhancing agents. According to an embodiment, the solid
dosage form comprises an enteric coating that permits the release
of a cannabinoid or cannabinoid analog alone or in combination with
one or more drugs at a specifc location within the gastrointestinal
tract, optionally, in a delayed manner. Exemplary of such coating
materials include glyceryl monostearate or glyceryl distearate may
be employed, polymeric substances and waxes. The cannabinoid
extract, for instance, a cannabinoid or cannabinoid analog alone or
in combination with one or more drugs can also be in
micro-encapsulated form, if appropriate, with one or more of the
above-mentioned excipients.
[0052] A dietary composition according to the present invention is
any ingestible preparation that contains the cannabinoid
suspensions of the invention mixed with a food product. The food
product can be dried, cooked, boiled, lyophilized or baked. Breads,
teas, soups, cereals, salads, sandwiches, sprouts, vegetables,
animal feed, pills and tablets, are among the vast number of
different food products contemplated in the present invention.
[0053] Compositions for parenteral injection comprise
pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions as well as sterile
powders for reconstitution into sterile injectable solutions or
dispersions prior to use. Examples of suitable aqueous and
nonaqueous carriers, diluents, solvents or vehicles include water,
ethanol, polyols (such as glycerol, propylene glycol, polyethylene
glycol, and the like), carboxymethylcellulose and suitable mixtures
thereof, vegetable oils (such as olive oil), and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants. The compositions of the
present invention can also contain adjuvants such as, but not
limited to, preservatives, wetting agents, emulsifying agents, and
dispersing agents. Compositions for parenteral delivery generally
include isotonic agents such as sugars, sodium chloride, and the
like. Prolonged absorption of the injectable pharmaceutical
formulation can be brought about by the inclusion of agents which
delay absorption such as aluminum monostearate and gelatin.
[0054] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0055] Dosage forms for topical administration include, but are not
limited to, ointments, creams, emulsions, lotions, gels, sunscreens
and agents that favor penetration within the epidermis. Various
additives, known to those skilled in the art, may be included in
the topical formulations of the invention. Examples of additives
include, but are not limited to, solubilizers, skin permeation
enhancers, preservatives (e.g., anti-oxidants), moisturizers,
gelling agents, buffering agents, surfactants, emulsifiers,
emollients, thickening agents, stabilizers, humectants, dispersing
agents and pharmaceutical carriers. Examples of moisturizers
include jojoba oil and evening primrose oil. Suitable skin
permeation enhancers are well known in the art and include lower
alkanols, such as methanol ethanol and 2-propanol; alkyl methyl
sulfoxides such as dimethylsulfoxide (DMSO), decylmethylsulfoxide
(C10 MSO) and tetradecylmethyl sulfoxide; pyrrolidones, urea;
N,N-diethyl-m-toluamide; C2-C6 alkanediols; dimethyl formamide
(DMF), N,N-dimethylacetamide (DMA) and tetrahydrofurfuryl alcohol.
Examples of solubilizers include, but are not limited to,
hydrophilic ethers such as diethylene glycol monoethyl ether
(ethoxydiglycol, available commercially as Transcutol.RTM.) and
diethylene glycol monoethyl ether oleate (available commercially as
Softcutol.RTM.); polyoxy 35 castor oil, polyoxy 40 hydrogenated
castor oil, polyethylene glycol (PEG), particularly low molecular
weight PEGs, such as PEG 300 and PEG 400, and polyethylene glycol
derivatives such as PEG-8 caprylic/capric glycerides (available
commercially as Labrasol.RTM.); alkyl methyl sulfoxides, such as
DMSO; pyrrolidones, DMA, and mixtures thereof.
[0056] Prevention and/or treatment of infections can be achieved by
the inclusion of antibiotics, as well as various antibacterial and
antifungal agents, for example, paraben, chlorobutanol, phenol
sorbic acid, and the like, in the compositions of the
invention.
[0057] One of ordinary skill will appreciate that effective amounts
of the agents in the compositions used in the methods of the
invention can be determined empirically. It will be understood
that, when administered to a human patient, the total daily usage
of the composition of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors: the type and degree
of the response to be achieved; the activity of the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the duration of the treatment; drugs used in
combination or coincidental with the method of the invention; and
like factors well known in the medical arts.
[0058] The potential commercial uses of the disclosed preparations
include, for example, protective/prophylactic and medical uses. The
compositions of the invention can also be administered by a variety
of other routes, including mucosal, subcutaneous and intramuscular
administration, and may comprise a variety of carriers or
excipients known in the formulary art, such as, non-toxic solid,
semisolid or liquid filler, diluent, encapsulating material and
formulation auxiliaries that are pharmaceutically acceptable.
[0059] The present invention thus generally described, will be
understood more readily by reference to the following examples,
which are provided by way of illustration only, and are not
intended to be limiting the present invention.
EXAMPLES
A. General Protocol for the Manufacture of Micelles:
[0060] A cannabinoid, its analog or cannabinoid extract are
dissolved in a water miscible organic solvent. This solvent
cannabinoid solution is rapidly mixed or injected into an
appropriate aqueous environment. The rapid dissolution of the
organic solvent causes the dissolved cannabinoids to self align
into micro or nano micellar particles. Size, composition and
concentration of the micells are controlled by the chemical
properties of the cannabinoids, the organic solvent/aqueous
environment and the physical parameters of the solvent
addition.
B. General Protocol for the Manufacture of Liposomes
[0061] Pure Cannabinoids or cannabinoid extracts are dissolved in a
water miscible organic solvent. To this solution various
amphipathic molecules such as phospholipids, sterols, and/or fatty
acids are also dissolved. This solution containing the cannabinoids
and amphipathic molecules is rapidly mixed or injected into an
appropriate aqueous environment. The rapid dissolution of the
organic solvent causes the dissolved cannabinoids and amphipathic
molecules initiates the spontaneous formation of ordered lipid
layers which self assemble into micro or nano liposomal particles.
The size, composition and concentration of the liposomes are
controlled by the chemical properties and relative concentrations
of the cannabinoids and lipids, the organic solvent/aqueous
environment and the physical parameters of the solvent
addition.
[0062] In an exemplary composition, the hydrophobic/lipophilic
membrane comprises about 40% phosphatidylcholine, about 3.5%
phosphatidylethanolamine, about 6% phosphonophospholipids, and
about 0.5% of other phospholipids. According to another embodiment,
the hydrophobic/lipophilic membrane of liposomes in the inventive
composition comprises about 26% phosphatidylcholine, about 10%
phosphatidylethanolamine, about 13% phosphonophospholipids, and
about 1% of other phospholipids.
C. General Protocol for Encapsulation of Micelles or Liposomes
[0063] To a liposomal or micellular suspension, a polymer or
encapsulating matrix is added to a desired concentration. If so
desired a cross linking agent can be added. The polymer liposomal
mixture is then dehydrated through various means, such as
filtration, evaporation, freeze drying, or spray drying. The
dehydrated encapsulant or film can be further milled to a desired
average particle size.
[0064] The present invention uses micelles and liposomes as
vehicles for delivery a cannabinoid, its analog, or both to a
subject in need of treatment. The micelles and liposomes containing
a cannabinoid, its analog, or both are dispersed in a
pharmaceutically acceptable solvent that is suitable for a specific
route of delivery to a subject in need of treatment. The inventive
micellar or liposomal formulations can readily be manufactured by
methods further described herein.
I. Micelle Formulation
Example 1: 1 g/L Micelle Suspension of a Cannabinoid without
Stabilizer
[0065] Cannabinoids were obtained from plant tissue by
supercritical fluid extraction (SFE). Supercritical carbon dioxide
was used as the extractant. Briefly, the plant material was
contacted with carbon dioxide maintained above the critical
temperature and pressure, for example, a temperature above 350
Kelvin (K) and a pressure above 150 bar to extract cannabinoids
from the tissue. This cannabinoid extract was used to manufacture
the inventive micellar compositions. The compositions manufactured
using the protocol further described below has no added stabilizers
and can be stored as a stable aqueous suspension for 3 days at
25.degree. C.
TABLE-US-00001 TABLE 1 Micelle Formulation Ethanol Injection
Phospholipid Content None Drug Amount 850 mg Extract Drug Source
70% THC conent Cannabis Flower Extract obtained from supercritical
CO2 extniction. Injection Drug Concentration 20 ml of 30 mg/ml THC
in 95% Ethanol at 10.degree. C. Injection Type 50 ml Syringe w/22
gauge needle 50 psi 10 ml/min Aqueous Medium 195 ml Distilled H2O
at 25.degree. C. Final Ethanol to Aqueous Ratio 1:10, ethanol
removed via rotor evaporation at 30 mm Hg at less than 30 C.
Encapsulation Efficiency >95% Maximum final drug concentraion 20
mls og 1 g/l THC in suspension External Stablizer None Micell
Characterisation .2-1 u, no core apparent underl oil oil immersion,
stable at RT for 3 days
[0066] Thus, 850 mg of a 70% THC cannabis flower extract was
dissolved in 95% ethanol (20 mL) and this solution was cooled to
10.degree. C. prior to its injection under pressure (50 psi, 10
mL/min), into 195 mL, of distilled water at 25.degree. C. A 50 mL
lurlock syringe equipped with a 22 gauge needle was used to inject
the cannabinoid solution into water. The resultant aqueous micelle
suspension was subjected to rotary evaporation at a reduced
pressure of 30 mm mercury to remove ethanol. The temperature of the
round bottom flask containing the aqueous micelle suspension was
maintained below 30.degree. C. The micelle formation efficiency
using this protocol is greater than 95%. The final maximum
concentration of THC in the micelles is 1 g/L of the micelle
suspension. Micelles obtained using this protocol were 0.2-1.0
.mu.m in diameter and the aqueous micelle suspension was stable for
3 days at 25.degree. C. No aqueous core was visible under oil
immersion microscopy.
Example 2: 1 g/L Micelle Suspension of THC with Stabilizer
TABLE-US-00002 [0067] TABLE 2 Micelle Formulation Ethanol Injection
Phospholipid Content None Drug Amount 850 mg Exract Drug Source 70%
THC content Cannabis Flower Extract obtained from supercritical CO2
extraction. Injection Drug Concentration 20 ml of 30 mg/ml THC in
95% Ethanol at 25.degree. C. Injection Type 50 ml Syringe w/22
gauge needle 50 psi 10 ml/min Aqueous Medium 195 ml Distilled H2O
at 25.degree. C. Final Ethanol to Aqueous Ratio 1:10, ethanol
removed via rotor evaporation at 30 mm Hg at less than 30 C.
Encapsulation Efficiency >95% Maximum final drug concentration
20 mls og 1 g/l THC in suspension External Stablizer 0.1% w/v Guar
Gum added in 10 mg portions Micell Characterisation .2-1 u, no core
apparent under oil oil immersion, stable at RT for 7 days
[0068] The cannabinoids were obtained from plant tissue using
supercritical carbon dioxide as the extractant. 850 mg of a 70% THC
cannabis flower extract was dissolved in 95% ethanol and brought to
a final volume of 20 mL using 95% EtOH. The resultant solution was
cooled to 10.degree. C. and injected (50 psi, 10 mL/min), into 195
mL of distilled water (25.degree. C.) using a 50 mL lurlock syringe
equipped with a 22 gauge needle. Ethanol was removed from the
resultant aqueous suspension of the micelle by rotary evaporation
under a reduced pressure of 30 mm Hg to keep the temperature of
this solution below 30.degree. C. After removal of the ethanol, 0.2
g, (0.1% w/v), guar gum was added in 10 mg portions. The micelle
formation efficiency is >95%, with a final maximum THC
concentration of 1 g/L. The micelles obtained using this protocol
were 0.2-1.0 .mu.m in diameter and the aqueous micelle suspension
was stable for 7 days at 25.degree. C. No aqueous core was visible
under oil immersion microscopy.
[0069] Micelles prepared according to this embodiment of the
technology were unilamellar, as confirmed by freeze fracture
electron microscopy (data not shown). As shown in FIG. 1, staining
with a cannabinoid specific dye (Fast Blue) demonstrated that the
membrane, and not the core of the micelles, stained with the dye.
Moreover, the addition of the dye to the suspension caused
immediate precipitation of the micelles. These data clearly
demonstrated that the cannabinoid was entrapped in the membrane and
not in the core of the micelles.
Example 3: 2 g/L Micelle Suspension Using Synthesized Delta-9 THC
(Dronabinol)
TABLE-US-00003 [0070] TABLE 3 Micelle Formulation Ethanol Injection
Phospholipid Content None Drug Amount 420 mg D9 THC Drug Source
Drobabinol from sigma (D9 THC) Injection Drug Concentration 20 ml
of 21.0 mg/ml THC in 95% Ethanol at 10.degree. C. Injection Type
0.17 mm stainless steel orifice at 10 ml/min at 300 psi Ethanol to
Aqueous Ratio 195 ml Distilled at H2O at 37.degree. C. Ethanol to
Aqueous 1:10, ethanol removed via rotor evaporation at 30 mm Hg at
less than 30 C. Encapsulation Efficiency >95% Maximum final drug
concentration 200 mls of 2 g/l THC in suspension External
Stabilizer 0.1% Guar Gum in 10 mg portions Characterization .1-5 u,
no core apparent un oil immersion, stable a RT for 1 week
[0071] 10.5 g Dronabinol was dissolved 95% ethanol (final volume 20
mL). The solution was cooled to 10.degree. C. and injected through
a 0.17 mm stainless steel orifice at 300 psi into 195 mL, of
distilled water at 37.degree. C. The resultant aqueous suspension
micelles was subjected to rotary evaporation at 30 mm Hg to remove
ethanol at a solution temperature below 30.degree. C. After removal
of the ethanol, 0.2 g, (0.1% w/v), guar gum was added in 10 mg
portions. The micelle formation efficiency using this protocol was
greater than 95% and the final concentration of THC was 2 g/L.
Micelles 0.1-0.5 .mu.m in diameter were obtained and this aqueous
micelle suspension was stable for 7 days at 25.degree. C. No
aqueous core was visible under oil immersion microscopy.
Example 4: 2 g/L Micelle Suspension Using a Mixture of
Canabinoids
TABLE-US-00004 [0072] TABLE 4 Micelle Formulation Ethanol Injection
Phospholipid Content None Drug Amount 200 mg THC, 110 mg CBD, 110
mg CBC Drug Source Synthsised In House Injection Drug Concentration
20 ml of 21.9 mg/ml Cannasbinpoids in 95% Ethanol at 25.degree. C.
Injection Type Ultrasonic Atomizer Nozzle @ 60 Hz. 20 + drop size,
10 ml/min Aqueous Medium 195 ml PBS at 25.degree. C. Ethanol to
Aqueous Ratio 1:10, ethanol removed via rotor evaporation at 30 mm
Hg at less than 30 C. Encapsulation Efficiency >95% Maximum
final drug concentration 20 mls of 1 g/L THC. 0.5 g/l CBD, 0.5 g/l
CBC in suspension External Stabilizer 0.1% Guar Gum in 10 mg
portions Characterization 50-220 nm, no core apperent un oil
immersion, stable a RT for 4 weeks
[0073] 200 mg of chemically synthesized THC was combined with 110
mg chemically synthesized CB and 110 mg synthetic CBC and the
mixture was dissolved in 95% ethanol (final volume of 20 ml) The
resultant solution was cooled to 10.degree. C. and injected using
an Ultrasonic Atomizer Nozzle at 60 Hz (20 .mu.m drop size, 10
mL/min), into 195 mL, of distilled water (37.degree. C.). Ethanol
was removed from the resultant aqueous suspension of the micelle by
rotary evaporation under a reduced pressure of 30 mm Hg to keep the
temperature of this solution below 30.degree. C. The final volume
of this solution was 200 mL. To this solution was added 0.2 g,
(0.1% w/v), guar gum in 10 mg portions. The micelle formation
efficiency using this method was >95%. The final maximum
cannabinoid concentration was 2 g/L and micelles 50-200 nm in
diameter were obtained. The aqueous micelle suspension was stable
for 4 weeks at 25.degree. C.
II. Liposome Formulation
Example 5: 50 g/L Liposomal Suspension of THC
TABLE-US-00005 [0074] TABLE 5 Micelle Formulation Ethanol Injection
Lipid Amount 15 grams Ethanolic Soluable Soy Lecitein 50 Lipid
Content Phosphatidylcholine (PC)~52%, Phosphatidylethanolamine
(PE)~20%, Phospholipids (PPI.)~26%, other -2% Drug Amount 15 grams
Drug Source 70% THC content Cannabis Flower Extract obtained from
supercritical CO2 extraction. Ethanol Injection 60 ml of 250 mg/ml
THC, 130 mg/ml PC, 50 mg/ml PE, 65 mg/ml PPI. in 95% Ethanol at
10.degree. C. Injection Type 100 ml Syringe w/22 gauge needle 50
psi 10 ml/min Aqueous Medium 540 ml Distilled H2O at 25.degree. C.
Final Ethanol to Aquoue Ratio 1:10, ethanol and water removed via
rotor evaporation at 30 mm Hg at less than 55 C. take to a final
volume of 200 ml Encapsulation Efficiency >95% Maximum final
drug concentration in 200 mls of 50 g/l THC suspensions External
Stabilizer None Micell Characterisation diameter 200-400 nm,
aqueous core apparent under oil immersion, stable at RT for >3
months
[0075] 15 g of a 70% THC cannabis flower extract obtained using
supercritical CO.sub.2 extraction was dissolved in 95% ethanol
(final volume of 30 ml). This ethanolic extraction solution was
combined with an ethanolic solution of Lecithin-50 (30 ml), which
was prepared by dissolving 15 grams of Lecithin-50 using small
portions of 95% EtOH and bringing the final volume of the
lipid/EtOH solution to 30 mL using 95% EtOH. The ethanolic solution
of lipid and THC was cooled to 10.degree. C. and injected at a
pressure of 50 psi (10 mL/min), into 540 mL of distilled water
(25.degree. C.), using a 100 mL lurlock syringe equipped with a 22
gauge needle. A pressure of 50 psi, and a flow rate of 10 mL/min
was maintained during the injection process. The liposomal
suspension was concentrated to 200 mL by rotary evaporation at 30
mm Hg keeping the temperature of the liposomal suspension below
55.degree. C. The liposome formation efficiency using this protocol
was greater than 95%. The final maximum THC concentration was 50
g/L. Liposomes 200-400 nm in diameter were obtained and had an
aqueous core visible under oil immersion microscopy. The aqueous
liposomal suspension was stable for more than 3 months at
25.degree. C.
[0076] The liposomes have a size of about 0.22 .mu.m, as determined
by gel filtration, and a spherical shape, as demonstrated by oil
immersion light microscopy (FIG. 2), and are unilamellar, as shown
by freeze fracture electron microscopy (data not shown). As shown
in FIG. 3, staining with a cannabinoid specific dye (Fast Blue)
demonstrated that the membrane, and not the core of the liposomes,
stained with the dye. These data clearly demonstrated that the
cannabinoid was entrapped in the membrane and not in the core of
the liposomes.
Example 6: 50 g/L Liposomal Suspension of Pure Delta-9-THC
TABLE-US-00006 [0077] TABLE 6 Micelle Formulation Ethanol Injection
Lipid Amount 10.5 grams Ethanolic Soluable Soy Lecitein 80 Lipid
Content Phosphatidylcholine (PC)~81%, Phosphatidylethanolamine
(PE)~7.5%, Phospholipids (PPI.)~11%, other~0.5% Drug Amount 10.5
grams Drug Source Drobabinol from sigma (D9 THC) Ethanol Injection
40 ml of 262.5 mg/ml THC, 212 mg/ml PC, 19.6 mg/ml PE, 28.8 mg/ml
PPI. in 95% Ethanol at 30.degree. C. Injection type 0.17 mm
stainless steel orifice at 10 ml/min at 300 psi Aqueous Medium 360
ml Distilled H2O at 25.degree. C. Final Ethanol to Aqueous Ratio
1:10, ethanol and water removed via rotor evaporation at 30 mm Hg
at less than 55 C. take to a final volume at 200 ml Encapsulation
Efficiency >95% Maximum final drug concentration 200 mls of 50
g/l THC in suspension External Stabilizer None Micell
Characterisation diameter 20-250 nm, aqueous core apparent under
oil immersion, stable at RT for >3 months
[0078] 10.5 g of Dronobinol was dissolved in a portion of 95%
ethanol (EtOH) and the final volume of this solution was brought to
20 ml using 95% EtOH. This ethanolic solution was combined with 20
ml of an ethanolic solution of soluble soy lecithin-80 which was
prepared by dissolving 10.5 grams of Lecithin-80 into a portion of
95% EtOH and adjusting the volume of the lipid/EtOH solution to 20
mL using 95% EtOH. The resultant solution was cooled to 30.degree.
C. and injected through a 0.17 mm stainless steel orifice at 300
psi into 360 mL of distilled water (25.degree. C.). Concentration
of the ethanolic/aqueous liposomal suspension to 200 mL by rotary
evaporation at 30 mm Hg to keep the temperature below 55.degree. C.
gave the desired liposomal composition. The liposome formation
efficiency was >95% and the final concentration of THC was 50
g/L.
[0079] Liposomes 20-250 nm in diameter were obtained and had an
aqueous core visible under oil immersion microscopy. The aqueous
liposomal suspension was stable for more than 3 months at
25.degree. C.
Example 7: 40 g/L Liposomal Suspension of a Mixture of
Cannabiniods
TABLE-US-00007 [0080] TABLE 7 Micelle Formulation Ethanol Injection
Lipid Amount 126 grams Ethanolic Soluable Soy Lecitein 80 Lipid
Content Phosphatidylcholine (PC)~81%, Phosphatidylethanolamine
(PE)~7.5%, Phospholipids (PPI.)~11%, other~0.5% Drug Amount 15.75 g
THC, 7.875 g CBD, 7.875, g CBC Drug Source Synthsised In House
Ethanol Injection 200 ml of 77.5 mg/ml THC, 39.375 mg/ml CBD,
39.375 mg/ml CBC, 510 mg/ml PC, 47.25 mg/ml PE, 69.3 mg/ml PPI. in
95% Ethanol at 25.degree. C. Injection type Ultrasonic Atomizer
Nozzle @ 60 Hz, 29 um drop size, 10 ml/min Aqueous Medium 1.21
Distilled H2O at 25.degree. C. Final Ethanol to Aqueous Ratio 1:7,
ethanol and water removed via rotor evaporation at 30 mm Hg at less
than 55 C. take to a final volume at 500 ml Encapsulation
Efficiency >95% Maximum final drug concentration 750 mls of 21
g/l THC, 10 g/l CBD, 10 g/T CBC in suspension External Stabilizer
None Micell Characterisation diameter 20-100 nm, aqueous core
apparent under oil immersion, stable at RT for 24 H
[0081] 15.75 g of a 2:1:1 (w:w:w) ratio of THC, CBD, CBC were
dissolved in a portion of 95% ethanol and brought to a final volume
of 100 mL with 95% EtOH. This ethanolic solution was combined with
an ethanolic solution of soluble soy Lecithin-80 (100 mL) which was
prepared by dissolving 126 g of Lecithin-80 into a portion of 95%
EtOH and bringing the volume of the lipid/EtOH solution to 100 mL.
The resultant mixture was cooled to 25.degree. C. and injected
using an Ultrasonic Atomizer Nozzle at 60 Hz (20 .mu.m drop size,
10 mL/min), into 1.20 L of distilled water (25.degree. C.). The
ethanolic-aqueous liposomal suspension was concentrated by rotary
evaporation at 30 mm Hg and a temperature below 55.degree. C. to a
final volume of 200 mL. The liposome formation efficiency was
>95% and the final maximum concentration of THC was 40 g/L.
Liposomes 20-100 nm in diameter and having an aqueous core visible
under oil immersion microscopy were obtained. The aqueous liposomal
suspension was stable for more than 3 months at 25.degree. C.
III. Encapsulation Formulations
Example 8: Calcium Alginate Encapsulated Liposomal Suspensions of
Cannabinoids
TABLE-US-00008 [0082] TABLE 8 Example 8: Encapsulation of Liposomal
suspension of Plant Extract Componets Liposomal Suspension Source
Example 5 Liposome Drug Concentration 50 g/T. Encapulant Sodium
Alginate Encapsulant Concentration 2% or 20 g/T. Addition Method
Bulk Addition Crosslinking Agent Ca Cl2 Cross Linking agent
concentration 40 mls of 25% Crosslinking Incubation 10 mins Drying
conditions Warm Air 50 C. for 24 H Final Product Description ~25 g
Free Flowing Powder, disloves in buffered H2O Content 10 g d9 THC,
10 g Lecthicin 50, 5 g Alginate Active Drug Content -40% Release
Profile 100% in 60 mM citrate ph 7.0
[0083] 4 g of sodium alginate was dissolved in 200 mL of a 50 g/L
liposomal suspension (Example 5) of THC. The alginate/THC mixture
was poured into 40 mL of a stirring 25% aqueous solution of calcium
chloride. The resultant solution was further stirred for an
additional 10 mins to allow crosslinking (polymerization) of
alginic acid. The solid mass of calcium alginate encapsulated THC
liposomal suspension is cold pressed to remove the majority of the
water. The pressed material is further dried in warm air,
50.degree. C., for 24 hrs. This air-dried material is milled to a
free flowing yellowish white powder that readily dissolves in
buffered water. The cannabinoid content of the alginate powder is
.about.40%, and the entrapped material is completely released in 60
mM, pH 7, citrate buffer.
Example 9: Film Formation of Liposomal Suspension
TABLE-US-00009 [0084] TABLE 9 Example 9: Film Formation of
Liposomal suspension from pure D9 THC Liposomal Suspension Source
Example 6 Liposome Drug Concentration 50 g/T. Encapulant Sodium
Alginate or Agarose of Felatin or pectin Encapsulant Concentration
4% or 40 g/T. Crosslinking Agent none Cross Linking agent
concentration None Crosslinking Incubation None Drying conditions
Freeze Drying or Spray Drying Final Product Description Free
Flowing Powder, disloves in H2O Content 10 g d9 THC, 10 g Lecthicin
50, 8 g Alginate (or other encapsulant) Active Drug Content -20%
Release Profile 100% in distilled H2O
[0085] To the liposomal suspension prepared using the protocol of
Example 6 was added sodium alginate in a amount sufficient to
provide a 4% w/v (8 grams) solution of alginate in liposomal
suspension. The suspension is stirred at room temperature to
dissolve the alginate. Once dissolved the entire suspension is
shell frozen over a dry ice/acetone bath and freeze dried to a
solid mass which is milled to a free flowing powder. Yield 28
grams. The powder thus obtained contains .about.40% cannabinoids
and dissolves completely in distilled water.
Example 10: Calcium Alginate Encapsulated Liposomal Suspension of
Mixed Cannabinoids
TABLE-US-00010 [0086] TABLE 10 Example 10: Encapsulation of
Liposomal suspension of Mixed Cannabinoid Formulations Liposomal
Suspension Example 7 Source Drug Concentration 21 g/T. THC, 10 g/T.
CBD, 19 g/T. CBC Encapulant Sodium Alginate Encapsulant
Concentration 4% or 20 g/T. Addition Method Injection through .17
urn orifice 1 ml/min Crosslinking Agent Ca Cl2 Cross Linking agent
40 mls of 25% concentration Crosslinking Incubation 10 mins Drying
conditions Warm Air 50 C. for 24 H Final Product Description Free
Flowing Powder, disloves in H2O Content 15.0 g d9 THC, 7.5 g CBD,
7.5 g CBC, 120 g Lecthicin 80, 15 g Alginate Active Drug Content
-9.5% THC, ~4.7% CBD, ~4.7% CBC Release Profile 100% in 60 mM
citrate ph 7.0
[0087] To the liposomal suspension of mixed cannabinoids containing
15.0 g THC, 7.5 g CBD, 7.5 g CBC and 120 g Lecithin-80 (Example 7),
was added 4 g of sodium alginate. The resultant solution was
injected through a 0.17 mm stainless steel orifice at 300 psi into
40 mL of a stirring solution of 25% aqueous calcium chloride. The
resultant solution was further stirred for an additional 10 mins to
allow crosslinking (polymerization) of alginic acid. The solid mass
of calcium alginate encapsulated THC liposomal suspension is cold
pressed to remove the majority of the water. The pressed material
is further dried in warm air, 50.degree. C., for 24 hrs. This
air-dried material is milled to a free flowing yellowish white
powder that readily dissolves in buffered water.
[0088] The cannabinoid content of the alginate powder is
.about.9.5% THC, .about.4.7% CBD, .about.4.7% CBC, and these
compounds wer completely released in 60 mM, pH 7, citrate
buffer.
Example 11: Formation of a Dispersible Delta-9-THC Dry Powder
TABLE-US-00011 [0089] TABLE 11 Example 11: Dispersiable Dry Powder
D9 THC Liposmal Preperation Liposomal Suspension Source Example 6
Drug Concentration Diluted 1:10 to 20 ml of 5 g/T. Encapulant
Lactose of Sucrose Encapsulant Concentration 200 mg/ml Lactose of
Sucrose, 0.6 mg/ml L-Lucine or Isolucine Crosslinking Agent none
Cross Linking agent concentration None Crosslinking Incubation None
Drying conditions Spray Drying or Freeze Drying Final Product
Description 42.5 grams white Free Flowing Powder, disloves in H2O
Content 1 g d9 THC, 1 g Lethicin 50, 40 grams Lactose, 0.12
L-Lucine Active Drug Content -2.3% Release Profile 100% in
distilled H2O
[0090] The liposomal preparation from Example 6 was diluted 1:10
with distilled water. To 200 ml of the resulting solution was added
lactose or sucrose in an amount sufficient to provide a 200 mg/ml
(40 grams) solution of these reagents. L-lucine in an amount of 0.6
mg/ml (0.12 grams) was then added to the reaction mixture. The
resultant solution was frozen using a dry ice/acetone bath and
freeze dried to obtain a solid mass. Alternatively the solution can
be spray dried with a forced air spray dryer at a temperature of
55.degree. C. The crystalline solid thus obtain was milled to a
free flowing powder. Approximately 42 grams of resulting powder
containing approximately 1 g of THC, (i.e., a solid composition
having a cannabinoid content of .about.2.3%) was obtained. This
powder dissolves completely in water releasing the liposomes. The
resulting suspension contains >90% of the starting
liposomes.
* * * * *