NZ750272B2 - Cannabis composition - Google Patents
Cannabis composition Download PDFInfo
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- NZ750272B2 NZ750272B2 NZ750272A NZ75027217A NZ750272B2 NZ 750272 B2 NZ750272 B2 NZ 750272B2 NZ 750272 A NZ750272 A NZ 750272A NZ 75027217 A NZ75027217 A NZ 75027217A NZ 750272 B2 NZ750272 B2 NZ 750272B2
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- New Zealand
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- weight
- pharmaceutical composition
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- cannabis extract
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- 239000000203 mixture Substances 0.000 title claims abstract description 60
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Abstract
The invention relates to a method for treating cancer or a symptom associated with cancer. In particular, the present invention relates to a method for treating cancer or a symptom associated with cancer, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition comprising a Cannabis extract that comprises either ?9-tetrahydrocannabinol (THC) in an amount of from 50% to 99% or cannabidiol (CBD) in an amount of from 60% to 99% by weight of the pharmaceutical composition, together with a terpene fraction comprising beta-caryophyllene and one or more of linalool and/or beta-pinene. composition comprising a Cannabis extract that comprises either ?9-tetrahydrocannabinol (THC) in an amount of from 50% to 99% or cannabidiol (CBD) in an amount of from 60% to 99% by weight of the pharmaceutical composition, together with a terpene fraction comprising beta-caryophyllene and one or more of linalool and/or beta-pinene.
Description
Cannabis composition
Field
The invention relates to a method for treating cancer or a symptom associated with
cancer. The invention also relates to a pharmaceutical composition comprising an extract from
a Cannabis plant, and its use in the ent of cancer or a symptom associated with cancer.
Background
The biological activity of Cannabis is well known, and has led it to become a
“recreational” drug. However, with the discovery of a class of cannabinoid (CB) receptors, and
the tion of laws regulating Cannabis use - in some ictions decriminalisation - there
now exists the opportunity to explore the potential of Cannabis as a source of new therapeutics.
There is also a growing movement of patients suffering from severe diseases, such
as cancer, to seek natural remedies as ative or mentary therapy.
Accordingly, there is a continuing need to develop new treatments for cancer or its
symptoms, which is derived, at least in part, from a natural source. Advantageously, the
present invention may provide a pharmaceutical composition comprising a Cannabis t that
shows an efficacy comparable to an existing cancer chemotherapy.
Summary
Described herein is a method of treating cancer or a symptom associated with
cancer comprising administering to a t in need thereof an effective amount of a
pharmaceutical composition comprising a Cannabis extract. Accordingly, also provided is a
pharmaceutical composition sing a Cannabis extract and optionally one or more
pharmaceutically able carriers, diluents, adjuvants, excipients or any combination thereof.
[0005a] In one aspect, the present invention provides a pharmaceutical composition
comprising a Cannabis extract and optionally one or more pharmaceutically acceptable carriers,
diluents, nts, ents or any combination thereof, the Cannabis extract comprising a
cannabinoid on and a terpene fraction, wherein the Cannabis extract comprises either:
- ≥ 0.3% w/w of the terpene fraction;
- ≥ 50% w/w Δ9-Tetrahydrocannabinol (THC);
- ≥ 0.3% w/w Cannabigerol (CBG); and
17861217_1 (GHMatters) P103046.NZ
- ≤ 0.5% w/w Cannabinol (CBN);
or B:
- ≥ 0.5% w/w of the terpene fraction;
- ≥ 60% w/w cannabidiol (CBD);
- ≤ 3% w/w THC; and
- ≤ 0.1% w/w CBN;
wherein the terpene fraction comprises:
• ß-caryophyllene in an amount of at least 11% by weight of the terpene fraction,
one or more of:
- linalool in an amount of at least 5% by weight of the e fraction; and
- ne in an amount of at least 1% by weight of the terpene fraction.
In a further aspect, there is provided use of a Cannabis extract in the preparation of
a medicament for treating cancer or a symptom associated with cancer, wherein the Cannabis
extract comprises a cannabinoid fraction and a terpene fraction, and wherein the Cannabis
t comprises either:
- ≥ 0.3% w/w of the terpene fraction;
- ≥ 50% w/w Δ9-Tetrahydrocannabinol (THC);
- ≥ 0.3% w/w Cannabigerol (CBG); and
- ≤ 0.5% w/w Cannabinol (CBN);
or B:
- ≥ 0.5% w/w of the e fraction;
- ≥ 60% w/w cannabidiol (CBD);
- ≤ 3% w/w THC; and
- ≤ 0.1% w/w CBN.
In yet another aspect, there is provided a pharmaceutical composition for treating
cancer or a symptom associated with cancer, wherein the pharmaceutical composition
comprises a Cannabis extract and optionally one or more pharmaceutically acceptable carriers,
diluents, adjuvants, ents or any combination thereof.
17_1 ters) P103046.NZ
Brief Description of Drawings
The present application will be further described, by way of e only, with
reference to the accompanying drawings, in which:
Figure 1 shows a chart of tumour volume over time for ectopic xenografts of BT474 human
breast HER2+ adenocarcinoma cells in female immunodeficient (nude) mice d with
(i) vehicle alone, (ii) THC and (iii) a Cannabis extract.
Figure 2 shows a chart of tumour volume over time for ectopic xenografts of BT474 human
breast HER2+ adenocarcinoma cells in female immunodeficient (nude) mice treated with
(i) e alone, (ii) lapatinib, (iii) THC, and (iv) the combination of lapatinib and THC.
Figure 3 shows a chart of tumour volume over time for c xenografts of BT474 human
breast HER2+ adenocarcinoma cells in female immunodeficient (nude) mice treated with
(i) vehicle, (ii) lapatinib, (iii) a Cannabis extract, and (iv) the combination of nib and the
Cannabis extract.
Figure 4 shows a chart of tumor volume over time for ectopic xenografts of BT474 human
breast HER2+ adenocarcinoma cells in female immunodeficient (nude) mice treated with (i)
vehicle, (ii) lapatinib, (iii) the combination of lapatinib and THC.
Figure 5 shows a series of charts comparing the activity of THC and a Cannabis extract (THC-
rich extract) against (A) BT474 cells, (B) 4 cells and (C) SKBR3 cells. BT474,
4 and SKBR3 cells are all HER2+ breast cancer cells.
Figure 6 shows a series of charts comparing the activity of THC and a Cannabis extract against
(A) MDA-MB-231 cells and (B) SUM159 cells. MDA-MB-231 and SUM159 cells are triple
negative breast cancer cells.
Figure 7 shows a series of charts comparing the activity of THC and a Cannabis extract against
(A) MCF7 cells and (B) T47D cells. MCF7 and T47D cells are hormone receptor positive breast
cancer cells.
Figure 8 shows a chart of cell viability as a percentage versus l of the various breast
cancer cells after treatment with a Cannabis extract.
Description of Embodiment(s)
The present invention es a pharmaceutical composition comprising a
Cannabis extract and optionally one or more pharmaceutically acceptable carriers, ts,
adjuvants, excipients or any combination thereof.
Cannabis plants produce a diverse array of secondary metabolites, including
cannabinoids, terpenes and terpenoids, sterols, triglycerides, alkanes, squalenes, tocopherols,
carotenoids and ids. The mix of these secondary metabolites varies depending on
17861217_1 ters) P103046.NZ
several factors, including Cannabis variety, part of the Cannabis plant extracted, method of
extraction, processing of the t, and season.
There are several ies of Cannabis plant, which have been described under two
distinct naming conventions. One of these conventions identifies three distinct species of
Cannabis plant, namely Cannabis sativa Linnaeus, Cannabis indica LAM., and Cannabis
ruderalis. Another tion identifies all Cannabis plants as belonging to the Cannabis sativa
L. species, with the various varieties divided amongst several subspecies, including: Cannabis
sativa ssp. sativa and ssp. indica. As used herein, the term “Cannabis” refers to any and all of
these plant varieties.
Extracts of Cannabis may be prepared by any means known in the art. The extracts
may be formed from any part of the is plant containing cannabinoid, terpene and
oid compounds. ts may be formed by ting an extractant with a leaf, seed,
trichome, flower, keif, shake, bud, stem or a combination f. In some embodiments, the
extract is formed from the flowers and shake of a Cannabis plant. Any suitable extractant
known in the art may be used, including, for example, alcohols (e.g. methanol, ethanol,
propanol, butanol, propylene glycol etc.), water, hydrocarbons (e.g. butane, hexane, etc.), oils
(e.g. olive oil, vegetable oil, essential oil, etc.), a polar organic solvent (e.g. ethyl acetate,
polyethylene glycol, etc.) or a supercritical fluid (e.g. liquid CO2). The extractant may be
completely or partially removed prior to incorporation of the Cannabis extract into the
pharmaceutical composition, or it may be included in the pharmaceutical composition as a
carrier. The extractant may be removed by heating the extract optionally under reduced
pressure (e.g. under vacuum). It will be appreciated that some of the more volatile plant
metabolites (such as es) may also be removed with the extractant. ingly, in some
embodiments, removing the extractant may enrich the cannabinoid fraction of the extract. In
some embodiments, the extract is filtered to remove particulate material, for example, by
passing the extract through filter paper or a fine sieve (e.g. a sieve with pore sizes of 5 m).
In some ments, the Cannabis extract is formed by applying heat and
pressure to the plant material. Typically, in these embodiments, no extractant is ed.
In some embodiments, the Cannabis extract is a Cannabis oil. As used , a
“Cannabis oil” is an extract formed by ting at least a part of a Cannabis plant with an oil.
The extracting oil may optionally be removed. Extracting oils may be selected from olive oil,
hemp oil, sesame oil, coconut oil, vegetable oil, canola oil, grape seed oil, almond oil, medium-
17861217_1 (GHMatters) P103046.NZ
chain triglyceride (MCT) oil, and any other edible oil, or a combination thereof.
In some embodiments, one or more additional compounds (e.g. cannabinoid,
terpene or terpenoid compounds) may be added to the Cannabis extract. The addition of
compounds may be to compensate for natural variations in the relative amounts of certain
compounds being expressed in the Cannabis plant. The added compounds may be synthetic
versions of the desired compounds, they may be purified compounds obtained from other
Cannabis extracts, or they may be added by blending two or more Cannabis extracts.
The term "cannabinoid" as used herein relates to any cannabinoid that have been
isolated from a is plant or synthetically created to have activity involving the
endocannabinoid system.
The term “cannabinoid fraction” is used to be the combination of inoid
compounds present in the Cannabis extract.
The term nes" or "terpenoids" as used herein refers to a class of hydrocarbon
molecules, which often provide a unique smell. Terpenes are derived from units of isoprene,
which has the molecular formula C5H8. The basic molecular formula of terpenes are les of
the isoprene unit, i.e. (C5H8)n, where n is the number of linked isoprene units. oids are
e compounds that have been further metabolised in the plant, typically through an
oxidative s, and ore usually contain at least one oxygen atom.
The term “terpene fraction” is used to describe the combination of terpene and
terpenoid compounds present in the Cannabis extract.
One embodiment provides a pharmaceutical composition comprising a Cannabis
t and optionally one or more ceutically acceptable carriers, diluents, adjuvants,
excipients or any combination thereof, wherein the Cannabis extract comprises either:
- ≥ 0.3% w/w terpene fraction;
- ≥ 50% w/w Δ9-Tetrahydrocannabinol (THC);
- ≥ 0.3% w/w Cannabigerol (CBG); and
- ≤ 0.5% w/w Cannabinol (CBN)
- ≥ 0.5% w/w e fraction;
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- ≥ 60% w/w CBD;
- ≤ 3% w/w THC; and
- ≤ 0.1% w/w CBN.
Another embodiment provides a pharmaceutical ition comprising a Cannabis
extract and optionally one or more pharmaceutically able carriers, ts, adjuvants,
excipients or any combination thereof, the Cannabis t comprising a terpene fraction
comprising:
• ß-caryophyllene in an amount of at least 11% by weight of the terpene fraction,
one or more of:
- linalool in an amount of at least 5% by weight of the terpene fraction; and
- ß-pinene in an amount of at least 1% by weight of the terpene fraction.
Cannabinoid Fraction
The cannabinoid fraction typically accounts for the majority of the compounds
present in the Cannabis extract.
In some embodiments, the Cannabis extract may comprise about 35% to about 95%
by weight cannabinoids, for example, about 40% to about 90%, about 45% to about 70% or
about 45% to about 55% by weight of the Cannabis extract. In some embodiments, the
Cannabis extract comprises about 5% to about 65% by weight of non-cannabinoids, for
example, about 5% to about 50%, about 10% to about 40% by weight or about 15% to about
% by weight non-cannabinoids.
To date, over 100 cannabinoids have been identified in is plants. A
comprehensive list of these cannabinoids may be found in Mahmoud A. El Sohly and Waseem
Gul, “Constituents of Cannabis .” In Handbook of Cannabis Roger Pertwee (Ed.) Oxford
sity Press (2014) (ISBN: 9780199662685). Cannabinoids that have been identified in
Cannabis plants include: Cannabigerol (E)-CBG-C5, Cannabigerol monomethyl ether (E)-
CBGM-C5 A, Cannabigerolic acid A (Z)-CBGA-C5 A, Cannabigerovarin (E)-CBGV-C3,
Cannabigerolic acid A (E)-CBGA-C5 A, Cannabigerolic acid A monomethyl ether (E)CBGAM-C5
A and Cannabigerovarinic acid A (E)-CBGVAC3A; (±)-Cannabichromene CBC-C5,
nnabichromenic acid A CBCA-C5 A, (±)-Cannabivarichromene, nnabichromevarin
CBCV-C3, (±)-Cannabichromevarinic acid A CBCVA-C3 A; (-)-Cannabidiol CBD-C5,
Cannabidiol momomethyl ether CBDMC5, Cannabidiol-C4 CBD-C4, (-)-Cannabidivarin
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CBDVC3, idiorcol CBD-Cl, Cannabidiolic acid CBDA-C5, Cannabidivarinic acid CBDVAC3
; Cannabinodiol CBNDC5, Cannabinodivarin CBND-C3; Δ9-Tetrahydrocannabinol Δ9-THC-
C5, Δ9-Tetrahydrocannabinol-C4 C4, Δ9-Tetrahydrocannabivarin Δ9-THCV-C3,
Δ9-Tetrahydrocannabiorcol Δ9-THCO-Cl, Δ9-Tetrahydrocannabinolic acid A Δ9-THCA-C5 A,
Δ9-Tetrahydrocannabinolic acid B Δ9-THCA-C5 B, Δ9-Tetrahydrocannabinolic acid-C4 A and/or
B Δ9-THCA-C4 A and/or B, Δ9-Tetrahydro-cannabivarinic acid A Δ9-THCVA-C3 A,
Δ9-Tetrahydrocannabiorcolic acid A and/or B Δ9-THCOA-Cl A and/or B),
(-)-Δ8-trans-(6aR,10aR)-Δ8-Tetrahydrocannabinol Δ8-THC-C5,
-trans-(6aR,10aR)-Tetrahydrocannabinolic acid A Δ8-THCA-C5 A,
(-)-(6aS,10aR)-Δ9-Tetrahydrocannabinol (-)-cis-Δ9-THC-C5; inol CBN-C5,
Cannabinol-C4 CBN-C4, Cannabivarin CBN-C3, inol C2 CBN-C2, Cannabiorcol
CBN-Cl, Cannabinolic acid A CBNA-C5 A, Cannabinol methyl ether 5,
(-)-(9R,10R)-trans-Cannabitriol (-)-trans-CBT-C5, (+)-(9S,10S)-Cannabitriol (+)-trans-CBT-C5,
(±)-(9R,10S/9S,10R)—); Cannabitriol (±)-cis-CBT-C5, R,10R)-transO-Ethyl-cannabitriol
(-)-trans-CBT-OEt-C5, (±)-(9R,10R/9S,10S)-Cannabitriol-C3 (±)-trans-CBT-C3,
8,9-Dihydroxy-Δ6a(10a)-tetrahydrocannabinol 8,9-Di-OH-CBT-C5, Cannabidiolic acid A
cannabitriol ester CBDA-C5 9-OH-CBT-C5 ester, (-)-(6aR,9S,10S,10aR)-9,10-
Dihydroxyhexahydrocannabinol, Cannabiripsol, Cannabiripsol-C5,
(-)-6a,7,10a-Trihydroxy-Δ9-tetrahydrocannabinol (-)-Cannabitetrol,
-Oxo-Δ6a(10a)tetrahydrocannabinol OTHC); (5aS,6S,9R,9aR)-Cannabielsoin CBE-C5,
(5aS,6S,9R,9aR)-C3-Cannabielsoin CBE-C3, (5aS,6S,9R,9aR)-Cannabielsoic acid A
CBEA-C5 A, (5aS,6S,9R,9aR)-Cannabielsoic acid B CBEA-C5 B;
(5aS,6S,9R,9aR)-C3-Cannabielsoic acid B CBEA-C3 B, Cannabiglendol-C3 OH-iso-HHCV-C3,
Dehydrocannabifuran DCBF-C5, Cannabifuran CBF-C5),
-trans-(1R,3R,6R)-Isotetrahydrocannabinol,
(±)-Δ7-1,2-cis-(1R,3R,6S/1S,3S,6R)-Isotetrahydrocannabivarin,
(-)-Δ7-trans-(1R,3R,6R)-Isotetrahydrocannabivarin; aS,3aR,8bR,8cR)-Cannabicyclol
CBL-C5, (±)-(1aS,3aR,8bR,8cR)-Cannabicyclolic acid A CBLA-C5 A,
(±)-(laS,3aR,8bR,8cR)-Cannabicyclovarin CBLV-C3; Cannabicitran CBTC5;
Cannabichromanone CBCN-C5, CannabichromanoneC3 CBCN-C3, and Cannabicoumaronone
CBCON-C5.
The cannabinoid on may comprise a main cannabinoid.
Δ9-Tetrahydrocannabinol (THC) or idiol (CBD) may be the main cannabinoid. The main
cannabinoid may be present in the is extract in an amount of at least about 40%, about
45%, about 50% or about 55% by weight of the Cannabis extract. Accordingly, when THC is
17861217_1 (GHMatters) P103046.NZ
the main cannabinoid, the Cannabis extract may comprise at least about 40%, 45%, 50% or
55% by weight Δ9-tetrahydrocannabinol (THC), for example, 40-97% or 50-90% by weight of
Δ9-tetrahydrocannabinol (THC). When CBD is the main cannabinoid, the is extract may
comprise at least about 40%, 45%, 50%, 55% or 60% by weight CBD, for example, 40-97% or
50-90% by weight of CBD.
In some embodiments, the Cannabis extract is enriched in one or the other of THC
or CBD. It has been shown that endocannabinoids (i.e. naturally occurring cannabinoids),
including THC and CBD, ct with a class of G protein-coupled receptors (GPCRs) named
the “cannabinoid receptors”, e.g. the CB1 or CB2 receptors. However, structurally related
cannabinoid compounds may have vastly different activity. For example, it has been reported
that THC is a CB1 agonist, and that CBD is a CB1 antagonist. Accordingly, in the present
invention, the Cannabis extract contains 50-90% by weight of only one of THC and CBD. It will
be iated that Cannabis extracts sing 50-90% of THC, may comprise low amounts
of CBD, for e, less than 50% by weight CBD, or less than 40%, 30%, 20%, 15%, 10%,
%, 4%, 3%, 2%, 1%, 0.5% or 0.1% by weight CBD, or may not comprise any measurable
amount of CBD. Similarly, Cannabis extracts comprising 50-90% of CBD, may comprise low
amounts of THC, for e, less than 50% by weight THC, or less than 40%, 30%, 20%,
%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% by weight THC or may not comprise any
able amount of THC.
In some embodiments, the Cannabis extract may comprise 50-80% by weight THC
or CBD, 50-75% by weight THC or CBD, 50-70% by weight THC or CBD, 50-65% by weight
THC or CBD, 52-80% by weight THC or CBD, 53-80% THC or CBD, or 52-65% by weight THC
or CBD.
In some embodiments, the Cannabis extract may comprise THC and CBD in a
combined weight of 50-90% by weight of the composition. In these ments, the ratio of
THC to CBD may be about 1:1, for example, the ratio of THC to CBD may be from 100:0 to
0:100, 100:1 to 1:100, 80:1 to 1:80, 60:1 to 1:60, 40:1 to 1:40 or 20:1 to 1:20.
Typically, the Cannabis extract may also comprise other cannabinoids in addition to
THC and/or CBD. These cannabinoids include Δ9-Tetrahydrocannabinolic acid (THCA),
Δ9-Tetrahydrocannabivarin (THCV), (-)-Cannabidivarin (CBDV), Cannabinol (CBN) and
Cannabigerol (CBG). Each of these inoids may be present in an amount from 0.001% to
40% by weight of the Cannabis extract. For example, CBN may be t in an amount of not
more than 0.5% by weight of the extract, for example, not more than 0.4%, 0.3%, 0.2% or 0.1%
17861217_1 (GHMatters) P103046.NZ
by weight of the extract. CBN may be present in the is extract in an amount of 0.001-
0.5% or 0.001-0.1% by weight. CBG may be present in an amount of at least 0.3% by weight of
the extract, for example, % or 0.35-5% by weight of the extract.
In some ments, certain cannabinoids may be absent, or present in nondetectable
amounts (e.g. less than 0.001% by weight of the analyte). In some embodiments,
the Cannabis extract may exclude one or more of the following cannabinoids:
Δ9-Tetrahydrocannabivarin (THCV), Cannabidiolic acid , Cannabinol (CBN),
(-)-Cannabidivarin (CBDV) and Cannabichromene (CBC).
Terpene on
The Cannabis extract comprises non-cannabinoid compounds, which typically
includes a terpene fraction. In some embodiments, the Cannabis extract comprises a terpene
fraction in an amount of less than 50% by , for example, less than 45%, 40%, 35%, 30%,
%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% by weight of the extract. In
some embodiments, the Cannabis extract may comprise terpene and terpenoid compounds in
an amount of at least 0.001% by weight of the extract, for example, at least 0.005%, 0.01%,
0.05%, 0.1%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 10%,
% or more of the total weight of the extract. In some embodiments, the is extract
comprises about 0.001% to about 50% by weight of terpene and terpenoid compounds, for
example, about 0.01% to about 50% by weight, about 0.01% to about 10% by weight, about
0.01% to about 6% by weight or about 0.01 to about 5% by weight of the composition.
Typically, the terpene fraction in the plant material used to form the t may
have a different terpene/terpenoid profile than the terpene profile of the final extract, both in
terms of the s of specific compounds in the e fraction and the weight of the
terpene fraction relative to the other components. For example, a Cannabis flower may
comprise about 20% by weight cannabinoids and about 3% by weight terpenes. Following
extraction and concentration (i.e. removal of the extractant), the amount of cannabinoids may
increase to an amount of about 50-90% by weight and the terpene fraction may amount to
about 0.1-6% by weight of the is extract. This l scenario shows that while the
inoids are concentrated when the extractant is removed, the relative amount of the
terpene fraction is reduced, likely due to the volatility of many of the terpenes/terpenoids
present in the terpene fraction. Therefore, the profile of the terpene fraction present in the
is extract is significantly different from the profile of the terpene fraction that exists in
Nature.
17861217_1 (GHMatters) P103046.NZ
The efficacy of a pharmaceutical composition may be enhanced when the terpene
fraction has a n profile, i.e. a n proportion of particular terpenes/terpenoids are
present in the extract. It is believed that the increase in efficacy may be synergistic (i.e. nonadditive
). It is also believed that the presence of specific components in the terpene fraction
may enhance the patient’s tolerance to cannabinoid therapy.
A y of terpenes and terpenoids have also been identified in Cannabis extracts,
including monoterpenes, monoterpenoids, terpenes and sesquiterpenoids. For example,
the following terpenes and terpenoids have been identified in Cannabis extracts:
Alloaromadendrene, allyl hexanoate, benzaldehyde, (Z)-a-cis-bergamotene, (Z)-a-transbergamotene
, ß-bisabolol, epi-a-bisabolol, ß-bisabolene, borneol ol), cis-y-bisabolene,
bomeol acetate (bomyl acetate), -cadinene, camphene, camphor, cis-carveol, caryophyllene
(ß-caryophyllene), -humulene (-caryophyllene), γ-cadinene, Δcarene, caryophyllene oxide,
1,8-cineole, citral A, citral B, cinnameldehyde, -copaene (aglaiene), γ-curcumene, ne,
ß-elemene, γ-elemene, ethyl decdienoate, ethyl maltol, ethyl propionate, anillin,
eucalyptol, -eudesmol, ß-eudesmol, smol, eugenol, famesene ((Z)-ß-farnesene),
trans--farnesene, trans-ß-famesene, trans-γ-bisabolene, fenchone, fenchol (norbomanol,
hol), geraniol, -guaiene, guaiol, methyl anthranilate, methyl late, 2-methyl
heptanone, 3-methylheptanone, hexyl acetate, nol, isoamyl acetate, lemenol, limonene,
d-limonene (limonene), linolool (linalyl alcohol, ß-linolool), -longipinene, menthol, γ-muurolene,
myrcene (ß-myrcene), nerolidol, trans-nerolidol, nerol, ß-ocimene (cis-ocimene), octyl acetate,
-phellandrene, phytol, -pinene (2-pinene), ß-pinene, pulegone, sabinene, cis-sabinene
hydrate (cis-thujanol), ß-selinene, -selinene, γ-terpinene, terpinolene (isoterpine), terpineol
(-terpineol), terpineolol, -terpinene (terpilene), ene (origanene), vanillin, viridiflorene
(ledene), and -ylange.
It is ed that the presence of the particular terpenes/terpenoids in the specified
amounts present in the terpene fraction is associated with increased efficacy of the
pharmaceutical composition in in vivo studies (see Example 2).
The Cannabis extract ed in the pharmaceutical compositions ses
ß-caryophyllene in an amount of at least 11% by weight of the terpene fraction. It is believed
that ß-caryophyllene may counteract the sedative effects of some of the cannabinoids.
In some ments, the extract ses ß-carylophyllene in amount of at least
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about 11%, about 12%, about 13%, about 14% or about 15% by weight of the terpene fraction.
In some embodiments, the extract comprises less than about 60%, about 55%, about 50%, or
about 45% by weight of the terpene fraction. Any of the minimum levels may be combined with
a maximum level without tion, save for the requirement that the minimum level be below
the m water level. For example, in some embodiments, the extract may comprise ßcaryophyllene
in an amount from 11% to 60% by weight of the total terpene fraction, for
example, from 13% to 60%, from 14% to 60%, from 15% to 60%, from 15% to 50% or from 15%
to 45% by weight of the terpene fraction.
The is t may also comprise one or more of: ß-myrcene, D-limonene,
ol, a nerolidol (e.g. nerolidol 1 and/or 2) and a pinene (e.g. -pinene and/or ß-pinene).
In some embodiments, the extract also comprises ß-myrcene. It is believed that ßmyrcene
may enhance the bioavailability of the cannabinoids present in the extract and/or may
assist in allowing the cannabinoids to pass the blood-brain-barrier. Myrcene may be present in
the extract in an amount of at least 0.4% by weight of the total composition, for example, from
0.4% to about 40% by weight of the total composition. Myrcene may be present in the extract in
an amount of up to 50% by weight of the terpene on, for e, from 0.05% to 50% by
weight, from 0.05% to 25% by , from 0.05% to 5% by weight of the terpene fraction.
In some embodiments, the ratio of ß-caryophyllene to myrcene is greater than about
:1, for example, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or 97.5:1. In some embodiments, the ratio
of ß-caryophyllene to myrcene is less than 170:1, for example, 160:1, 150:1, 140:1 or 130:1. In
some embodiments, the ratio of ß-caryophyllene to myrcene is within a particular range of
ratios, such as any combination of the above described ratios, for example, from 30:1 to 170:1,
40:1 to 160:1, 50:1 to 150:1, 60:1 to 140:1, 70:1 to 130:1, 80:1 to 120:1 or 90:1 to 110:1.
Limonene is a cyclic monoterpene having the molecular formula C10H16. There are
a number of different naturally occurring s; however, the most common form is the
dextrorotatory isomer, namely D-limonene. Limonene may be present in the extract in an
amount of at least about 0.1% by weight of the terpene fraction, for example, from 0.1 to about
% by weight of the e fraction. In some embodiments, ne is absent from the
extract, or only present in an amount below the limit of detection.
Linalool is a terpenoid that is found in many flower and spice plants having the
molecular formula C10H18O. It is believed that when linalool is present in a Cannabis t,
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that is may provide a sedative effect. In some embodiments, linalool may be present in an
amount of at least 0.05% by weight of the terpene fraction. In some preferred embodiments,
linalool is present in an amount of at least 5% by weight of the terpene fraction. In other
embodiments, linalool is present in amount of from 0.05% to 25% by weight of the terpene
fraction, for example, from 0.1% to 20% by weight of the terpene fraction.
Nerolidol is a terpenoid having the molecular formula of C15H26O. It exists in
Nature in two isomeric forms, namely nerolidol 1 and dol 2, which differ in the geometry
around a central olefin, i.e. either cis or trans isomers. The extract may comprise nerolidol (i.e.
both nerolidol 1 and nerolidol 2) in an amount of at least 0.01% by weight of the terpene
fraction, for example, from 0.01% to 20% by weight of the terpene fraction. Typically, dol 1
is t in greater amount relative to nerolidol 2; however, in other embodiments, nerolidol 2
may be present in a greater amount relative to nerolidol 1. The ratio of nerolidol 1 to nerolidol 2
may be about 1:1, about 2:1, about 2:1, about 3:1, about 1:3, about 4:1, about 1:4, about 5:1, or
about 1:5. In some embodiments, nerolidol 1 or nerolidol 2 may be absent (or t in an
amount below the limit of ion). Nerolidol 1 may be present in the extract in an amount of
at least about 0.01% by weight of the terpene fraction, for example, from 0.01% to 20% or 0.1 to
% by weight of the terpene fraction. Nerolidol 2 may be present in the extract in an amount of
at least about 0.01% by weight of the terpene fraction, for example, 0.01% to 5% or 0.1% to 2%
by weight of the terpene fraction.
Pinene is a bicyclic rpene having the molecular formula C10H16. Pinene is
found in Nature in two isomeric forms: -pinene and ß-pinene. The t may comprise
pinene (i.e. -pinene and ß-pinene) in an amount of at least 5% by weight of the terpene
fraction, for e, at least 6%, 8%, 10%, 15% or 20% by weight of the composition. In some
embodiments, -pinene is present in greater amount relative to ß-pinene. In other
embodiments, ß-pinene is present in a greater amount relative to -pinene. The ratio of
ne to ß-pinene may be about 1:1, about 2:1, about 2:1, about 10:1, about 1:10, about
:1, about 1:15, about 20:1, about 1:20, about 25:1, about 1:25, about 30:1 or about 1:30. In
some embodiments, ne or ß-pinene may be absent (or present in an amount below the
limit of detection). -Pinene may be present in the extract in an amount of at least about 0.01%
by weight of the terpene fraction, for example, from 0.01% to 5% by weight. ne may be
present in the extract in an amount of at least about 0.01% by weight of the terpene fraction, for
example, 0.01% to 50% or 5% to 40% by weight of the terpene fraction.
In some embodiments, the terpene fraction may be present in the ition in an
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amount from 0.01% to 6% by weight of the extract and may comprise:
• ß-caryophyllene in an amount of from 11% to 50% by weight of the terpene
fraction;
• optionally ß-myrcene in an amount of from 0.01% to 40% by weight of the
terpene on;
• optionally D-limonene in an amount of from 0.01% to 10% by weight of the
e fraction;
• optionally linalool in an amount of from 5% to 20% by weight of the terpene
fraction;
• ally ß-pinene in an amount of from 1% to 50% by weight of the terpene
fraction;
• optionally -pinene in an amount of from 0.01% to 5% by weight of the terpene
fraction;
• optionally nerolidol 1 in an amount of from 0.01% to 20% by weight of the terpene
fraction; and
• optionally nerolidol 2 in an amount of from 0.001% to 5% by weight of the terpene
fraction.
In some embodiments, the extract further comprises humulene. It is believed that
that humulene may enhance the sedative properties of the extract. Humulene is also
sometimes called ophyllene. Humulene may be present in the extract in an amount of at
least about 1% by weight of the terpene fraction, for example, from about 1% to about 25% or
about 5% to about 15% by weight of the terpene fraction.
In some embodiments, the ratio of humulene to e is greater than about 12:1,
for example, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 25:1, 26:1, 27:1 or 28:1. In some embodiments,
the ratio of humulene to myrcene is less than 50:1, for example, 45:1, 40:1, 38:1, 36:1, 34:1,
33:1, 32:1, 31:1 or 30:1. In some embodiments, the ratio of humulene to myrcene is within a
ular range of ratios, such as any combination of the above described ratios, for example,
from 14:1 to 50:1, 16:1 to 40:1, 18:1 to 38:1, 20:1 to 36:1, 22:1 to 34:1, 24:1 to 33:1 or 26:1 to
:1.
The Cannabis extract may include additional terpenes and oids which, it is
believed, also potentiate the efficacy of the pharmaceutical itions. These terpenes may
include one or more of -bisabolol, caryophyllene oxide, p-cymene, isopulegol, ocimene,
-terpinene, γ-terpinene, δ-s-carene, guaiol, and terpinolene.
17861217_1 ters) P103046.NZ
In some embodiments, ic terpenes or terpenoids may be absent, or t in
non-detectable s (e.g. less than 0.001% by weight of the analyte). In some
embodiments, the Cannabis extract one or more of the following terpenes or terpenoids are
absent, or present in non-detectable s: camphene, δ-s-carene, geraniol, guaiol and
D-limonene.
One exemplary Cannabis extract is set out in the table below. Amounts of
cannabinoids are ed as determined by high-performance liquid chromatography (HPLC)
and amounts of terpenes are ed as determined by gas chromatography (GC). It will be
appreciated that, as the Cannabis extract is derived from Nature, the amount of each
ent may vary in some cases by +/- 10%, +/- 25% or +/- 50%. The ranges of amounts
corresponding to each of these limits to account for the potential variation in the composition are
also shown in the following table.
Compound Amount +/- 10% +/- 25% +/- 50%
(wt% of total
composition)
THCA 0.345 0.311-0.380 0.259-0.431 0.1725-0.5175
THC 55.131 49.618-60.644 41.348-68.914 27.5655-82.6965
THCV Not detected
(ND)
CBD ND
CBDA ND
CBG 0.367 0.330-0.404 0.275-0.459 0.1835-0.5505
CBN ND
CBC ND
-bisabolol 0.018 0.016-0.020 0.0135-0.0225 0.009-0.027
camphene ND
δ-s-carene ND
ß- 0.195 0.176-0.215 0.146-0.244 0.0975-0.2925
caryophyllene
caryophyllene 0.003 0.0027-0.0033 0.00225-0.00375 0.0015-0.0045
oxide
p-cymene 0.018 0.0162-0.0198 0.0135-0.0225 0.009-0.027
geraniol ND
guaiol ND
-humulene 0.056 0.0504-0.0616 0.042-0.070 0.028-0.084
egol 0.002 0.0018-0.0022 -0.0025 0.003
D-limonene ND
linalool 0.062 0.056-0.068 0.047-0.078 0.031-0.093
ß-myrcene 0.002 0.0018-0.0022 0.0015-0.0025 0.001-0.003
17861217_1 (GHMatters) P103046.NZ
nerolidol 1 0.036 0.032-0.040 0.027-0.045 0.018-0.054
dol 2 0.008 0.0072-0.0088 0.006-0.010 0.004-0.012
ocimene 0.005 0.0045-0.0055 0.00375-0.00625 0.0025-0.0075
ne 0.001 0.0009-0.0011 0.00075-0.00125 0.0005-0.0015
ß-pinene 0.032 0.0288-0.0352 0.024-0.04 0.016-0.048
-terpinene 0.001 0.0009-0.0011 5-0.00125 0.0005-0.0015
inene 0.001 0.0009-0.0011 0.00075-0.00125 0.0005-0.0015
terpinolene 0.002 0.0018-0.0022 0.0015-0.0025 0.001-0.003
Mass (terpene 0.442 0.3978-0.4862 0.3315-0.5525 0.221-0.663
fraction)
Mass (% of 56.285 50.657-61.914 42.214-70.356 28.143-84.428
total extract)
The pharmaceutical composition may further comprise one or more
ceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.
The carrier, diluent, adjuvant and/or ent are “pharmaceutically able”
meaning that they are ible with the other ingredients of the composition and is not
deleterious to a subject upon or following administration. The pharmaceutical compositions may
be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as
well as pharmaceutical additives of a type appropriate to the mode of desired administration (for
example, excipients, binders, preservatives, stabilisers, flavours, etc.) according to techniques
such as those well known in the art of pharmaceutical formulation (See, for example,
Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams &
Wilkins). The pharmaceutically acceptable carrier may be any r included in the United
States Pharmacopeia/National Formulary (USP/NF), the British Pharmacopoeia (BP), the
European Pharmacopoeia (EP), or the Japanese Pharmacopoeia (JP). In some embodiments,
the carrier, diluent, adjuvant and/or excipient may be tural (e.g. synthetically produced).
The ceutical composition includes those suitable for oral, rectal, nasal,
l (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous
and intravenous) administration or in a form suitable for stration by inhalation
or insufflation.
The Cannabis extract, together with a conventional adjuvant, carrier, ent or
diluent, may thus be placed into the form of pharmaceutical compositions and unit s
thereof, and in such form may be employed as solids, such as tablets or filled capsules, or
liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for
17861217_1 (GHMatters) P103046.NZ
oral use, in the form of suppositories for rectal administration; or in the form of e injectable
solutions for parenteral (including subcutaneous) use.
Such pharmaceutical itions and unit dosage forms thereof may comprise
conventional ients in conventional proportions, with or without additional active
compounds or principles, and such unit dosage forms may contain any suitable effective
amount of the active ingredient commensurate with the intended daily dosage range to be
employed.
For ing pharmaceutical compositions from the Cannabis extract described
herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form
preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable
granules. A solid carrier can be one or more substances which may also act as diluents,
ring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet
disintegrating agents, or an encapsulating material.
Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar,
lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is
intended to e the formulation of the active compound with encapsulating al as
carrier providing a e in which the active component, with or without carriers, is
surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are
ed. s, powders, capsules, pills, s, and lozenges can be used as solid forms
suitable for oral administration.
Liquid form preparations include solutions, dispersions, suspensions, and
emulsions, for example, water or water-propylene glycol solutions. For example, parenteral
injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol
Sterile liquid form compositions include e solutions, suspensions, emulsions,
syrups and elixirs. The Cannabis extract can be suspended in a pharmaceutically acceptable
carrier, such as sterile water, sterile organic solvent or a mixture of both.
Other liquid form preparations include those prepared by combining the Cannabis
extract with one or more naturally derived oils (e.g. an essential oil) or waxes. An “essential oil”
17861217_1 (GHMatters) P103046.NZ
is an oil derived by tion (e.g. steam extraction, or contacting the plant material with an
extractant) or pressing, which contains ily hydrophobic, and generally fragrant,
components of the plant material. Suitable naturally derived oils and waxes include Sesame oil,
Olive oil, Arnica essential oil, Lavender essential oil, Lavender Spike essential oil, Frankincense
essential oil, Lemongrass essential oil, Cinnamon Leaf essential oil, ry Cineole
essential oil, Rosemary essential oil, ot essential oil, Myrrh essential oil, Sage essential
oil, Coconut oil, Bees wax and Hemp oil.
The pharmaceutical compositions may be formulated for parenteral administration
(e. g. by injection, for e bolus injection or continuous infusion) and may be presented in
unit dose form in ampoules, lled syringes, small volume infusion or in multi-dose containers
optionally with an added preservative. The compositions may take such forms as suspensions,
solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as
suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from on, for
constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
ceutical forms suitable for injectable use include e injectable solutions
or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable
solutions. They should be stable under the conditions of manufacture and storage and may be
preserved against oxidation and the inating action of rganisms such as bacteria or
fungi.
The solvent or dispersion medium for the injectable solution or dispersion may
contain any of the conventional solvent or carrier systems, and may contain, for example, water,
ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the
like), suitable mixtures f, and vegetable oils.
Pharmaceutical forms le for injectable use may be delivered by any
appropriate route ing intravenous, intramuscular, intracerebral, intrathecal, epidural
injection or infusion.
e injectable solutions are prepared by incorporating the Cannabis extract in the
required amount in the appropriate carrier with various other ingredients such as those
enumerated above, as required, followed by sterilisation. Generally, dispersions are prepared
by incorporating the s sterilised active ingredients into a e vehicle which contains the
17861217_1 (GHMatters) P103046.NZ
basic dispersion medium and the required other ingredients from those enumerated above. In
the case of sterile s for the preparation of sterile injectable solutions, preferred methods
of preparation are vacuum drying or -drying of a previously sterile suspension of the
active ient plus any additional desired ingredients.
When the active ingredients are suitably protected they may be orally administered,
for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in
hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be
incorporated directly with the food of the diet. For oral therapeutic administration, the active may
be incorporated with excipients and used in the form of ingestible tablets, buccal s,
troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
The amount of active ingredient in therapeutically useful compositions should be
sufficient that a le dosage will be obtained.
The tablets, troches, pills, capsules and the like may also contain the components
as listed hereafter: a binder such as gum, acacia, corn starch or n; excipients such as
dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and
the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose,
lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen,
or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to
materials of the above type, a liquid carrier.
Various other materials may be present as coatings or to otherwise modify the
physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with
shellac, sugar or both. A syrup or elixir may contain the active nd, sucrose as a
sweetening agent, methyl and propylparabens as vatives, a dye and flavouring such as
cherry or orange flavour. Of course, any material used in preparing any dosage unit form should
be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the
active compound(s) may be incorporated into sustained-release preparations and formulations,
ing those that allow specific ry of the active peptide to specific regions of the gut.
Aqueous solutions suitable for oral use can be prepared by dissolving the active
component in water and adding suitable colorants, flavours, ising and ning agents,
as d. Aqueous sions suitable for oral use can be made by dispersing the finely
divided active component in water with viscous material, such as natural or synthetic gums,
17861217_1 (GHMatters) P103046.NZ
resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending
agents.
ceutically acceptable carriers and/or diluents include any and all ts,
dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying
agents and the like.
Also ed are solid form preparations that are intended to be converted, shortly
before use, to liquid form preparations for oral administration. Such liquid forms include
ons, suspensions, and emulsions. These preparations may contain, in on to the
active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners,
dispersants, thickeners, solubilising agents, and the like.
For topical administration to the epidermis the active ingredients may be formulated
as ointments, creams or lotions, or as a ermal patch. Ointments and creams may, for
example, be formulated with an aqueous or oily base with the addition of le thickening
and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in
general also contain one or more emulsifying agents, ising agents, dispersing agents,
suspending agents, thickening agents, or ing .
Formulations suitable for topical administration in the mouth include lozenges
comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ient in an inert base such as gelatin and glycerin or sucrose and
acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional
means, for example with a r, pipette or spray. The formulations may be provided in single
or ose form. In the latter case of a dropper or pipette, this may be achieved by the patient
administering an appropriate, predetermined volume of the solution or suspension.
In the case of a spray, this may be achieved for example by means of a metering
atomising spray pump. To improve nasal delivery and retention the compounds according to the
ion may be encapsulated with cyclodextrins, or formulated with other agents expected to
enhance delivery and retention in the nasal mucosa.
17861217_1 (GHMatters) P103046.NZ
Administration to the respiratory tract may also be achieved by means of an aerosol
formulation in which the active ient is ed in a pressurised pack with a suitable
lant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
The l may conveniently also contain a tant such as lecithin. The dose of
drug may be controlled by provision of a metered valve.
Alternatively the active ingredients may be ed in the form of a dry , for
example a powder mix of the compound in a le powder base such as lactose, starch,
starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
Conveniently the powder carrier may form a gel in the nasal cavity. The powder composition
may be presented in unit dose form for example in capsules or dges of, e.g. n, or
r packs from which the powder may be administered by means of an inhaler.
In formulations intended for administration to the atory tract, including
intranasal formulations, the compound will generally have a small particle size for example of
the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in
the art, for example by micronisation.
When desired, formulations adapted to give sustained release of the active
ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such form,
the preparation is subdivided into unit doses containing appropriate quantities of the active
component. The unit dosage form can be a ed preparation, the package containing
discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or
ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it
can be the appropriate number of any of these in packaged form.
It is especially advantageous to formulate parenteral compositions in dosage unit
form for ease of administration and uniformity of dosage. Dosage unit form as used herein
refers to physically discrete units suited as unitary dosages for the subjects to be treated; each
unit containing a predetermined quantity of active material calculated to produce the desired
therapeutic effect in association with the required pharmaceutical carrier. The specification for
the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of
17861217_1 (GHMatters) P103046.NZ
the active al and the particular therapeutic effect to be achieved, and (b) the limitations
inherent in the art of compounding such an active material for the treatment of cancer of an
associated symptom in living subjects having a diseased condition in which bodily health is
impaired.
Also described herein are compositions absent a carrier where the compositions are
in unit dosage form. Accordingly, also provided is a medicament comprising the Cannabis
In some embodiments, the pharmaceutical composition further comprises an active
agent other than the Cannabis extract. Any suitable active agent may be used provided that the
activity of the active agent and/or the Cannabis extract is not diminished when combined.
Preferably, the active agent is an anti-cancer drug. Suitable anti-cancer drugs include
trastuzumab (e.g., Herceptin.RTM.) or n ne kinase inhibitors (e.g. nib (e.g.,
Tykerb.RTM.)). In some embodiments, the t has previously been administered, or is
currently being administered, an aromatase inhibitor. In some embodiments, the aromatase
inhibitor is selected from aminoglutethimide, testolactone (e.g., Teslac.RTM.), anastrozole (e.g.,
Arimidex.RTM.), letrozole (e.g., Femara.RTM.), exemestane (e.g., Aromasin.RTM.), vorozole
(e.g., Rivisor.RTM.), formestane (e.g., Lentaron.RTM.), rol acetate (e.g., Megase.RTM.),
and fadrozole (e.g., RTM.). In some embodiments, a subject with breast cancer has
previously been administered, or is currently being administered, an ER nist. In some
embodiments, the subject has previously been determined to have ER positive breast cancer.
Non-limiting exemplary ER antagonists include tamoxifen (e.g., Nolvadex.RTM., Istubal.RTM.,
and Valodex.RTM.) and fulvestrant (e.g., ex.RTM.) or a ation thereof.
Methods of treatment
In another aspect, also provided is a method for treating cancer or a symptom
associated with cancer. The method comprising administering to a patient in need thereof an
effective amount of the ceutical ition described herein.
The pharmaceutical compositions may be used to treat cancer or a symptom
associated with cancer. In particular, the pharm aceutical compositions may be effective in the
treatment of a breast cancer, for example, HER2 positive, triple negative and/or hormone
or positive breast cancer. In some embodiments, the breast cancer is HER2 positive
breast cancer. HER2 positive breast cancer is one of the more aggressive forms of breast
cancer, and ts for about 20% of all breast cancers. HER2 is the abbreviation for “human
17861217_1 (GHMatters) P103046.NZ
epidermal growth factor receptor 2” which is a protein expressed by HER2 positive breast
tumour cells. In some embodiments, the breast cancer is triple negative breast cancer. There
are currently no targeted eutic options for triple negative breast cancer on the market. In
some embodiments, the breast cancer is hormone receptor positive breast cancer. The
inventors have shown that a Cannabis extract possesses efficacy t HER2+, triple
negative and hormone receptor positive breast cancer cells. In addition, for THC-rich extracts
(e.g. an extract comprising ≥ 0.3% w/w of the terpene fraction, ≥ 50% w/w
rahydrocannabinol (THC); ≥ 0.3% w/w Cannabigerol (CBG); and ≤ 0.5% w/w Cannabinol
(CBN), the inventors have shown that the Cannabis extract has greater activity against the
tested breast cancer cells than THC alone (see s 5-8).
The ors observed that the volume of ectopic xenografts of human HER2
positive malignant cells are reduced following treatment with the pharmaceutical ition by
similar volumes compared to the approved drug lapatinib (see Figures 1, 2 and 3). The
reduction in tumour volume for the pharmaceutical compositions comprising a high-THC
Cannabis t are greater than those for an equivalent dose of THC alone.
Symptoms associated with cancer include unexplained weight loss, fever, e,
pain, and skin changes. Symptoms specifically associated with breast cancer include
thickening or lumps forming in the breast tissue.
Symptoms of cancer are also commonly associated with many, if not all, of ng
cancer therapies, including herapy and radiotherapy. The present composition may also
be used to treat the symptoms of cancer therapy.
By tive amount” it is meant an amount sufficient that when administered to the
patient an amount of the drug is provided to achieve an . In the case of a therapeutic
method, this effect may be the treatment of cancer or a symptom associated with cancer.
Therefore, the “effective amount” may be a “therapeutically effective amount”. By
peutically effective amount” it is meant an amount sufficient that when administered to the
patient an amount of drug is provided to treat the e or a symptom of the e.
As used herein, the terms “treating”, "treatment", “treat” and the like mean affecting
a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect. The
effect may be prophylactic in terms of completely or partially preventing, or reducing the severity
of, a disease or associated symptom, and/or may be therapeutic in terms of a partial or
complete cure of a disease. A reference to “treating” cancer therefore encompasses: (a)
17861217_1 (GHMatters) P103046.NZ
inhibiting cancer cell growth, e.g. arresting tumour development or further development; (b)
ing or ameliorating the effects of the cancer, i.e. causing regression of the effects of the
cancer; (c) reducing the incidence of metastasis; or (d) preventing the cancer or symptom
associated with cancer from occurring in a t predisposed to cancer or at risk thereof so
that the cancer does not develop or occur in the subject.
The method may comprise administering more than one pharmaceutical
composition of the present invention to the patient in need thereof. For e, in some
circumstances, it is preferred to administer a pharmaceutical composition high in THC and a
pharmaceutical composition high in CBD to the patient. These compositions may be
administered in an alternating order and separated by a period of time. The pharmaceutical
composition high in THC may comprise ≥ 50% w/w THC, ≥ 0.3% w/w CBG, ≤ 0.5% w/w CBN
and ≥ 0.3% w/w terpene on. The pharmaceutical composition high in CBD may se ≥
60% w/w CBD, ≤ 3% w/w THC, ≤ 0.1% w/w CBN and ≥ 0.5% w/w terpene fraction.
The method may also comprise administering an active agent other than the
Cannabis extract. This active agent may be administered simultaneously or consecutively with
the Cannabis extract. By consecutively it is meant that each of the Cannabis extract and the
other active agent are administered separately and may be at different times. Typically, when
the Cannabis extract and the other active agent are administered consecutively they are
administered within 24 hours, or within 12, 8, 6, 5, 4, 3, 2, or 1 hour(s) of each other. The
Cannabis extract may be stered before or after the other active agent. Further, the route
of administration for the Cannabis extract and the other active agent may be the same or
different.
In another aspect, also provided is the use of the Cannabis extract in the
ation of a ment for the ent of cancer or a symptom associated with cancer.
Also provided is a kit comprising in separate parts:
(a) an effective amount of the Cannabis extract; and
(b) a pharmaceutically acceptable carrier, t, adjuvant, excipient or a combination
thereof.
In some embodiments, the kit may comprise in a separate part (b’) an effective
amount of an active agent other than the Cannabis extract. Part (b’) may be included in the kit,
in addition to parts (a) and (b), or in place of part (b).
17_1 (GHMatters) P103046.NZ
In another aspect, there is provided the pharmaceutical composition for treating
cancer or a symptom associated with cancer. The pharmaceutical composition may be any of
the pharmaceutical compositions described above, comprising any above-described
combination of components, provided that it comprises the Cannabis t with the ied
terpene fraction. The cancer and its ms may also be any of those described above.
Examples
The ion will be further described by way of non-limiting examples. It will be
understood to persons skilled in the art of the invention that many modifications may be made
without departing from the spirit and scope of the invention.
Example 1 – THC compositions
The following THC compositions are described:
AZ1 – extract of Purple Urkl Cannabis plant.
AZ2 – extract of Granddaddy Purple Cannabis plant.
AZ3 – extract of Sensi Star is plant.
AZ4 – extract of Ogre Kush Cannabis plant.
AZ5 – t of Harletsu Cannabis plant.
AZ6 – extract of ACDC Cannabis plant.
Component AZ1 AZ2 AZ3 AZ4 AZ5 AZ6
Cannabinoids1 wt%3 wt%3 wt%3 wt%3 wt%3 wt%3
THCA 0.345 0.497 2.918 0.002 1.161 0.275
THC 55.131 75.442 65.066 75.127 2.876 2.717
THCV 0.000 0.899 0.436 0.265 0 0
CBD 0.000 0.000 0.000 0.000 65.304 61.298
CBDA 0.000 0.000 0.000 0.000 0 0.239
CBG 0.367 2.047 2.525 1.453 1.563 1.187
CBGA -- 0.000 1.252 -- 0.176 0
CBN 0.000 0.637 0.433 0.052 0 0
CBC 0.000 0.995 0.747 1.092 3.303 0.123
Terpenes2
-bisabolol 0.018 0.016 0.007 0.013 0.006 0.016
camphene 0.000 0.000 0.000 0.000 0.000 0
δ-s-carene 0.000 0.004 0.001 0.000 0.010 0.005
ß-caryophyllene 0.195 0.220 0.053 0.226 0.080 0.195
caryophyllene oxide 0.003 0.004 0.002 0.002 0.003 0.004
p-cymene 0.018 0.000 0.000 0.071 0.003 0.004
17861217_1 (GHMatters) P103046.NZ
geraniol 0.000 0.000 0.000 0.000 0.000 0
guaiol 0.000 0.026 0.009 0.006 0.008 0.037
-humulene 0.056 0.072 0.023 0.044 0.029 0.062
isopulegol 0.002 0.007 0.004 0.000 0.005 0.008
D-limonene 0.000 0.025 0.015 0.000 0.033 0.035
linalool 0.062 0.113 0.026 0.070 0.001 0.056
ß-myrcene 0.002 0.007 0.003 0.007 0.009 0.009
nerolidol 1 0.036 0.071 0.020 0.001 0.015 0.011
nerolidol 2 0.008 0.009 0.005 0.000 0.004 0.007
ocimene 0.005 0.012 0.032 0.030 0.027 0.009
-pinene 0.001 0.004 0.000 0.003 0.004 0.005
ne 0.032 0.066 0.093 0.283 0.132 0.125
-terpinene 0.001 0.003 0.000 0.001 0.011 0.005
γ-terpinene 0.001 0.003 0.001 0.000 0.006 0.004
terpinolene 0.002 0.006 0.006 0.025 0.144 0.006
total es 0.442 0.666 0.300 0.783 0.531 0.601
total 56.285 81.185 73.677 78.773 74.913 66.442
Notes: (1) Cannabinoids were detected using HPLC analysis, an amount reported as 0 wt%
indicates that the compound was either not detected, or present in an amount below the
ion limit of the HPLC; (2) Terpenes were detected using GC analysis, an amount reported
as 0 wt% indicates that the compound was either not detected, or present in an amount below
the detection limit of the GC; (3) In order to allow for Natural variation, amount within +/- 10%,
+/- 25% or +/- 50% of the reported .
Example 2 – In vivo study comparing compositions comprising a Cannabis extract, THC
only and lapatinib against HER2 positive tumour volume
Methodology. 5x106 viable BT474 human breast HER2+ adenocarcinoma cells
were subcutaneously injected into the right flank of 6-week-old athymic mice. When tumors
reached circa 200 mm3, animals were randomly assigned to the following mental groups
and the indicated treatments were started and maintained for 4 weeks:
VEHICLE: sesame oil (THC e, 3 times/week) + 0.5% hydroxypropylmethyl
cellulose + 0.1% Tween 80, in water (Lapatinib vehicle, daily)
LAPATINIB (100mg/Kg, daily)
THC (45mg/Kg, 3 times/week)
PATINIB
17861217_1 (GHMatters) P103046.NZ
THC AZ (45mg/Kg THC, 3 times/week). THC AZ ses e (sesame oil)
and AZ1 as described in Example 1.
THC AZ + LAPATINIB
All treatments were stered by oral gavage. Tumors were routinely measured
with external caliper, and volume was calculated as (4π/3) x (width/2)2 x h/2).
Results are shown in Figures 1-4. In can be seen from Figure 1 that treatment with
the THC AZ composition results in a greater reduction in tumor volume than treatment with the
THC only and vehicle only treatments. Further, the efficacy of THC AZ is approximately the
same as the approved chemotherapy lapatinib (see Figures 2-4). r, these data suggest
that the combination therapy of THC AZ and lapatinib is non-deleterious (Figure 3).
Example 3 – In vitro study of efficacy of pure THC and Cannabis extract ich
extract) against various breast cancer cells
Cancer cells were plated at a density of 5000 cells/cm2 and incubated in the media
indicated below for 24h at 37ºC and 5% CO2 atmosphere:
CELL LINE CULTURE MEDIUM SUPPLEMENTS
% FBS
MCF7 MEM 50 U/mL P/S
2 mM L-Glutamine
ER+/PR+ 10 µg/mL Insuline
% FBS
T47D RPMI 50 U/mL P/S
µg/mL Insuline
HCC 1954 RPMI 10% FBS
50 U/mL P/S
HER2+
% FBS
SKBR3 McCoy’s 5A 50 U/mL P/S
1% ine
MDA-MD-231 DMEM 10% FBS
Triple 50 U/mL P/S
negative
% FBS
SUM 159 Ham’s F12 50 U/mL P/S
µg/mL Insuline
0,5 µg/mL HC
FBS: fetal bovine serum; P/S: penicillin/streptomycin; HC: hydrocortisone
Cells were then transferred to serum-free medium for 5h and after that, challenged
17861217_1 (GHMatters) P103046.NZ
with the corresponding treatments (pure THC, THC-rich extract (AZ1) or the corresponding
e -DMSO-). Cell viability was determined after 24h incubation with the different ents
by violet crystal staining: 0.1% violet crystal in 20% methanol was added to the wells, and after
a 20min incubation at room temperature, the stained cells were ended in methanol. Cell
viability was determined by measuring absorbance at 570nm, and expressed as % versus
e-treated cells (set at 100%).
The results of these experiments are shown in Figures 5-7. In each experiment, the
Cannabis extract demonstrated enhanced efficacy relative to THC alone. The Cannabis extract
demonstrated ed efficacy relative to THC alone against each of the tested HER2 positive
(figure 5), triple negative (figure 6) and hormone receptor positive e 7) breast cancer cells.
The s of this example are summarised in Figure 8, which shows that the
Cannabis extract is effective against all cancer cell lines tested.
Unless the context requires otherwise, all percentages referred to herein are
percentages by weight of the pharmaceutical composition.
The term “about”, when used to describe a value, preferably means an amount
within ±10% of that value.
The terms “a”, “an”, “and” and/or “the” and similar nts in the context of
describing the invention and the claims which follow are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
It is to be understood that, if any prior art publication is referred to herein, such
reference does not constitute an admission that the publication forms a part of the common
general knowledge in the art, in Australia or any other country.
In the claims which follow and in the preceding description of the invention, except
where the context es otherwise due to express ge or necessary implication, the
word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense,
i.e. to specify the presence of the stated features but not to preclude the presence or addition of
further features in various embodiments of the invention.
17861217_1 (GHMatters) P103046.NZ
Claims (17)
1. A ceutical composition comprising a Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, ents or any combination thereof, the Cannabis extract comprising a cannabinoid fraction and a terpene fraction, n the Cannabis extract comprises : - ≥ 0.3% w/w of the terpene fraction; - ≥ 50% w/w Δ9-Tetrahydrocannabinol (THC); - ≥ 0.3% w/w Cannabigerol (CBG); and - ≤ 0.5% w/w Cannabinol (CBN); or B: - ≥ 0.5% w/w of the terpene fraction; - ≥ 60% w/w cannabidiol (CBD); - ≤ 3% w/w THC; and - ≤ 0.1% w/w CBN; wherein the terpene on comprises: • ß-caryophyllene in an amount of at least 11% by weight of the terpene fraction, one or more of: - linalool in an amount of at least 5% by weight of the terpene fraction; and - ß-pinene in an amount of at least 1% by weight of the terpene fraction.
2. The pharmaceutical composition according to claim 1, wherein the Cannabis extract is a Cannabis oil.
3. The pharmaceutical composition according to claim 1 or 2, wherein, for ition A, the Cannabis extract comprises Δ9-tetrahydrocannabinol (THC) in an amount of from 50% to 99% by weight of the pharmaceutical composition.
4. The pharmaceutical composition according to claim 1 or 2, wherein, for composition B, the Cannabis extract comprises cannabidiol (CBD) in an amount of from 60% to 99% by weight of the pharmaceutical composition. 17861217_1 (GHMatters) P103046.NZ
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the Cannabis extract comprises one or more additional cannabinoids selected from Δ9-Tetrahydrocannabinolic acid , Δ9-Tetrahydrocannabivarin (THCV), and (-)-Cannabidivarin (CBDV).
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the terpene fraction comprises both linalool and ß-pinene.
7. The pharmaceutical composition ing to any one of claims 1 to 6, n the e fraction further comprises one or more of ß-myrcene, D-limonene, a nerolidol and -pinene.
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the terpene fraction further ses one or more of -bisabolol, caryophyllene oxide, p-cymene, isopulegol, ocimene, -terpinene, inene, δ-s-carene, guaiol, and terpinolene.
9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutically acceptable carrier is sesame oil.
10. The pharmaceutical composition according to any one of claims 1 to 9, further comprising an active agent other than the Cannabis extract.
11. Use of a pharmaceutical composition according to any one of claims 1 to 10, in the preparation of a ment for treating cancer or a symptom ated with cancer.
12. Use of a Cannabis extract in the preparation of a medicament for treating cancer or a symptom associated with cancer, wherein the Cannabis extract comprises a cannabinoid fraction and a terpene fraction, and wherein the Cannabis extract comprises either: - ≥ 0.3% w/w of the e fraction; - ≥ 50% w/w Δ9-Tetrahydrocannabinol (THC); - ≥ 0.3% w/w Cannabigerol (CBG); and - ≤ 0.5% w/w Cannabinol (CBN); or B: 17_1 (GHMatters) P103046.NZ - ≥ 0.5% w/w of the terpene fraction; - ≥ 60% w/w cannabidiol (CBD); - ≤ 3% w/w THC; and - ≤ 0.1% w/w CBN.
13. The use according to claim 12, wherein the Cannabis extract is incorporated into a pharmaceutical composition, wherein the pharmaceutical composition comprises the Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or any combination thereof.
14. The use ing to any one of claims 11 to 13, wherein the cancer is breast cancer.
15. The use according to claim 14, wherein the cancer is selected from HER2 positive, triple ve, and hormone receptor positive breast cancer.
16. The use of any one of claims 11 to 15, wherein the e fraction comprises: • ß-caryophyllene in an amount of at least 11% by weight of the terpene on, one or more of: - linalool in an amount of at least 5% by weight of the terpene fraction; and - ß-pinene in an amount of at least 1% by weight of the terpene fraction.
17. A pharmaceutical composition according to any one of claims 1 to 10, substantially as herein described, with reference to any one of the Examples and/or
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662370299P | 2016-08-03 | 2016-08-03 | |
US62/370,299 | 2016-08-03 | ||
AU2017901222 | 2017-04-04 | ||
AU2017901222A AU2017901222A0 (en) | 2017-04-04 | Cannabis composition | |
AU2017902065 | 2017-05-31 | ||
AU2017902065A AU2017902065A0 (en) | 2017-05-31 | Cannabis composition | |
PCT/AU2017/050817 WO2018023166A1 (en) | 2016-08-03 | 2017-08-03 | Cannabis composition |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ750272A NZ750272A (en) | 2021-09-24 |
NZ750272B2 true NZ750272B2 (en) | 2022-01-06 |
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