U.S. patent application number 16/117482 was filed with the patent office on 2019-01-31 for hydrogenation of cannabis oil.
The applicant listed for this patent is MARK ANDREW SCIALDONE. Invention is credited to MARK ANDREW SCIALDONE.
Application Number | 20190030102 16/117482 |
Document ID | / |
Family ID | 57218412 |
Filed Date | 2019-01-31 |
United States Patent
Application |
20190030102 |
Kind Code |
A1 |
SCIALDONE; MARK ANDREW |
January 31, 2019 |
HYDROGENATION OF CANNABIS OIL
Abstract
The present invention relates to the extraction and
hydrogenation of essential oil of a cannabis plant. The invention
includes hydrogenated cannabis compounds and compositions, as well
as methods of preparation and therapeutic uses for regressing
tumors in a cancer patient. The extract can include
9-tetrahydrocannabinoic acid and 9-cannabidiolic acid, and the
hydrogenated cannabis oil can include hydrogenated
9-tetrahydrocannabinoic acid, hydrogenated 9-cannabidioc acid and,
mixtures and blends thereof.
Inventors: |
SCIALDONE; MARK ANDREW;
(WEST GROVE, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SCIALDONE; MARK ANDREW |
WEST GROVE |
PA |
US |
|
|
Family ID: |
57218412 |
Appl. No.: |
16/117482 |
Filed: |
August 30, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15613633 |
Jun 5, 2017 |
10071127 |
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16117482 |
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15149721 |
May 9, 2016 |
9694040 |
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15613633 |
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62158025 |
May 7, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 36/185 20130101;
C07D 311/80 20130101; A61K 31/352 20130101; A61P 35/00 20180101;
A61K 2236/31 20130101; A61K 31/192 20130101; A61K 31/05 20130101;
A61K 31/05 20130101; A61K 2300/00 20130101; A61K 31/352 20130101;
A61K 2300/00 20130101; A61K 31/192 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 36/185 20060101
A61K036/185; A61K 31/192 20060101 A61K031/192; A61K 31/352 20060101
A61K031/352; C07D 311/80 20060101 C07D311/80; A61K 31/05 20060101
A61K031/05; A61P 35/00 20060101 A61P035/00 |
Claims
1. A method of hydrogenating cannabis oil, comprising: obtaining a
cannabis plant having essential oil, comprising at least one of
.DELTA.-9-tetrahydrocannabinolic acid and .DELTA.-9-cannabidiolic
acid; extracting the essential oil from the cannabis plant to form
an essential oil extract; and hydrogenating the essential oil
extract to form hydrogenated cannabis oil, comprising at least one
of hydrogenated .DELTA.-9-tetrahydrocannabinolic acid and
.DELTA.-9-cannabidiolic acid.
2. The method of claim 1, wherein the extracting and hydrogenating
steps, comprising extracting the essential oil from the cannabis
plant employing an extraction solvent, separating an essential oil
extract, comprising at least one of
.DELTA.-9-tetrahydrocannabinolic acid and .DELTA.-9-cannabidiolic
acid, and hydrogenating the essential oil extract in absence of the
extraction solvent.
3. The method of claim 1, wherein the essential oil comprises
terpenoids, flavonoids, sterols and, mixtures and blends
thereof
4. The method of claim 1, wherein the extracting step comprises
contacting the essential oil with an extraction solvent.
5. The method of claim 4, wherein the extraction solvent comprises
butane.
6. The method of claim 1, wherein the hydrogenating step comprises
contacting the essential oil extract with at least one of a
catalyst and a solvent.
7. A method for regressing tumors in a cancer patient, comprising:
preparing a hydrogenated cannabis oil composition, comprising:
obtaining a cannabis plant having essential oil, comprising at
least one of .DELTA.-9-tetrahydrocannabinolic acid and
.DELTA.-9-cannabidiolic acid; extracting the essential oil from the
cannabis plant to form an essential oil extract; and hydrogenating
the essential oil extract to form hydrogenated cannabis oil,
comprising at least one of hydrogenated
.DELTA.-9-tetrahydrocannabinolic acid and .DELTA.-9-cannabidiolic
acid; and administering a therapeutically effective amount of the
hydrogenated cannabis oil composition to the cancer patient.
8. A hydrogenated cannabis oil composition, comprising a
hydrogenated acid selected from the group consisting of
hydrogenated .DELTA.-9-tetrahydrocannabinolic acid, hydrogenated
.DELTA.-9-cannabidiolic acid and, mixtures and blends thereof
9. A composition, comprising one or more hexahydrocannabinoids
selected from the group consisting of formulas 3a, 3b, 3c, 3d, 4a
and 4b: ##STR00006##
10. The composition of claim 9, further comprising one or more
compounds selected from the group consisting of hydrogenated
terpenes, hydrogenated terpenoids, hydrogenated flavonoids,
hydrogenated cannabinoids, and hydrogenated sterols.
11. A method of preparing a hydrogenated cannabis oil, comprising:
extracting cannabis oil from a cannabis plant to provide an extract
comprising one or more .DELTA.-9-tetrahydrocannabinoic acids and
.DELTA.-9-tetrahydrocannabinols selected from the group consisting
of formulas 1a, 1b, 2a and 2b: ##STR00007## and hydrogenating the
extract to produce a hydrogenated cannabis oil comprising one or
more hexahydrocannabinoids selected from the group consisting of
formulas 3a, 3b, 3c and 3d: ##STR00008##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 15/613,633, entitled "HYDROGENATION OF CANNABIS OIL",
filed on Jun. 5, 2017, which is a divisional of U.S. patent
application Ser. No. 15/149,721, entitled "HYDROGENATION OF
CANNABIS OIL", filed on May 9, 2016, now U.S. Pat. No. 9,694,040,
issued Jul. 4, 2017, which claims priority under 35 U.S.C.
.sctn.119(e) to U.S. Provisional Patent Application Ser. No.
62/158,025, filed May 7, 2015, entitled "HYDROGENATION OF CANNABIS
OIL", which applications are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention generally relates to hydrogenation of the
essential oil of cannabis plants, including cannabis plant species
Cannabis sativa, C. indica and C. ruderalis. The hydrogenation of
the plant essential oil provides an enriched source of
hexahydrocannabanoids for use in treating various conditions and
diseases, such as, but not limited to, cancer.
BACKGROUND
[0003] In general, hexahydrocannabanoids (HHCs) have been
demonstrated to be anticancer compounds that inhibit cell
proliferation and tumor angiogenesis (Eur J Pharmacol. 2011
650(1):64-71). The anti-tumor activity of the hexahydrocannabinol
analog LYR-8 in human colorectal tumor xenograft is mediated
through the inhibition of Akt and hypoxia-inducible factor-la
activation. HHC compounds have been prepared by various methods,
including the methods described in U.S. Patent Application
Publication 2010/0298579 A1. This synthetic preparation involves a
key amine-catalyzed cyclization of citronellal with a substituted
3-acyl-resorcinol.
[0004] There is a need in the art to improve the methods for
producing a hydrogenated cannabis oil that includes HHCs, as well
as therapeutic uses for the hydrogenated cannabis oil.
SUMMARY
[0005] The present invention relates to a product, e.g., compound,
obtained from the hydrogenation of cannabis oil, compositions that
include the product, and methods of preparing the product.
Hydrogenation converts cannabinoids, as well as, terpenoids,
flavonoids and sterols present in cannabis oil into their
hydrogenated derivatives in a hydrogenated cannabis oil (HCO)
mixture. The amounts of the hydrogenated compounds in the HCO
product depends on the amounts of the precursors in the starting
cannabis oil, which may vary based on the plant variety employed.
Further, the hydrogenated compounds formed may depend on the
hydrogenation reaction conditions used and different product
compounds can be formed by changing the reaction conditions and
hydrogenation catalyst used.
[0006] In one aspect, the present invention provides a method of
hydrogenating cannabis oil that includes obtaining a cannabis plant
having essential oil, including at least one of
9-tetrahydrocannabinoic acid and 9-cannabidiolic acid;
[0007] extracting the essential oil from the cannabis plant to form
an essential oil extract; and hydrogenating the essential oil
extract to form hydrogenated cannabis oil, including at least one
of hydrogenated 9-tetrahydrocannabinoic acid and 9-cannabidioc
acid.
[0008] The extracting and hydrogenating steps can include
extracting the essential oil from the cannabis plant employing an
extraction solvent, separating an essential oil extract, including
at least one of 9-tetrahydrocannabinoic acid and 9-cannabidiolic
acid, and hydrogenating the essential oil extract in absence of the
extraction solvent.
[0009] In another aspect, the present invention provides a
hydrogenated cannabis oil composition that includes a hydrogentated
acid selected from the group consisting of hydrogenated
9-tetrahydrocannabinoic acid, hydrogenated 9-cannabidioc acid and,
mixtures and blends thereof.
[0010] In still another aspect, the present invention provides a
method for regressing tumors in a cancer patient, including
preparing hydrogenated cannabis oil composition, which includes
obtaining a cannabis plant having essential oil, including at least
one of 9-tetrahydrocannabinoic acid and 9-cannabidiolic acid,
extracting the essential oil from the cannabis plant to form an
essential oil extract, and hydrogenating the essential oil extract
to form hydrogenated cannabis oil, including at least one of
hydrogenated 9-tetrahydrocannabinoic acid and 9-cannabidioc acid;
and administering a therapeutically effective amount of the
hydrogenated cannabis oil composition to the cancer patient.
BRIEF DESCRIPTION OF THE DRAWING
[0011] FIG. 1 is a bar graph showing the effect of cannabinoids on
the glioblastoma tumor (U87) weight following treatment of one
week, in accordance with certain embodiments of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0012] The present invention relates to novel compounds,
compositions and methods for extracting and hydrogenating essential
oils of the cannabis plant. Hexahydrocannabanoids (HHCs) can be
produced by hydrogenating mixtures of tetrahydrocannabanoid
compounds, the principal component of the essential oil from
cannabis plants, herein referred to as cannabis oil. Cannabis oil
can be obtained from plants of the Cannabis sativa, C. indica and
C. ruderalis by various conventional isolation processes, including
steam distillation, organic solvent extraction, microwave-assisted
organic solvent extraction, supercritical fluid extraction and
cryo-mechanical methods. The crude cannabis oil, extract or
concentrate obtained from these processes can be used without any
purification to produce HHC-enriched cannabis oil by hydrogenation
of the oil directly to reduce the carbon-carbon double bonds of the
tetrahydrocannabinoid compounds in the oil such as
.DELTA.-9-tetrahydrocannabinoic acid (THCA) and
.DELTA.-9-cannabidioc acid (CBDA).
[0013] The direct hydrogenation of the crude cannabis oil will also
hydrogenate the unsaturated groups in the other compounds present
in cannabis oil such as terpenes, terpenoids, flavonoids, sterols
and other unsaturated compounds. Chemical transformation of these
compounds in cannabis oil by hydrogenation of their unsaturated
functional groups changes the properties of the product herein
referred to as hydrogenated cannabis oil (HCO). HCO is the product
of cannabis oil hydrogenation that is enriched with
hexahydrocannabanoids and hydrogenated terpenoids. The
concentration of the individual cannabinoids and terpenes, which
varies in different varieties of cannabis plants, in the starting
cannabis oil determines the concentration of the hydrogenated
compounds in the HCO product.
[0014] Thus, cannabis oil produced by extraction of whole plants
can be used in the hydrogenation reaction to produce hydrogenated
cannabis oil (HCO), which is enriched with HHCs, as well as
hydrogenated terpenes, e.g., terpenoids.
[0015] As used herein, the following terms have the definitions
provided.
[0016] The term "tetrahydrocannabinoic acids" as used herein refers
to the compounds having the chemical structures of
.DELTA.-9-tetrahydrocannabinoic acid (THCA) and
.DELTA.-9-cannabidiolic acid (CBDA) as depicted in Formulas 1a and
1b.
##STR00001##
[0017] The term "tetrahydrocannabinols" as used herein refers to
the compounds having the chemical structures of THC and CBD as
depicted in Formulas 2a and 2b.
##STR00002##
[0018] The term "hexahydrocannabanoids" ("HHC") formed by
hydrogenation of cannabinoids as used herein refers to the
compounds having the chemical structures of HTHCA, HCBDA, HTHC and
HCBD as depicted in Formulas 3a, 3b, 3c and 3d.
##STR00003##
[0019] The term "2-hydroxymethyl-hexahydrocannabanoids"
("2-HM-HHC") formed by hydrogenation of cannabinoids as used herein
refers to the compounds having the chemical structures of 2-HMHTHC
and 2-HMHCBT as depicted in Formulas 4a and 4b.
##STR00004##
[0020] The term "partially hydrogenated cannabidiol" ("PHCBD")
formed by hydrogenation of CBD to selectively reduce the
isopropenyl group as used herein refers to the compound having the
chemical structure as depicted in Formula 5.
##STR00005##
[0021] The term "cannabis oil" as used herein refers to the
isolated extract from cannabis plants. Cannabis oil is obtained
from plants of the Cannabis sativa, C. indica and C. ruderalis by
various isolation processes, including steam distillation, organic
solvent extraction, microwave-assisted organic solvent extraction,
supercritical fluid extraction and cryo-mechanical methods, which
are suitable for use in this invention. Crude cannabis oil, extract
or concentrate so obtained can be used without any purification to
produce HHC-enriched cannabis oil by hydrogenation of the oil
directly to reduce the carbon-carbon double bonds of the
tetrahydrocannabinoid compounds in the oil such as
.DELTA.-9-tetrahydrocannabinoic acid (THCA) and
.DELTA.-9-cannabidiolic acid (CBDA).
[0022] The endocannabinoid system (ECS) is a chemical-based
signaling system found throughout the human body in the brain,
organs, connective tissues, glands, and immune cells. The ECS
system functions based on ligands binding membrane bound G-protein
coupled receptors, namely the CB1 and CB2 receptors. The known
endocannahanoids are anandarnide and 2-arachidonoylglycerol. The
phytocannabinoids produced by cannabis also bind and activate these
receptors.
[0023] Synthetic derivatives that are not plant-derived that have
receptor subtype selectivity towards either CB1 or CB2 are known in
the art.
[0024] The term "hydrogenation" as used herein refers to the
chemical reaction of molecular hydrogen (H.sub.2) with organic
compounds resulting in the addition of a hydrogen molecule to the
organic compound. The hydrogenation of organic compounds and
mixtures of organic compounds is well known in the art. The
hydrogenation of organic compounds and mixtures of organic
compounds having carbon-carbon and carbon-oxygen double bonds is
generally known in the art.
[0025] Catalytic hydrogenations employ catalysts that increase the
rate of the reaction between the organic compounds. Hydrogenation
catalysts used can be heterogeneous in the reaction medium, such
as, a solution over a solid catalyst or homogeneous in the reaction
solvent. The use of both heterogeneous and homogeneous catalysts in
the hydrogenation of organic compounds and mixtures of organic
compounds is also generally known in the art.
[0026] The term "catalyst" as used herein refers to a substance
that affects the rate of a chemical reaction (but not the reaction
equilibrium), and emerges from the process chemically unchanged.
The term "promoter" as used herein refers to a compound that is
added to enhance the physical or chemical function of a catalyst. A
chemical promoter generally augments the activity of a catalyst,
and may be incorporated into the catalyst during any step in the
chemical processing of the catalyst constituent. The chemical
promoter generally enhances the physical or chemical function of
the catalyst agent, but can also be added to retard undesirable
side reactions. A "metal promoter" refers to a metallic compound
that is added to enhance the physical or chemical function of a
catalyst.
[0027] Many hydrogenation catalysts are effective, including
(without limitation) those containing as the principal component,
e.g., element, iridium, palladium, rhodium, nickel, ruthenium,
platinum, rhenium, compounds thereof, combinations thereof, and the
supported versions thereof. A supported catalyst is one in which
the active catalyst agent is deposited on a support material by
spraying, soaking or physical mixing, followed by drying,
calcination, and if necessary, activation through methods such as
reduction or oxidation. Materials frequently used as support are
porous solids with high total surface areas (external and internal)
which can provide high concentrations of active sites per unit
weight of catalyst. The catalyst support may enhance the function
of the catalyst agent; and supported catalysts are generally
preferred because the active metal catalyst is used more
efficiently. A catalyst which is not supported on a catalyst
support material is an unsupported catalyst. The metal catalyst
used in the process of this invention may be used as a supported or
as an unsupported catalyst.
[0028] The catalyst support can be any solid, inert substance
including, but not limited to, oxides such as silica, alumina,
titania, calcium carbonate, barium sulfate, and carbons. The
catalyst support can be in the form of powder, granules, pellets,
or the like. In certain embodiments, the support material of the
present invention is selected from the group consisting of carbon,
alumina, silica, silica-alumina, titania, titania-alumina,
titania-silica, barium, calcium, compounds thereof and combinations
thereof. Suitable supports include carbon, SiO.sub.2, CaCO.sub.3,
BaSO.sub.4 and Al.sub.2O.sub.3. Moreover, supported catalytic
metals may have the same supporting material or different
supporting materials. In one embodiment of the instant invention,
the support is carbon. Further, the supports, e.g., carbon, can
have a surface area from about 100 to about 200 m.sup.2/g.
Furthermore, the supports, e.g., carbon, can have a surface area of
at least about 200 m.sup.2/g or at least about 300 m.sup.2/g.
[0029] Commercially available carbons which may be used in this
invention as catalyst supports include those sold under the
following trademarks: Bameby & SutclilTe.TM., Darco.TM.,
Nuchar.TM., Columbia JXN.TM., Columbia LCK.TM., Calgon PCB.TM.,
Calgon BPL.TM., Westvaco.TM., Norit.TM. and Barnaby Cheny NB.TM..
The commercially available carbon can also include Calsicat C,
Sibunit C, or Calgon C (commercially available under the registered
trademark Centaur.RTM.). In certain embodiments, combinations of
catalytic metal and support system include nickel on carbon, nickel
on Al.sub.2O.sub.3, nickel on CaCO.sub.3, nickel on BaSO.sub.4,
nickel on SiO.sub.2, platinum on carbon, platinum on A1203,
platinum on CaCO3, platinum on BaSO4, platinum on SiO.sub.2,
palladium on carbon, palladium on Al.sub.2O.sub.3, palladium on
CaCO.sub.3, palladium on BaSO.sub.4, palladium on SiO.sub.2,
iridium on carbon, iridium on Al.sub.2O.sub.3, iridium on
SiO.sub.2, iridium on CaCO.sub.3, iridium on BaSO.sub.4, rhenium on
carbon, rhenium on Al.sub.2O.sub.3, rhenium on SiO.sub.2, rhenium
on CaCO.sub.3, rhenium on BaSO.sub.4, rhodium on carbon, rhodium on
Al.sub.2O.sub.3, rhodium on SiO.sub.2, rhodium on CaCO.sub.3,
rhodium on BaSO.sub.4, ruthenium on carbon, ruthenium on
Al.sub.2O.sub.3, ruthenium on CaCO.sub.3, ruthenium on BaSO.sub.4,
and ruthenium on SiO.sub.2. As stated above, useful catalytic
metals include component, e.g., elemental, iridium, palladium,
rhodium, nickel, ruthenium, platinum and rhenium; and useful
support materials include carbon, alumina, silica, silica-alumina,
titania, titania-alumina, titania-silica, barium and calcium, and
more particularly, carbon, SiO.sub.2, CaCO.sub.3, BaSO.sub.4 and
Al.sub.2O.sub.3.
[0030] A supported catalyst may be made from any combination of the
above named metals and support materials. A supported catalyst may
also, however, be made from combinations of various metals and/or
various support materials selected from subgroup(s) of the
foregoing formed by omitting any one or more members from the whole
groups as set forth in the lists above. As a result, the supported
catalyst may, in such instance, not only be made from one or more
metals and/or support materials selected from subgroup(s) of any
size that may be formed from the whole groups as set forth in the
lists above, but may also be made in the absence of the members
that have been omitted from the whole groups to form the
subgroup(s). The subgroup(s) formed by omitting various members
from the whole groups in the lists above may, moreover, contain any
number of the members of the whole groups such that those members
of the whole groups that are excluded to form the subgroup(s) are
absent from the subgroup(s). For example, it may be desired in
certain instances to run the process in the absence of a catalyst
formed from palladium on carbon.
[0031] While the weight percent of catalyst on the support is not
critical, it will be appreciated that the higher the weight percent
of metal, the faster the reaction. In certain embodiments, the
content range of the metal in a supported catalyst is from about
0.1 wt % to about 20 wt % of the whole of the supported catalyst
(catalyst weight plus the support weight). In other embodiments,
the catalytic metal content range is from about 1 wt % to about 10
wt % by weight of the whole of the supported catalyst. Still
further, another catalytic metal content range is from about 3 wt %
to about 7 wt % by weight of the whole of the supported catalyst.
Optionally, a metal promoter may be used with the catalytic metal
in the method of the present invention. Suitable metal promoters
include: 1) those elements from Groups 1 and 2 of the Periodic
Table; 2) tin, copper, gold, silver, and combinations thereof; and
3) combinations of Group 8 metals of the Periodic Table in lesser
amounts.
[0032] Temperature, solvent, catalyst, pressure and mixing rate are
all parameters that affect the hydrogenation. The relationships
among these parameters may be adjusted to effect the desired
conversion, reaction rate, and selectivity in the reaction of the
process. Within the context of the present invention, in certain
embodiments, the temperature is from about 25.degree. C. to
250.degree. C., or from about 50.degree. C. to about 150.degree.
C., or from about 50.degree. C. to 100.degree. C.
[0033] In certain embodiments, the hydrogen pressure is from about
0.1 to about 20 MPa, or from about 0.3 to 10 MPa, or from about 0.3
to 4 MPa.
[0034] The reaction may be performed neat or in the presence of a
solvent. Useful solvents include those known in the art for use in
hydrogenation reactions, such as, hydrocarbons, ethers, alcohols
and mixtures and blends thereof. In certain embodiments, alcohols
are used, e.g., lower alkanols, such as, methanol, ethanol,
propanol, butanol, and pentanol.
[0035] Where the reaction is carried out according to certain
embodiments, selectivity in the range of at least 70% is attainable
where selectivity of at least 85% may be typical. Selectivity is
the weight percent of the converted material that is HCO where the
converted material is the portion of the starting material that
participates in the hydrogenation reaction.
[0036] The process of the present invention may be carried out in
batch, sequential batch (i.e. a series of batch reactors) or in
continuous mode in any of the equipment customarily employed for
continuous processes.
[0037] In U.S. Pat. No. 2,419,937, the hydrogenation of THC as a
pure compound to HHC using a heterogeneous catalyst (Pt.sub.2O,
Adams catalyst) is disclosed. The purified THC used was synthesized
by the acid catalyzed isomerization of CDB that was isolated from
"red oil" hemp extract by precipitation in a procedure described in
U.S. Pat. No. 2,304,669.
[0038] A method for the selective hydrogenation of the isopropenyl
moiety of the terpene L-carvone using the homogeneous catalyst
tris-triphenylphosphine rhodium chloride (Wilkinson's catalyst) is
known in the art.
[0039] While hydrogenation of isolated, pure CBD and THC to their
corresponding hexahydro derivatives is known, e.g., as reported in
Tetrahedron 1966, Vol. 22, pp. 1481 to 1488, the direct
hydrogenation of cannabis oil or extract comprising mixtures of
CBDA, THCA and other cannabinoids, terpenoids and flavonoids,
sterols and other minor compounds present in the oil or extract, is
novel. Hydrogenation converts the unsaturated groups, here defined
as non-aromatic carbon-carbon double bonds in the cannabinoids,
terpenoids, flavonoids, sterols and other minor compounds present
in the oil or extract into saturated groups by the addition of
hydrogen to the molecules. This hydrogenation or saturation of the
unsaturated groups changes the properties of the hydrogenated
product oil, such as, improvements in color, essence, taste, smell,
stability and biological activity.
[0040] Cannabis oil also includes unsaturated compounds such as the
monoterpenoids carvone, limonene, myrcene, linalool, pulegone,
1,8-cineole, .alpha.-pinene, .alpha.-terpineol, terpineol-4-ol,
p-cymene, borneol, .DELTA.-3-carene, geraniol, citronellal,
citronellol, citral, cyclocitral and the sesquiterpenes
.beta.-caryophyllene and nerolidols. The carbon-carbon double bonds
in the molecules react with hydrogen in the hydrogenation of
cannabis oil.
[0041] In addition, there are sterols and flavonoid compounds in
cannabis oil that contain carbon-carbon double bonds that will
react with hydrogen in the hydrogenation of cannabis oil.
[0042] Different reactions conditions (catalyst, solvent,
temperature, pressure) in the hydrogenation of cannabis oil
determine the compounds formed in the reaction and thus the
molecular makeup of the HCO product. Cannabis oil can be obtained
from the cannabis plant using various conventional extraction
techniques and apparatus that is known in the art. For example,
cannabis oil is obtained from plants of the Cannabis sativa, C.
indica and C. ruderalis by various isolation processes, including
steam distillation, organic solvent extraction, microwave-assisted
organic solvent extraction, supercritical fluid extraction and
cryo-mechanical methods are suitable for use in this invention. A
cannabis extract including crude cannabis oil, in the presence of
absence of a solvent, is suitable for use in this invention
directly without isolation of the cannabis oil, extract or
concentrate. A cannabis extract so obtained can be used without any
purification. In certain embodiments, direct hydrogenation of
cannabis extract is performed.
[0043] A cannabis extract including crude cannabis oil and a
volatile solvent can be purified by de-fatting the extract by a
cooling process known as winterization, which precipitates the
lipid fraction from the extract. A purified, de-fatted cannabis
extract so obtained is suitable for use in this invention. Direct
hydrogenation of de-fatted cannabis extract is preferred.
[0044] The hydrogenation reaction may be carried out in batch in a
single reactor, in sequential batch in a series of reactors, in
reaction zones within one or more reactors, or in continuous mode
in any of the equipment customarily employed for continuous
processes.
[0045] In certain embodiments, the extraction and hydrogenation
process can be conducted as follows. A cannabis plant is harvested.
It is known that decarboxylation of the essential oil is initiated
upon harvesting and subsequent aging of the cannabis plant. At room
temperature, decarboxylation is minimal. However, increased
temperature, e.g., by heating, accelerates the decarboxylation
process. With minimal decarboxylation, the cannabis plant and
essential oil contained therein are enriched with THCA and/or CBDA
as shown in Formulas 1a and 1b, respectively. The essential oil is
extracted using a conventional extraction process, such as, solvent
extraction, in the absence of heating or at a low temperature, to
produce a cannabis oil extraction enriched in THCA and/or CBDA. In
order to retain a significant concentration or level of THCA and
CBDA, e.g., acids, in the essential oil and the extract resulting
therefrom, the cannabis plant may be frozen after being harvested.
Thus, extraction of the essential oil of the cannabis plant can
produce THCA-enriched extract or CBDA-enriched extract or THCA- and
CBDA-enriched extract. The essential oil extract is hydrogenated
using conventional hydrogenation techniques and apparatus known in
the art. As previously described, hydrogenation generally refers to
treating a compound or composition with hydrogen, e.g., a chemical
reaction between molecular hydrogen (e.g., H.sub.2) typically in
the presence of a catalyst, such as, but not limited to, nickel,
palladium or platinum. Hydrogenation results in reducing double
bond(s) in a compound, e.g., hydrocarbon. Upon removal of any
solvent, hydrogenated essential oil enriched in HTHCA and/or HCBDA,
as shown in Formulas 3a and 3b, respectively, is produced.
[0046] In certain embodiments, the hydrogenation is conducted on an
isolated cannabis extract, e.g., a cannabis extract that has been
separated from, and is free of, extraction solvent. In other
embodiments, the hydrogenation is conducted on a cannabis extract
that includes the presence of an extraction solvent, such as,
saturated hydrocarbon, including but not limited to, butane,
propane and mixtures and blends thereof.
[0047] Following the hydrogenation reaction, the hydrogenated
cannabis oil can be recovered from the reaction mixture by methods
of separation well-known to those skilled in the art, such as
decantation or filtration. HHCs can be isolated and purified from
the hydrogenated cannabis oil, for example, by column
chromatography.
[0048] In addition to the THCA and/or CBDA being hydrogenated to
HTHCA and/or HCBDA, respectively, other components of the essential
oil of the cannabis plant can be hydrogenated. For example, it is
contemplated that the THCA- and/or CBDA-enriched oil and extract
will also contain THC and CBD, as shown in Formulas 2a and 2b,
respectively, since some level or degree of decarboxylation occurs
as a result of harvesting, and any subsequent aging of, the
cannabis plant. Although, the concentration or level of THCA and/or
CBDA in the essential oil and extract will be greater than the
concentration or level of THC and/or CBD. Thus, the HCO can also
include HTHC and/or HCBD, as shown in Formulas 3c and 3d,
respectively (e.g., in a lesser amount than the THCA and/or CBDA).
Furthermore, as aforementioned, terpenoids flavonoids, sterols and
other minor compounds that are present in the oil and extract are
also hydrogenated in the process of hydrogenating the essential oil
and therefore, be present (e.g., in a lesser amount than the THCA
and/or CBDA) in the HCO.
[0049] Cannabinoid and cannabinoid derivatives are useful in the
treatment of many diseases some of which are mediated by the
endocannabinoid system are well known in the art. Cannabinoid
receptor subtypes CB1 and CB2 as well as both synthetic antagonists
and agonists that modulate those receptors are also well known in
the art. Therapeutic applications can be administered to treat
various conditions and diseases, such as, cancer, epilepsy,
post-traumatic stress disorder, diabetes, Crohn's disease, gout,
pain relief, glaucoma, opioid dependence, alcohol abuse, insomnia,
psoriasis, shingles, anorexia, asthma, fibromyalgia, rheumatoid
arthritis, migraine headaches, Dravet syndrome, multiple sclerosis,
autism, and menstrual pain.
[0050] Excessive abdominal obesity along with other risk factors
results in the metabolic syndrome, which can lead to heart disease,
Type-2 diabetes, and death. The endocannabinoid system (ECS) is
composed of neutral lipids which signal through the G-protein
coupled cannabinoid receptors CB1 and CB2. In abdominal obesity,
the ECS is generally up-regulated in central and peripheral tissues
and its blockade results in positive metabolic changes.
[0051] The CB1 receptor is implicated in the maintenance of
homeostasis and is potentially a clinically relevant target for the
design of therapies against metabolic syndrome, deserving the
development and clinical testing of CB1-neutral antagonists which
can pass the blood-brain barrier or of peripherally restricted
inverse agonists/neutral antagonists. Selective CB1 antagonists are
useful in weight reduction and smoking cessation.
[0052] Selective CB1 agonists may be used to isolate the effects of
receptor from the CB2 receptor as most cannabinoids and
endocannabinoids bind to both receptor subtypes.
[0053] As can be demonstrated by competitive binding assays
described above, the compounds of the invention are useful in
modulating the CB2 receptor function. By virtue of this fact, these
compounds have therapeutic use in treating disease-states and
conditions mediated by the CB2 receptor function or that would
benefit from modulation of the CB2 receptor function.
[0054] As the compounds of the invention modulate the CB2 receptor
function, they have very useful anti-inflammatory and
immune-suppressive activity and they can be used in patients as
drugs, particularly in the form of pharmaceutical compositions as
set forth below, for the treatment of disease-states and
conditions.
[0055] As noted before, those compounds which are CB2 agonists can
also be employed for the treatment of pain.
[0056] The agonist, antagonist and inverse agonist compounds
according to the invention can be used in patients as
pharmaceutical compositions, e.g., drugs, for the treatment of the
following disease-states, conditions or indications that are
accompanied by inflammatory processes:
[0057] (i) Lung diseases: e.g. asthma, bronchitis, allergic
rhinitis, emphysema, adult respiratory distress syndrome (ARDS),
pigeon fancier's disease, farmer's lung, chronic obstructive
pulmonary disease (COPD), asthma including allergic asthma (atopic
or non-atopic) as well as exercise-induced bronchoconstriction,
occupational asthma, viral- or bacterial exacerbation of asthma,
other non-allergic asthmas and "wheezy-infant syndrome",
pneumoconiosis, including aluminosis, anthracosis, asbestosis,
chalicosis, ptilosis, siderosis, silicosis, tabacosis and
byssinosis;
[0058] (ii) Rheumatic diseases or autoimmune diseases or
musculoskeletal diseases: all forms of rheumatic diseases,
especially rheumatoid arthritis, acute rheumatic fever, and
polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue
diseases; inflammatory soft tissue diseases of other genesis;
arthritic symptoms in degenerative joint diseases (arthroses);
tendinitis, bursitis, osteoarthritis, traumatic arthritis;
collagenoses of any genesis, e.g., systemic lupus erythematosus,
scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still
disease, Felty syndrome; and osteoporosis and other bone resorption
diseases;
[0059] (iii) Allergic diseases: all forms of allergic reactions,
e.g., angioneurotic edema, hay fever, insect bites, allergic
reactions to drugs, blood derivatives, contrast agents, etc.,
anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema,
and contact dermatitis;
[0060] (iv) Vascular diseases: panarteritis nodosa, polyarteritis
nodosa, periarteritis nodosa, arteritis temporalis, Wegner
granulomatosis, giant cell arthritis, atherosclerosis, reperfusion
injury and erythema nodosum;
[0061] (v) Dermatological diseases: e.g. dermatitis, psoriasis;
sunburn, burns, eczema;
[0062] (vi) Renal diseases: e.g. nephrotic syndrome; and all types
of nephritis, e.g., glomerulonephritis; and pancreatits;
[0063] (vii) Hepatic diseases: e.g. acute liver cell
disintegration; acute hepatitis of various genesis, e.g., viral,
toxic, drug-induced; and chronically aggressive and/or chronically
intermittent hepatitis;
[0064] (viii) Gastrointestinal diseases: e.g. inflammatory bowel
diseases, irritable bowel syndrome, regional enteritis (Crohns
disease), colitis ulcerosa; gastritis; aphthous ulcer, celiac
disease, regional ileitis, gastroesophageal reflux disease;
[0065] (ix) Neuroprotection: e.g. in the treatment of
neurodegeneration following stroke; cardiac arrest; pulmonary
bypass; traumatic brain injury; spinal cord injury or the like;
[0066] (x) Eye diseases: allergic keratitis, uveitis, or iritis;
conjunctivitis; blepharitis; neuritis nervi optici; choroiditis;
glaucoma and sympathetic ophthalmia;
[0067] (xi) Diseases of the ear, nose, and throat (ENT) area: e.g.
tinnitus; allergic rhinitis or hay fever; otitis externa; caused by
contact eczema, infection, etc.; and otitis media;
[0068] (xii) Neurological diseases: e.g. brain edema, particularly
tumor-related brain edema; multiple sclerosis; acute
encephalomyelitis; meningitis; acute spinal cord injury; trauma;
dementia, particularly degenerative dementia (including senile
dementia, Alzheimer's disease; Parkinson's disease and
Creutzfeldt-Jacob disease; Huntington's chorea, Pick's disease;
motor neuron disease), vascular dementia (including multi-infarct
dementia) as well as dementia associated with intracranial space
occupying lesions; infections and related conditions (including
[0069] HIV infection); Guillain-Barre syndrome; myasthenia gravis,
stroke; and various forms of seizures, e.g., nodding spasms;
[0070] (xiii) Blood diseases: acquired hemolytic anemia; aplastic
anemia, and idiopathic thrombocytopenia;
[0071] (xiv) Tumor diseases: acute lymphatic leukemia; Hodgkin's
disease, malignant lymphoma; lymphogranulomatoses; lymphosarcoma;
solid malignant tumors; and extensive metastases;
[0072] (xv) Endocrine diseases: endocrine ophthalmopathy; endocrine
orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain; Hashimoto
thyroiditis; Morbus Basedow; granulomatous thyroiditis; struma
lymphomatosa; Graves disease; and type I diabetes
(insulin-dependent diabetes);
[0073] (xvi) Organ and tissue transplantations and
graft-versus-host diseases;
[0074] (xvii) Severe states of shock, e.g., septic shock,
anaphylactic shock, and systemic inflammatory response syndrome
(SIRS);
[0075] (xviii) Acute pain such as dental pain, perioperative,
post-operative pain, traumatic pain, muscle pain, pain in burned
skin, sun burn, trigeminal neuralgia, sun burn; spasm of the
gastrointestinal tract or uterus, and colic;
[0076] (xix) Visceral pain such as pain associated with chronic
pelvic pain, pancreatitis, peptic ulcer, interstitial cystitis,
renal colic, angina, dysmenorrhoea, menstruation, gynaecological
pain, irritable bowel syndrome (IBS), non-ulcer dyspepsia,
non-cardiac chest pain, and myocardial ischemia;
[0077] (xx) Neuropathic pain such as low back pain, non-herpetic
neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve
injury, acquired immune deficiency syndrome (AIDS) related
neuropathic pain, head trauma, painful traumatic mononeuropathy,
toxin and chemotherapy induced pain, phantom limb pain, painful
polyneuropathy, thalamic pain syndrome, post-stroke pain, central
nervous system injury, post-surgical pain, stump pain, repetitive
motion pain, pain induced by post mastectomy syndrome, multiple
sclerosis, root avulsions, postthoracotomy syndrome, neuropathic
pain associated hyperalgesia and allodynia;
[0078] (xxi) Inflammatory/nociceptive pain induced by or associated
with disorders such as osteoarthritis, rheumatoid arthritis,
rheumatic disease, teno-synovitis, gout, vulvodynia, myofascial
pain (muscular injury, fibromyalgia), tendonitis, osteoarthritis,
juvenile arthritis, spondylitis, gouty arthritis, psoriatic
arthritis, muscoskeletal pain, fibromyalgia, sprains and strains,
sympathetically maintained pain, myositis, pain associated with
migraine, toothache, influenza and other viral infections such as
the common cold, rheumatic fever, systemic lupus and
erythematosus;
[0079] (xxii) Cancer pain induced by or associated with tumors such
as lymphatic leukemia; Hodgkin's disease, malignant lymphoma;
lymphogranulomatoses; lympho sarcoma; solid malignant tumors;
extensive metastases;
[0080] (xxiii) Headache such as cluster headache, migraine with and
without aura, tension type headache, headache with different
origins, headache disorders including prophylactic and acute use;
and
[0081] (xxiv) various other disease-states or conditions including,
restenosis following percutaneous transluminal coronary
angioplasty, acute and chronic pain, atherosclerosis, reperfusion
injury, congestive heart failure, myocardial infarction, thermal
injury, multiple organ injury secondary to trauma, necrotizing
enterocolitis and syndromes associated with hemodialysis,
leukopheresis, and granulocyte transfusion, sarcoidosis,
gingivitis, pyrexia. edema resulting from trauma associated with
bums, sprains or fracture, cerebral oedema and angioedema, Diabetes
such as diabetic vasculopathy, diabetic neuropathy, diabetic
retinopathy, post capillary resistance or diabetic symptoms
associated with insulitis (e.g. hypergiycemia, diuresis,
proteinuria and increased nitrite and kallikrein urinary
excretion).
[0082] Other indications include: epilepsy, septic shock e.g. as
antihypovolemic and/or antihypotensive agents, cancer, sepsis,
osteoporosis, benign prostatic hyperplasia and hyperactive bladder,
pruritis, vitiligo, general gastrointestinal disorders,
disturbances of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, tissue damage
and postoperative fever, syndromes associated with itching.
[0083] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals, rodents, and
the like.
[0084] For treatment of the above-described diseases and
conditions, a therapeutically effective dose will generally be in
the range from about 0.01 mg to about 100 mg/kg of body weight per
dosage of a compound of the invention; in certain embodiments, from
about 0.1 mg to about 20 mg/kg of body weight per dosage. For
example, for administration to a 70 kg person, the dosage range
would be from about 0.7 mg to about 7000 mg per dosage of a
compound of the invention, or from about 7.0 mg to about 1400 mg
per dosage. Some degree of routine dose optimization may be
required to determine an optimal dosing level and pattern. The
active ingredient may be administered from 1 to 6 times daily.
[0085] HCO can be administered by vaporization, smoking or making
use of a. carrier food, edible or pharmaceutical composition. When
used as pharmaceuticals, the HCO is typically compositions can be
prepared using procedures well known in the pharmaceutical art and
comprise the HCO products of this invention. The HCO products may
also be administered alone or in combination with adjuvants that
enhance stability of the compounds of the invention, facilitate
administration of pharmaceutical compositions containing them in
certain embodiments, provide increased dissolution or dispersion,
increased inhibitory activity, provide adjunct therapy, and the
like. The compounds according to the invention may be used on their
own or in conjunction with other active substances according to the
invention, optionally also in conjunction with other
pharmacologically active substances. In general, the HCO products
of this invention are administered in a therapeutically or
pharmaceutically effective amount, but may be administered in lower
amounts for diagnostic or other purposes.
[0086] Methods of administration of HCO in pure form or in an
appropriate pharmaceutical composition can be carried out using any
of the accepted modes of administration of pharmaceutical
compositions, Thus, administration can be, for example, orally,
buccally (e,g., sublingually), nasally, parenterally, topically,
transdermally, vaginally, or rectally, in the form of solid,
semi-solid, lyophilized powder, or liquid dosage forms, such as,
for example, tablets, suppositories, pills, soft elastic and hard
gelatin capsules, powders, solutions, suspensions, or aerosols, or
the like, preferably in unit dosage forms suitable for simple
administration of precise dosages. The pharmaceutical compositions
will generally include a conventional pharmaceutical carrier or
excipient and a compound of the invention as the/an active agent,
and, in addition, may include other medicinal agents,
pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or
combinations thereof. Such pharmaceutically acceptable excipients,
carriers, or additives as well as methods of making pharmaceutical
compositions for various modes or administration are well-known to
those of skill in the art.
[0087] Pharmaceutical compositions suitable for buccal
(sub-lingual) administration include lozenges including a compound
of the present invention in a flavored base, usually sucrose, and
acacia or tragacanth, and pastilles including the compound in an
inert base such as gelatin and glycerin or sucrose and acacia,
[0088] Pharmaceutical compositions suitable for parenteral
administration include sterile aqueous preparations of a compound
of the present invention. In certain embodiments, these
preparations are administered intravenously, although
administration can also be effected by means of subcutaneous,
intramuscular, or intradermal injection. Injectable pharmaceutical
formulations are commonly based upon injectable sterile saline,
phosphate-buffered saline, oleaginous suspensions, or other
injectable carriers known in the art and are generally rendered
sterile and isotonic with the blood. The injectable pharmaceutical
formulations may therefore be provided as a sterile injectable
solution or suspension in a nontoxic parenterally acceptable
diluent or solvent, including 1,3-butanediol, water. Ringer's
solution, isotonic sodium chloride solution, fixed oils such as
synthetic mono- or diglycerides, fatty acids such as oleic acid,
and the like. Such injectable pharmaceutical formulations are
formulated according to the known art using suitable dispersing or
setting agents and suspending agents. Injectable compositions will
generally contain from 0.1 to 5% w/w of a The HCO product of the
invention.
[0089] Solid dosage forms for oral administration of the compounds
include capsules, tablets, pills, powders, and granules. For such
oral administration, a pharmaceutically acceptable composition
containing a compound(s) of the invention is formed by the
incorporation of any of the normally employed excipients, such as,
for example, pharmaceutical grades of mannitol, lactose, starch,
pregelatinized starch, magnesium stearate, sodium saccharine,
talcum, cellulose ether derivatives, glucose, gelatin, sucrose,
citrate, propyl gallate, and the like. Such solid pharmaceutical
formulations may include formulations, as are well-known in the
art, to provide prolonged or sustained delivery of the drug to the
gastrointestinal tract by any number of mechanisms, which include,
but are not limited to, pH sensitive release from the dosage form
based on the changing pH of the small intestine, slow erosion of a
tablet or capsule, retention in the stomach based on the physical
properties of the formulation, bioadhesion of the dosage form to
the mucosal lining of the intestinal tract, or enzymatic release of
the active drug from the dosage form.
[0090] Liquid dosage forms for oral administration of the compounds
include emulsions, microemulsions, solutions, suspensions, syrups,
and elixirs, optionally containing pharmaceutical adjuvants in a
carrier, such as, for example, water, saline, aqueous dextrose,
glycerol, ethanol and the like. These compositions can also contain
additional adjuvants such as wetting, emulsifying, suspending,
sweetening, flavoring, and perfuming agents.
[0091] Topical dosage forms of the compounds include ointments,
pastes, creams, lotions, gels, powders, solutions, sprays,
inhalants, eye ointments, eye or ear drops, impregnated dressings
and aerosols, and may contain appropriate conventional additives
such as preservatives, solvents to assist drug penetration and
emollients in ointments and creams. Topical application may be once
or more than once per day depending upon the usual medical
considerations. Furthermore, in certain embodiments, compounds for
the present invention can be administered in intranasal form via
topical use of suitable intranasal vehicles. The formulations may
also contain compatible conventional carriers, such as cream or
ointment bases and ethanol or oleyl alcohol for lotions. Such
carriers may be present as from about 1% up to about 98% of the
formulation, more usually they will form up to about 80% of the
formulation.
[0092] Transdermal administration is also possible. Pharmaceutical
compositions suitable for transdermal administration can be
presented as discrete patches adapted to remain in intimate contact
with the epidermis of the recipient for a prolonged period of time.
To be administered in the form of a transdermal delivery system,
the dosage administration will, of course, be continuous rather
than intermittent throughout the dosage regimen. Such patches
suitably contain a compound of the invention in an optionally
buffered, aqueous solution, dissolved and/or dispersed in an
adhesive, or dispersed in a polymer. A suitable concentration of
the HCO product is from about 1% to 35%, or from about 3% to
15%.
[0093] For administration by inhalation, the HCO products of the
invention are conveniently delivered in the form of an aerosol
spray from a pump spray device not requiring a propellant gas or
from a pressurized pack or a nebulizer with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane,
carbon dioxide, or other suitable gas. In any case, the aerosol
spray dosage unit may be determined by providing a valve to deliver
a metered amount so that the resulting metered dose inhaler (MDI)
is used to administer the compounds of the invention in a
reproducible and controlled way. Such inhaler, nebulizer, or
atomizer devices are known in the prior art, for example, in PCT
International Publication Nos. WO 97/12687 (particularly FIG. 6
thereof, which is the basis for the commercial RESPIMAT.RTM.
nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590.
[0094] Rectal administration can be effected utilizing unit dose
suppositories in which the compound is admixed with low-melting
water-soluble or insoluble solids such as fats, cocoa butter,
glycerinated gelatin, hydrogenated vegetable oils, mixtures of
polyethylene, glycols of various molecular weights, or fatty acid
esters of polyethylene glycols, or the like. The active compound is
usually a minor component, often from about 0.05 to 10% by weight,
with the remainder being the base component.
[0095] In all of the above pharmaceutical compositions, the
compounds of the invention are formulated with an acceptable
carrier or excipient. The carriers or excipients used must, of
course, be acceptable in the sense of being compatible with the
other ingredients of the composition and must not be deleterious to
the patient. The carrier or excipient can be a solid or a liquid,
or both, and is preferably formulated with the compound of the
invention as a unit-dose composition, for example, a tablet, which
can contain from 0.05% to 95% by weight of the active compound.
Such carriers or excipients include inert fillers or diluents,
binders, lubricants, disintegrating agents, solution retardants,
resorption accelerators, absorption agents, and coloring agents.
Suitable binders include starch, gelatin, natural sugars such as
glucose or .beta.-lactose, corn sweeteners, natural and synthetic
gums such as acacia, tragacanth or sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes, and the like.
Lubricants include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. Disintegrators include starch, methyl cellulose, agar,
bentonite, xanthan gum, and the like.
[0096] Pharmaceutically acceptable carriers and excipients
encompass all the foregoing additives and the like.
EXAMPLES
[0097] The present invention is further defined in the following
examples. These examples are given by way of illustration only.
From the above discussion and these examples, the artisan can
ascertain the essential characteristics of this invention, and,
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
[0098] The following abbreviations are used: GC is gas
chromatography; GC-MS is gas chromatography-mass spectrometry; FID
is flame ionization detector; NMR is nuclear magnetic resonance;
.degree. C. is degrees Centrigrade; MPa is mega Pascal; kPa is kilo
Pascal; Pa is Pascal; rpm is revolutions per minute; mL is
milliliter; CMO is cannabis oil; wt % is weight percent; TOS is
time on stream; NPL is tetrahydrocannabanoids; HHC is
hexahydrocannabanoids; h is hour; conc. is concentration; conv. is
conversion; temp. is temperature; .degree. C. is degrees
Centigrade; kg is kilogram; XRF is X-ray fluorescence spectroscopy;
ppm is parts per million.
Example 1
[0099] Pre-extracted cannabis extract (374 mg) enriched with THCA
was obtained. In a 100-mL round-bottomed flask, the cannabis
extract in absolute ethanol (20 mL) was treated with 10% Pd/C (36
mg, Aldrich) and stirred under nitrogen at room temperature.
Hydrogen gas was flushed in the vessel and bubbled through the
mixture. The mixture was stirred under a balloon of hydrogen
overnight. The mixture was filtered through a bed of Celite. Thin
layer chromatography showed a slightly less polar spot (30% ethyl
acetate/ hexanes on silica gel plates). The solvent was removed by
roto-evaporation to yield an HTHCA product as a clear oil (330 mg)
characterized by NMR and MS. The .sup.13C NMR spectrum of the
product showed loss of the olefinic carbons at 124 and 132 ppm
respectively. The molecular weight was confirmed by high resolution
mass spectroscopy where the observed M+H was 361.2375.
Example 2
[0100] Pre-extracted cannabis extract (100 mg) enriched with CBDA
was obtained. In a 50-mL round-bottomed flask, the cannabis extract
in absolute ethanol (10 mL) was treated with 10% Pd/C (10 mg,
Aldrich) and stirred under nitrogen at room temperature. Hydrogen
gas was flushed in the vessel and bubbled through the mixture. The
mixture was stirred under a balloon of hydrogen overnight. The
mixture was filtered through a bed of Celite. Thin layer
chromatography showed a slightly less polar spot (30% ethyl
acetate/ hexanes on silica gel plates). The solvent was removed by
roto-evaporation to yield the HCBDA product as a pale oil (86 mg)
characterized by NMR and MS. The NMR spectrum of the product showed
loss of all olefinic carbons. The molecular weight was confirmed by
mass spectroscopy where both the mono and dihydrogenated adducts
were observed as ammonium salts at 377 and 375 (the starting
material showed an ammonium salt at 373 m/e).
Example 3
[0101] The effect of the hydrogenated and non-hydrogenated cannabis
oil on tumor growth and angiogenesis were evaluated by implanting
U87 (Human glioblastoma) 3.times.106 cells (50% matrigel) in three
female athymic mice. The site of implantation was subcutaneous with
two implants per mouse. The date of implantation was Feb. 1, 2016
and the date of administering treatment was Feb. 3, 2016. There
were three mice in each of the following groups, and the treatment
consisted of feeding each of the three mice 10 mg/kg body weight of
the treatment corresponding to each one of the following groups:
[0102] 1. Untreated Vehicle [0103] 2. THCA [0104] 3. CBDA [0105] 4.
HCBDA [0106] 5. HTHCA
[0107] The termination date was Feb. 11, 2016. On this date, the
tumors were excised and weighed. The results are shown in Table 1
and illustrated in the below plot.
TABLE-US-00001 TABLE 1 Treatment Tumor weight (mg) Vehicle 73.8
THCA 46.0 CBDA 39.1 HCBDA 32.6 HTHCA 44.5
[0108] Table 1 shows that for the untreated "Vehicle" group, the
average weight of the excised tumors for the three mice was 73.8
mg, i.e., total weight of the excised tumors/six tumors (i.e., two
tumors in each of the three mice). It was assumed that the excised
tumor weight for the "Untreated Vehicle" was essentially equivalent
to its starting tumor weight. Thus, the results show that each of
the THCA, CBDA, HCBDA and HTHCA treatments were effective to reduce
tumor weight.
* * * * *