NZ622424B2 - A pharmaceutical composition comprising the phytocannabinoids cannabidivarin (cbdv) and cannabidiol (cbd) - Google Patents
A pharmaceutical composition comprising the phytocannabinoids cannabidivarin (cbdv) and cannabidiol (cbd) Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Abstract
Provided is a composition comprising a combination of cannabidivarin (CBDV) and cannabidiol (CBD), absent of tetrahydrocannabinol (THC) and tetrahydrocannabivarin (THCV). The composition is suitable for the treatment of epilepsy.
Description
A CEUTICAL COMPOSITION COMPRISING THE PHYTOCANNABINOIDS
CANNABIDIVARIN (CBDV) AND CANNABIDIOL (CBD)
This invention relates to a pharmaceutical composition comprising or ting
essentially of the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD).
The composition is particularly safe and cious for use in the treatment of
neurological conditions, characterized by excitability of the central nervous system,
convulsions or seizures such as occur in epilepsy.
Preferably the CBDV and the CBD are present with at least one nnabinoid
ent of is such as one or more terpenes or a terpene fraction.
More particularly the composition further comprises one or more cannabichromene
type compounds. Particularly cannabichromene propyl variant (CBCV) and / or
cannabichromene (CBC).
More particularly still the composition is absent or substantially absent of other
cannabinoids, including in particular tetrahydrocannabinol (THC) and tetrahydrocannabivarin
(THCV), which would ly be present in significant amounts in cannabis chemotypes bred
to contain a significant amount of CBDV and / or CBD.
BACKGROUND
[0006] Epilepsy is a chronic neurological disorder presenting a wide spectrum of diseases that
s approximately 50 million people worldwide (Sander, 2003). Advances in the
understanding of the body’s internal ‘endocannabinoid’ system has lead to the suggestion that
cannabis-based medicines may have the potential to treat this er of hyperexcitability in
the central nervous system (Mackie, 2006, Wingerchuk, 2004, Alger, 2006).
[0007] Cannabis has been ascribed both pro-convulsant (Brust et al., 1992) and anti-
convulsant s. Therefore, it remains to determine whether cannabinoids represent a yet to
be unmasked eutic anticonvulsant or, conversely, a ial risk factor to recreational
and medicinal users of cannabis (Ferdinand et al., 2005).
In 1975 Consroe et al. described the case of young man whose standard treatment
(phenobarbital and phenytoin), didn't control his seizures. When he began to smoke cannabis
socially he had no seizures. However when he took only cannabis the seizures returned. They
concluded that 'marihuana may possess an anti-convulsant effect in human epilepsy'.
A study by Ng (1990) involved a larger population of 308 epileptic patients who had
been admitted to hospital after their first seizure. They were compared to a control population of
294 patients who had not had seizures, and it was found that using cannabis seemed to reduce
the likelihood of having a e. However this study was criticized in an Institute of Medicine
report (1999) which claimed it was 'weak', as 'the study did not include es of health
status prior to hospital admissions and differences in their health status might have influenced
their drug use' rather than the other way round.
Three controlled trials have igated the anti-epilepsy potential of cannabidiol. In
each, cannabidiol was given in oral form to sufferers of generalised grand mal or focal seizures.
Cunha et al (1980) reported a study on 16 grand mal patients who were not doing well
on conventional medication. They received their r medication and either 200-300mg of
cannabidiol or a placebo. Of the patients who received CBD, 3 showed complete improvement,
2 partial, 2 minor, while 1 remained unchanged. The only unwanted effect was mild sedation.
Of the patients who received the placebo, 1 improved and 7 remained ged.
Ames (1986) reported a less sful study in which 12 epileptic patients were given
200-300mg of cannabidiol per day, in addition to standard antiepileptic drugs. There seemed to
be no significant improvement in seizure frequency.
Trembly et al (1990) performed an open trial with a single patient who was given 900-
1200mg of cannabidiol a day for 10 months. Seizure frequency was markedly d in this
single t.
[0014] In addition to the sures suggesting CBD may be beneficial there is a report
(Davis & Romsey) of tetrahydrocannabinol (THC) being administered to 5 institutionalized
children who were not responding to their standard treatment (phenobarbital and phenoytin).
One became entirely free of seizures, one became almost completely free of seizures, and the
other three did no worse than before.
[0015] In it is suggested that the cannabinoid tetrahydrocannabivarin
(THCV) may behave as anti-epileptic. However the main teaching in this nt is the
determination that THCV acts as a CB1 antagonist.
The application shows CBD to be an e agonist at the CB1 and
CB2 receptors and suggests this compound and structurally d compounds including
CBDV, may have a therapeutic benefit in a wide range of conditions which involve these
receptors. More specifically the data demonstrates that the cannabinoid CBD reduced
bodyweight in rats.
However other work on cannabinoids has shown that despite THCV’s structural
similarity to THC the two nds behave quite differently at the CB1 receptor and
consequently it does not follow that the propyl cannabinoid analogs will behave as their pentyl
equivalents.
In addition a study in 2007 by Deshpande etal. ished that the CB1 antagonist
rimonabant was a pro-convulsant; this study demonstrated that antagonism of the CB1 receptor
caused epileptic activity. The inference from this study is that inoids which act as
antagonists of the CB1 receptor may not be useful as anti-convulsants; indeed they may
exacerbate such a condition.
The ation describes the use of cannabis plant extracts with
neuroprotective properties. Cannabinoid extracts containing THC and CBD were shown to be
more effective than their pure counterparts in this area of medicine.
The application WO 02/064109 describes a pharmaceutical formulation where the
cannabinoids THC and CBD are used. The application goes on to state that the propyl analogs
of these cannabinoids may also be used in the formulation. Since this application was written it
has been shown that THCV behaves in a very different manner to THC and therefore the
assumption that the propyl analogs of cannabinoids may behave in a similar manner to their
pentyl counterparts is now not valid.
The application 565 describes the use of THCV for the treatment of
generalised seizures; it also describes the use of CBD in combination with THCV.
The application 364.3 (unpublished) describes the use of CBDV for use in the
treatment of epilepsy.
The condition of epilepsy is a very difficult to treat disease, there are more than forty
recognisable types of epileptic syndrome partly due to seizure tibility varying from patient
to t (McCormick and Contreras, 2001, Lutz, 2004) and a nge is finding drugs which
are effective t these differing types.
[0024] Neuronal ty is a prerequisite for proper brain function. However, disturbing the
excitatory - inhibitory equilibrium of neuronal activity may induce epileptic seizures. These
epileptic seizures can be grouped into two basic categories:
a) partial, and
b) generalised seizures.
Partial seizures originate in specific brain regions and remain sed — most commonly the
temporal lobes (containing the hippocampus), whereas generalised seizures appear in the
entire ain as a secondary generalisation of a partial seizure (McCormick and ras,
2001, Lutz, 2004). This t of partial and generalised seizure classification did not become
common practice until the International League Against Epilepsy published a classification
scheme of epileptic es in 1969 (Merlis, 1970, Gastaut, 1970, Dreifuss et al., 1981).
The International League Against Epilepsy further fied partial seizures,
separating them into simple and complex, depending on the presence or the impairment of a
consciousness state (Dreifuss et al., 1981 ).
The League also rized generalised seizures into numerous clinical seizure
types, some examples of which are outlined below:
e es occur frequently, having a sudden onset and interruption of g
activities. Additionally, speech is slowed or impeded with seizures lasting only a few seconds
(Dreifuss et al., 1981).
[0028] Tonic-clonic seizures, often known as “grand mal”, are the most frequently
tered of the lised seizures (Dreifuss et al., 1981). This lised seizure type
has two stages: tonic muscle contractions which then give way to a clonic stage of convulsive
movements. The patient remains unconscious throughout the e and for a variable period
of time aftenNards.
[0029] Atonic seizures, known as “drop attacks”, are the result of sudden loss of muscle tone
to either a specific muscle, muscle group or all muscles in the body (Dreifuss et al., 1981).
The onset of epileptic seizures can be life threatening with sufferers also experiencing
long-term health implications (Lutz, 2004). These implications may take many forms:
. mental health problems (e.g. prevention of normal glutamatergic synapse development
in childhood);
0 cognitive deficits (e.g. diminishing ability of neuronal circuits in the hippocampus to learn
and store memories); and
. morphological s (e.g. selective loss of neurons in the CA1 and CA3 regions of
the hippocampus in patients presenting mesial temporal lobe epilepsy as a result of
excitotoxicity) (Swann, 2004, Avoli et al., 2005)
It is noteworthy that epilepsy also greatly affects the lifestyle of the sufferer —
potentially living in fear of consequential injury (e.g. head injury) resulting from a grand mal
seizure or the inability to perform daily tasks or the inability to drive a car unless having had a
lengthy seizure-free period (Fisher et al., 2000).
[0032] Despite the historic work on CBD in epilepsy in the 1980’s/1990’s, research in the field
of anti-convulsants has focused on many other candidates many of which are now approved for
use in the treatment of epilepsy. Such drugs include: acetozolamide, carbamazepine,
am, clonazepam, ethosuximide, eslicarbazepine acetate, gabapentin, lacosamide,
2012/052284
Iamotriquine, Ievetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone,
rufinamide, sodium valproate, tiagabine, topiramate, valproate, vigabatrin, and mide.
The mode of action of some of these is understood and for others is unknown. 80me
modes of action are set out in Table 1 below: (Adapted from: 8chachter SC. Treatment of
es. In: 8chachter SC, 8chomer DL, eds. The comprehensive evaluation and treatment of
epilepsy. San Diego, CA: Academic Press; 1997. p. 61-74)
Table 1.
E $Sodium or calcium or
EAntiepiIeptic drug Mechanism of action GABA channel ‘
E ‘ involvement
Barbiturates: primidone GABA
(Mysoline), phenobarbital E $
..................................................................................... .....................................................................................................................................................................
Carbamazepine tol, Inhibits voltage-dependent sodium
TegretoI-XR, rol) channels
Modifies low-threshold or transient
Ethosuximide (Zarontin)
neuronal calcium currents
..................................................................................... .....................................................................................................................................................................
.........................................................................................................................................................................................................................................................
Inhibits voltage-dependent sodium $80dium
Echannels, resulting in decreased
Lamotrigine (LamictaI) release of the excitatory
neurotransmitters glutamate and
aspartate
Blocks -dependent action
$Sodium/Calcium
Phenytoin (Dilantin, Phenytek) potentials; reduces neuronal $
: EcaIcium uptake
.........................................................................................................................................................................................................................................................
Reduces high-frequency neuronal $80dium/ GABA
EVaIproate (Depakote, pepakote Efiring and sodium-dependent action ‘
2 ER, Depakene, valpr0Ic aCId) potentials; enhances GABA effects
r e the introduction of some twenty different compounds for treatment of
epilepsy over the last twenty years there remains a need for alternate drugs for several
reasons:
i) 1-2% of the world’s tion suffer from sy
(http:/I’wmv.ncbi.nEm.nih.gov/sites/pgmciarticies/PIVIC’E8084960;
ii) Of these 30% are refractory to existing treatments; and
iii) There are also notable motor side effects in the existing therapies
(http://en,Wikigedia.org/wiki/Epilepsy).
WO 45891
For example valproate and ethosuximide both exhibit notable motor and other side
effects (including sedation) when given to rats at doses r than 200mg/kg, as does
phenobarbital at doses greater than 250 mg/kg in rat models of epilepsy.
Three stablished and extensively used in vivo models of epilepsy are:
. pentylenetetrazole—induced (PTZ) model of generalised seizures (Obay et al., 2007,
Rauca et al., 2004);
. pilocarpine—induced model of temporal lobe (i.e. hippocampus) seizures (Pereira et al.,
2007); and
. penicillin-induced model of partial seizures (Bostanci and Bagirici, 2006).
These provide a range of seizure and epilepsy models, essential for therapeutic research in
humans.
In the foregoing specification the following terms are used and are intended to have
the following meanings / definitions:
“Cannabinoids” are a group of nds including the endocannabinoids, the
phytocannabinoids and those which are neither endocannabinoids or phytocannabinoids,
hereafter “syntho—cannabinoids”.
“Endocannabinoids” are nous cannabinoids, which are high affinity ligands of
CB1 and CB2 receptors.
“Phytocannabinoids” are cannabinoids that originate in nature and can be found in the
cannabis plant. The phytocannabinoids can be present in an extract ing a botanical drug
substance, ed, or reproduced synthetically.
“Syntho—cannabinoids” are those compounds e of cting with the
cannabinoid receptors (CB1 and / or CB2) but are not found nously or in the cannabis
plant. Examples include WIN 55212 and rimonabant.
An “isolated phytocannabinoid” is one which has been extracted from the cannabis
plant and ed to such an extent that all the additional components such as secondary and
minor cannabinoids and the non-cannabinoid fraction have been removed.
[0044] A “synthetic cannabinoid” is one which has been produced by chemical synthesis this
term includes modifying an isolated phytocannabinoid, by for example forming a
pharmaceutically acceptable salt thereof.
WO 45891
A “botanical drug substance” or “BDS” is defined in the Guidance for Industry Botanical
Drug Products Draft Guidance, August 2000, US Department of Health and Human Services,
Food and Drug Administration Centre for Drug Evaluation and Research as: “A drug derived
from one or more plants, algae, or microscopic fungi. It is prepared from botanical raw materials
by one or more of the following processes: pulverisation, decoction, expression, aqueous
extraction, ethanolic extraction or other r ses.” A botanical drug nce does not
e a highly purified or chemically modified substance derived from natural sources. Thus,
in the case of cannabis, BDS derived from cannabis plants do not include highly purified
Pharmacopoeial grade cannabinoids.
[0046] In the present ion a BDS is considered to have two components: the
phytocannabinoid-containing component and the non-phytocannabinoid containing component.
Preferably the phytocannabinoid-containing component is the larger ent comprising
greater than 50% (w/w) of the total BDS and the non-phytocannabinoid containing component
is the smaller component comprising less than 50% (w/w) of the total BDS.
[0047] The amount of phytocannabinoid-containing component in the BDS may be greater
than 55%, through 60%, 65%, 70%, 75%, 80% to 85% or more of the total extract. The actual
amount is likely to depend on the starting material used and the method of extraction used.
The “principle phytocannabinoid” in a BDS is the phytocannabinoid that is present in an
amount that is higher than that of the other phytocannabinoids. Preferably the ple
phytocannabinoid is present in an amount greater than 40% (w/w) of the total extract. More
preferably the principle phytocannabinoid is present in an amount greater than 50% (w/w) of the
total extract. More ably still the principle phytocannabinoid is present in an amount greater
than 60% (w/w) of the total t.
The amount of the principle phytocannabinoid in the BDS is preferably greater than
50% of the phytocannabinoid-containing fraction, more preferably still greater than 55% of the
phytocannabinoid-containing fraction, and more preferably still greater than 60% through 65%,
70%, 75%, 80%, 85%, 90% and 95% of the annabinoid-containing fraction.
The “secondary phytocannabinoid/s” in a BDS is the phytocannabinoid/s that is / are
t in significant proportions. ably the secondary phytocannabinoid is present in an
amount greater than 5% (w/w) of the total extract, more preferably greater than 10% (w/w) of
the total extract, more preferably still greater than 15% (w/w) of the total extract. Some BDS’s
will have two or more secondary phytocannabinoids that are present in icant amounts.
r not all BDS’s will have a secondary phytocannabinoid.
The “minor phytocannabinoid/s” in a BDS can be described as the remainder of all the
phytocannabinoid components once the principle and secondary phytocannabinoids are
accounted for. Preferably the minor phytocannabinoids are present in total in an amount of less
than 5% (w/w) of the total extract, and most ably the minor phytocannabinoid is present in
an amount less than 2% (w/w) of the total extract.
The term “absent” or “substantially absent” refers to less than 1%, preferably less than
0.5%, more preferably still less than 0.3%, most preferably less than 0.1% (w/w) of total extract.
The term “consisting essentially of” is limited to the phytocannabinoids which are
specified, it does not exclude non-cannabinoid ents that may also be present.
Typically the non-phytocannabinoid containing component of the BDS comprises
terpenes, sterols, triglycerides, alkanes, nes, tocopherols and carotenoids.
[0055] These compounds may play an important role in the pharmacology of the BDS either
alone or in combination with the phytocannabinoid.
The “terpene fraction” may be of significance and can be broken down by the type of
terpene: monoterpene or sesquiterpene. These terpene components can be further defined in a
similar manner to the cannabinoids.
[0057] The amount of non-phytocannabinoid containing component in the BDS may be less
than 45%, h 40%, 35%, 30%, 25%, 20% to 15% or less of the total extract. The actual
amount is likely to depend on the starting material used and the method of extraction used.
The “principle rpene/s” in a BDS is the monoterpene that is present in an
amount that is higher than that of the other monoterpenes. Preferably the principle
monoterpene/s is present in an amount greater than 20% (w/w) of the total e content.
More preferably the principle monoterpene is present in an amount greater than 30% (w/w) of
the total terpene t, more preferably still greater than 40% (w/w) of the total terpene
content, and more preferably still greater than 50% (w/w) of the total terpene content. The
principle monoterpene is preferably a myrcene or pinene. In some cases there may be two
principle monoterpenes. Where this is the case the ple rpenes are preferably a
pinene and / or a myrcene.
The “principle sesquiterpene” in a BDS is the sesquiterpene that is t in an
amount that is higher than all the other sesquiterpenes. Preferably the principle sesquiterpene
is present in an amount r than 20% (w/w) of the total terpene content, more preferably
still greater than 30% (w/w) of the total terpene content. The principle sesquiterpene is
preferably a caryophyllene and / or a humulene.
The sesquiterpene components may have a “secondary sesquiterpene”. The
secondary sesquiterpene is ably a , which is preferably present at an amount
greater than 5% (w/w) of the total terpene content, more preferably the secondary
2012/052284
sesquiterpene is present at an amount greater than 10% (w/w) of the total terpene content.
The secondary sesquiterpene is preferably a humulene which is preferably present at
an amount greater than 5% (w/w) of the total terpene content, more preferably the secondary
terpene is present at an amount greater than 10% (w/w) of the total terpene content.
atively botanical extracts may be prepared by introducing isolated
phytocannabinoids or their synthetic equivalent into a non-cannabinoid plant fraction as can be
obtained from a zero cannabinoid plant or one or more non-cannabinoid components found in
the cannabis plant such as es.
The structures of the phytocannabinoids CBDV, CBD, CBCV, CBC, THCV and THC
are as shown below:
Cannabidivarin
Cannabidiol
Cannabichromene propyl variant
Cannabichromene
Tetrahydrocannabivarin
THC Tetrahydrocannabinol
Phytocannabinoids can be found as either the neutral (decarboxylated form) or the
carboxylic acid form depending on the method used to extract the cannabinoids. For example it
is known that heating the carboxylic acid form will cause most of the carboxylic acid form to
oxylate into the neutral form.
Where a synthetic phytocannabinoid is used the term is intended to include
compounds, metabolites or derivatives thereof, and pharmaceutically acceptable salts of such
compounds.
The term “pharmaceutically acceptable salts” refers to salts or esters prepared from
pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and
organic bases or acids, as would be well known to s skilled in the art. Many suitable
inorganic and organic bases are known in the art.
Phytocannabinoids can occur as either the pentyl (5 carbon atoms) or propyl (3 carbon
atoms) variant. Initially it was thought that the propyl and pentyl variants would have similar
properties, however recent research suggests this is not true. For example the
phytocannabinoid THC is known to be a CB1 receptor agonist whereas the propyl t THCV
has been discovered to be a CB1 receptor nist meaning that it has almost opposite
effects. This is confirmed by Pertwee (2000) in Cannabinoid receptor ligands: clinical and
neuropharmacological erations relevant to future drug ery and development,
It is an object of the present invention to identify compositions which are safe and
efficacious for use in the treatment of neurological conditions, characterized by hyper-
excitability of the central nervous , convulsions or seizures such as occur in epilepsy.
Indeed, a major drawback with ng standard anti-epileptic drugs ) is that
30% are refractory to existing treatments and there are also notable motor side effects in the
existing ies. Thus it is desirable to use compounds or combinations which reduce or are
absent of such side effects.
BRIEF SUMMARY OF THE DISCLOSURE
In accordance with a first aspect of the present invention there is provided a
composition comprising or consisting essentially of the phytocannabinoids cannabidivarin
(CBDV) and idiol (CBD).
Preferably the composition further comprising one or more excipients.
Preferably the ition r comprises at least one non-cannabinoid component
of cannabis. More preferably the at least one non-cannabinoid component of cannabis is or
comprises a terpene.
With reference to terpenes it should be noted that terpenes can be fied further into
monoterpenes or sesquiterpenes. Common monoterpenes found in is include myrcene
and pinene and common sesquiterpenes found in cannabis include caryophyllenes and
humulene.
Preferably the composition comprises or ts essentially of CBDV, CBD and one or
more cannabichromene type nds. More preferably the one or more cannabichromene
type compounds is cannabichromene propyl variant (CBCV) and / or cannabichromene (CBC).
ably the composition is absent or substantially absent of any other cannabinoids.
More preferably the composition is absent or substantially absent of the cannabinoids
tetrahydrocannabivarin (THCV) and / or tetrahydrocannabinol (THC).
In particular the composition should comprise less than 0.3% (w/w) THC.
[0077] Preferably the composition comprises or ts essentially of the cannabinoids CBDV
and CBD in a ratio of from 7:1 to 1:2 (CBDV:CBD). More preferably the CBDV and CBD are
present in a ratio of from 5:1 to 1:1 (CBDV:CBD). More preferably still the CBDV and CBD are
present in a ratio of 4.5:1 to 2:1 (CBDV:CBD).
Preferably the composition is packaged for delivery in a unit dosage form. More
preferably the unit dosage form comprises from 500 to 2000 mg CBDV and from 100 to 600 mg
CBD.
A “unit dose” is herein defined as a maximum dose of medication that can be taken at
any one time or within a specified dosage period such as for example, 4 hours.
In a further ment of the present invention the composition further comprises a
standard anti-epileptic drug (SAED).
A standard pileptic drug is a medicament with anti-convulsant activity that is or has
been used in the treatment of epilepsy.
In accordance with a second aspect of the present invention there is provided an t
or BDS comprising the phytocannabinoids CBDV and CBD but substantially absent of the
cannabinoids THCV and THC.
The cannabinoids THCV and THC may not desirable components of a composition for
use in the ent of sy for several reasons. In the case of THCV the fact that this
phytocannabinoid is a known CB1 receptor antagonist gives rise to questions over the
riateness of THCV for use in the treatment of epilepsy, particularly when one considers
the ce provided by Deshpande et al. that CB1 antagonists may be pro-convulsant and
may give rise to suicidal tendencies. In the case of THC it is not clearly known whether THC is
a pro- or anti-convulsant, however it is widely acknowledged that some of the side effects
caused by THC, such as psychosis and anxiety, are ularly undesirable.
Preferably the extract or BDS further comprises one or more non-cannabinoid
component(s).
In accordance with a third aspect of the present invention there is provided a
combination of the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) for use in
the treatment of neurological conditions, characterised by hyper-excitability of the central
nervous system, convulsions or seizures.
Preferably the combination of the the neurological condition is epilepsy. More preferably
the type of epilepsy to be treated is generalised seizure.
[0087] Preferably the combination of the phytocannabinoids cannabidivarin (CBDV) and
cannabidiol (CBD) r comprises a standard pileptic drug (SAED).
Preferably the combination of the phytocannabinoids CBDV and CBD are absent or
substantially absent of any other inoids. More preferably the composition is absent or
substantially absent of the cannabinoids tetrahydrocannabivarin (THCV) and / or
tetrahydrocannabinol (THC).
In accordance with a fourth aspect of the present invention there is provided the use of
a combination of the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) in the
manufacture of a medicament for use in the treatment of neurological conditions, terised
by hyper-excitability of the l s system, convulsions or seizures.
[0090] Preferably the medicament is absent or substantially absent of any other inoids.
More preferably the ition is absent or substantially absent of the cannabinoids
tetrahydrocannabivarin (THCV) and / or tetrahydrocannabinol (THC).
In accordance with a fifth aspect of the present invention there is provided a method for
the treatment of neurological conditions, characterised by hyper-excitability of the central
2012/052284
s system, convulsions or seizures, which comprises stering to a subject in need
f a therapeutically effective amount of a combination of the phytocannabinoids
idivarin (CBDV) and cannabidiol (CBD).
Preferably the therapeutically ive amount of a combination of the
phytocannabinoids cannabidivarin (CBDV) and idiol (CBD) is absent or substantially
absent of any other cannabinoids. More preferably the composition is absent or substantially
absent of the cannabinoids tetrahydrocannabivarin (THCV) and / or tetrahydrocannabinol
(THC).
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments of the invention are further described hereinafter with reference to the
accompanying drawings, in which
Figure 1 shows the maximum seizure severity of the CBDV (-/-) BDS in the PTZ model
of epilepsy;
Figure 2 shows the percentage mortality of the CBDV (-/-) BDS in the PTZ model of
epilepsy;
Figure 3 shows the percentage of animals that were seizure free in the CBDV (-/-) BDS
in the PTZ model of epilepsy;
[0097] Figure 4 shows the latency to seizure onset in the CBDV (-/-) BDS in the PTZ model of
epilepsy; and
Figure 5 shows the percentage of animals that experienced tonic-clonic seizures in the
CBDV (-/-) BDS in the PTZ model of epilepsy.
The CBDV (-/-) BDS is used to designate a CBDV BDS from which THCV and THC
have been selectively removed.
DETAILED DESCRIPTION
] Example 1 below describes the use of a CBDV botanical drug substance (BDS) from
which the cannabinoids THCV and THC have been selectively removed, hereinafter CBDV (-/-)
BDS. The PTZ model of generalized seizures in epilepsy was used to determine the anti-
convulsant activity of the test article.
Example 1
Use of a composition comprising CBDV and CBD in the PTZ model of generalised
seizures
Methodology:
Animals:
Male Wistar rats (P24-29; 75-1 109) were used to assess the combined effect of a
composition comprising the phytocannabinoids CBDV and CBD in the PTZ model of
generalised seizures. Animals were habituated to the test environment, cages, ion
ol and handling prior to experimentation. Animals were housed in a room at 21°C on a 12
hour light: dark cycle (lights on 0900) in 50% humidity, with free access to food and water.
] The human dose equivalent (HED) can be estimated using the following formula:
HED = Animal dose (mg/kg) multiplied by Animal Km
Human Km
The Km for a rat is 6 and the Km for a human is 37.
Thus, for a human of approx 60Kg a 200mg/Kg dose in rat would equate to a human daily dose
of about 2000mg.
Composition
A composition was ed using a CBDV botanical drug substance (BDS) that had
been further prepared by centrifugal partition chromatography to remove the cannabinoids
THCV and THC, such that the inoids consisted essentially of CBDV and CBD, and
lesser amounts of CBCV and CBC. This BDS is termed CBDV (-/-) BDS for the e of this
application.
Experimental setup:
Five 6L Perspex tanks with lids were placed on a single bench with dividers between
them. -circuit television (CCTV) cameras were d onto the dividers to observe rat
behaviour. Sony Topica CCD cameras (Bluecherry, USA) were linked via BNC cables to a low-
noise PC via Brooktree digital capture cards (Bluecherry, USA). Zoneminder
(http://www.zoneminder.com) software was used to monitor rats, start and end recordings and
manage video files. ln-house Linux scripts were used to encode video files into a suitable
format for further offline analysis using The Observer (Noldus Technologies).
PTZ model:
] A range of doses of PTZ (50-100mg/kg body weight) were used to determine the best
dose for induction of seizures. As a result, a dose of 85mg/kg injected intra-peritoneally (IP;
stock solution l in 0.9% saline) were used to screen the CBDV (-/-) BDS test article.
Experimental Protocols:
On the day of testing, the CBDV (-/-) BDS was administered via intra-peritoneal (i.p.)
injection at doses of 50, 100, 200, 275 and 346 mg/kg alongside animals that were injected with
a matched volume of the cannabinoid e (2:1:17 ethanol : Cremophor : saline), which
served as the negative control group, (giving defined doses of CBDV and CBD as set out in
Table 1.1 below). Animals were then observed for 1 hour, after which time they received an IP
ion of 85mg/kg PTZ. Negative vehicle controls were performed in parallel with
cannabinoid-dosed ts. After receiving a dose of PTZ, animals were observed and
videoed to determine the severity of seizure and latency to l seizure behaviour types (see
in vivo analysis, below). Animals were filmed for half an hour after last sign of seizure, and then
returned to their cage.
Dose :
[00107] Table 1.1 below demonstrates the respective content of the cannabinoids CBDV and
CBD in the different dose groups of the CBDV (-/-) BDS.
Table 1.1:
Dose group Ratio
CBDV content CBD content
amount of test CBD)
(mg/kg) (mg/kg)
article)
—--—
In vivo analysis:
] Animals were observed during experimental procedures, but all analysis was
performed offline on recorded video files using The Observer behavioural analysis software
(Noldus, Netherlands). A seizure severity scoring system was used to determine the levels of
seizure experienced by subjects (Pohl & Mares, 1987). All signs of seizure were detailed for all
Table 1.2 Seizure severity g scale, d from Pohl & Mares, 1987.
Seizure score Behavioural expression Righting reflex
0 No changes to behaviour ved
0.5 Abnormal behaviour (sniffing, excessive g, Preserved
orientation)
1 Isolated myoclonic jerks Preserved
2 Atypical clonic seizure Preserved
3 Fully developed bilateral forelimb clonus Preserved
4 clonic seizure with suppressed tonic phase Lost
6 Death
Latency from injection of PTZ to specific indicators of seizure development:
The latency (in seconds) from injection of PTZ to first myoclonicjerk (FMJ; score of 1),
and to the animal attaining “forelimb clonus with tonic component and body twist” (score of 3.5)
were recorded. FMJ is an indicator of the onset of seizure activity, whilst >90% of animals
developed scores of 3.5, and so is a good marker of the development of more severe seizures.
Data are presented as the mean i S.E.M. within an experimental group.
Maximum seizure severity:
This is given as the median value for each experimental group based on the scoring
scale below.
Percentage mortality:
[00111] The tage of animals within an experimental group that died as a result of PTZ-
induced es. Note that the majority of animals that developed tonic-clonic seizures (scores
of 4 and 5) died as a result, and that a score of 6 (death) automatically denotes that the animal
also experienced tonic-clonic seizures.
Seizure duration:
[00112] The time (in seconds) from the first sign of seizure (typically FMJ) to either the last sign
of seizure or, in the case of subjects that died, the time of death — separated into s that
survived and those that did not. This is given as the mean i S.E.M. for each experimental
group.
Statistics:
For measures of latency and severity, one way analysis of ce (ANOVA) was
performed on all the groups together in order to detect overall effects of the test e (pS0.05
considered significant), and is denoted by a ‘*’ in the figures.
Significant ANOVA results were followed by post hoc tests to test differences between
e and drug groups (Tukey’s test, pS0.05 considered significant), and is denoted by a ‘*’ in
the figures.
Results:
[00115] Figure 1 illustrates the m seizure ty, a significant effect of the CBDV (-/-)
BDS on the maximum seizure severity was observed at a dose of 275mg/kg CBDV (-/-) BDS.
Figure 2 illustrates the percentage mortality of the animals dosed with the CBDV (-/-)
BDS. As can be observed the animals given the, 200 and 275 mg/kg CBDV (-/-) BDS had a
strongly statistical significance and the animals given the highest dose (346 mg/kg CBDV (-/-)
BDS had a less statistical significance but still resulted in a decrease in the percentage
mortality.
] Figure 3 illustrates that although no significant effect of the CBDV (-/-) BDS was
observed on the percentage of animals that were seizure free, the 275 mg/kg dose resulted in
% of the s becoming seizure free.
[00118] Figure 4 illustrates the latency to seizure onset was statistically increased in all of the
high dose groups (200, 275 and 346 mg/kg) of the CBDV (-/-) BDS.
Figure 5 illustrates the percentage of animals that experienced the severe tonic-clonic
seizures decreased in the higher dose groups (200, 275 and 346 mg/kg) of the CBDV (-/-)
BDS; however the decrease was not tically significant.
Conclusion:
From the above data it would appear that the CBDV (-/-) BDS composition will
reduce seizure severity and mortality and increase y to onset of seizures, making it a
desirable ition for use in the treatment of epilepsy.
The omission of the cannabinoids THCV and THC from a BDS further obviates
concerns associated with CB1 antagonism and psychosis.
Example 2
Analysis of CBDV (-I-) BDS
The CBDV (-/-) BDS which was used in e 1 above can be obtained using
centrifugal partition chromatography (CPC) of a CBDV (+/+) BDS.
A CBDV (-/-) BDS has been produced and analysed as described in Table 2.1 below:
Table 2.1 CBDV (-I-) BDS amount in total and range
Amount Range Range Range
CBDV (-/-) BDS
(% wlw) (1 10%) (1 25%) (1 50%)
CBDVA 0.14 0.13—0.15 0.11 —0.18 0.07—0.21
CBDV 37.07 — 45.31 30.89 — 51.49 20.60 — 61.79
CBDA 0.07 0.06—0.08 0.05—0.09 0.04—0.11
CBG 0.59 0.53 — 0.65 0.44 — 0.74 0.30 — 0.89
CBD 17.70 15.93 — 19.47 8.85 — 26.55
CBCV 4.35 3.92—4.79 3.26 — 5.44 2.18—6.53
CBDV (related .42 1.65 — 2.75 1.10—3.30
substances) 2.20
CBC 0.93 0.84— 1.02 0.70— 1.16 0.47— 1.40
Total Cannabinoids 67.17
Total Non-cannabinoids
The total phytocannabinoid containing fraction of CBDV (-/-) BDS comprises
approximately 41% of the total BDS. According to variation this on may vary by 1 10% up
to i 50%.
Table 2.2 Cannabidivarin (-l-) BDS by percentage cannabinoid
Amount
CBDV (-I-) BDS
(% of total cannabinoid)
CBDV (related
substances) 3.60
The amount of the principle phytocannabinoid in the CBDV (-/-) BDS as a percentage
of the phytocannabinoid containing fraction is approximately 61%. According to variation this
fraction may vary by i 10% up to i 50%.
In this Example it is intended that references be made to the ple or secondary
components ndently of the ‘other’ cannabinoids.
Comparative Example 3
CBDV (+l+) BDS analysis
[00127] The following example is included to provide details of the components of the CBDV
(+/+) BDS. The CBDV (+/+) BDS was obtained by subcritical C02 extraction. It comprises, as
well as CBDV, the cannabinoids CBD, THCV and THC in significant quantities (each greater
than 1% by weight as a percentage of total cannabinoid content). THC has been ascribed a
nvulsant and it can also have marked psychoactive s in addition to other side
effects such as anxiety which are not desired. THCV whilst showing anti-convulsant ty
specific to lized seizures in epilepsy is a CB1 antagonist and following evidence to
suggest that the CB1 antagonist rimonabant may cause epilepsy and other undesired effects it
may be desirable to remove these cannabinoids from a BDS whilst still retaining the non-
cannabinoid component(s) which may contribute to the activity of the BDS.
[00128] A CBDV (+l+) BDS can be obtained from extraction of CBDV-rich plants. Such
chemovars are bred specifically to produce a icant proportion of their cannabinoids as
CBDV.
The CBDV chemotype results from the breeding of plants which carry both postulated
BD and APR genes.
[00130] The BB gene ct the plants to synthesize the cyclic part of the CBD molecule and
the APR gene instructs the plant to synthesize this molecule with a propyl side chain, as
d to the usual pentyl chain found in CBD.
A CBDV chemovar has been bred and the BDS analysed as described in Table 3.1
below:
Table 3.1 CBDV (+l+) BDS amount in total and range
2012/052284
Range Range Range
CBDV (+l+) BDS Amount
(% wlw) (1 10%) (1 25%) (1 50%)
CBDVA 0.14 0.13—0.15 0.11 —0.18 0.07—0.21
CBDV 37.07 — 45.31 30.89 — 51.49 20.60 — 61.79
CBDA 0.07 0.06—0.08 0.05—0.09 0.04—0.11
CBG 0.59 0.53 — 0.65 0.44 — 0.74 0.30 — 0.89
CBD 17.70 15.93 — 19.47 13.28 — 22.13 8.85 — 26.55
THCV 3.06 2.75—6.12 2.30—3.83 1.53—4.59
CBCV 4.35 .79 3.26—5.44 2.18—6.53
_|I O 0.88 0.79—0.97 0.66— 1.10 0.44— 1.32
CBDV (related 1.98—2.42 1.65—2.75 1.10—3.30
substances) 2.20
OB0 0.93 0.84— 1.02 0.70— 1.16 0.47— 1.40
Total Cannabinoids 71.11
Total Non-cannabinoids 28.89
The total phytocannabinoid ning fraction of CBDV (+/+) BDS comprises
approximately 41% of the total BDS. According to variation this fraction may vary by 1 10% up
to i 50%.
Table 3.2 CBDV (+l+) BDS by percentage cannabinoid
Amount
CBDV (+l+) BDS
(% of total cannabinoid)
_—substances) 3.09
The amount of the principle phytocannabinoid in the CBDV (+/+) BDS as a percentage
of the phytocannabinoid containing fraction is approximately 58%. According to variation this
on may vary by i 10% up to i 50%.
In this Example it is intended that references be made to the principle or secondary
ents independently of the ‘other’ inoids.
Comparative Example 4
Non-cannabinoid profile of a high phytocannabinoid containing plant
[00135] This comparative Example is ed to demonstrate a typical terpene profile obtained
from a cannabis plant that has been bred to produce a high quantity of cannabinoids.
The nnabinoid components of a phytocannabinoid BDS may play an ant
role in the BDS’s pharmacology. As such the terpene profile is classified below. The following
tables rate the terpene profile of a CBD chemovar which is representative of a high
phytocannabinoid containing plant. Five plants were freshly harvested and extracted using
steam distillation. The principle monoterpene and sesquiterpene are highlighted in bold.
Table 4.1 Monoterpene amount by percentage of total terpene fraction and ranges
Amount Range Range Range
Monoterpenes (% 0f (1 10%) (i 25%) (i 50%)
terpene
Pinene (alpha & beta) 10.56 9.50 — 11.62 7.92 — 13.20 5.28 — 15.84
The monoterpene containing fraction comprises approximately 52-64% (w/w) of the
total terpene fraction.
Table 4.2 Monoterpene amount by percentage of monoterpenes
Amount
Monoterpenes (% 0f
monoterpene
fraction)
Pinene (alpha & beta) 18.14
Beta-ocimene 6.94
The amount of the principle monoterpene myrcene in the rpene fraction as a
percentage of the monoterpene fraction is imately 61-75% (w/w). The monoterpene
fraction also has a secondary monoterpene pinene which is present at approximately 16.3-20%
(w/w) of the monoterpene fraction.
Table 4.3 Sesquiterpene amount by percentage of total terpene fraction and ranges
Amount Range Range Range
Sesquiterpenes (% of (i 10%) (i 25%) (i 50%)
terpene
fraction)
Caryophyllenes (t & oxide) 29.27 14.64—43.91
Bergotamene 0.18 0.16 — 0.20 0.14 — 0.23 0.09 — 0.27
Humulene 7.97 7.17 — 8.77 5.98 — 9.96 3.99 — 11.96
endrene 0.33 0.30 — 0.36 0.25 — 0.41 0.17 — 0.50
Selinene 0.59 0.53 — 0.65 0.44 — 0.74 0.30 — 0.89
Anon 0.44 0.40 — 0.48 0.33 — 0.55 0.22 — 0.66
Farnesene (Z,E & alpha) 1.55 1.40 — 1.71 1.16 — 1.94 0.78 —2.33
alpha Gurjunene 0.12 0.11 — 0.13 0.09 — 0.15 0.06 — 0.18
Bisabolene 0.39 0.35 — 0.43 0.29 — 0.49 0.20 — 0.59
Nerolidol 0.43 0.39 — 0.47 0.32 — 0.54 0.22 — 0.65
Diepicedreneoxide 0.38 0.34 — 0.42 0.29 — 0.48 0.19 — 0.57
Alpha-Bisabolol 0.16 0.14 — 0.18 0.12 — 0.20 0.08 — 0.24
Total 41.80
] The sesquiterpene containing fraction comprises approximately 27-32% (w/w) of the
total terpene fraction.
Table 4.4 terpene amount by percentage of sesquiterpenes
Amount
Sesquiterpenes (% 0f
sesquiterpene
fraction)
Caryophyllenes (t & oxide) 70.02
Bergotamene 0.43
Humulene 19.07
Aromadendrene 0.79
Selinene 1.41
Anon 1.05
Farnesene (Z,E & alpha) 3.71
alpha Gurjunene 0.29
Bisabolene 0.93
Nerolidol 1.03
Diepicedreneoxide 0.91
Alpha-Bisabolol 0.38
Comparative Example 5
Non-cannabinoid profile of a ‘zero cannabinoid’ plant
This comparative e describes the terpene profile of a different cannabis plant to
that described on e 4 above and is reproduced here for comparative purposes.
Patent ation number PCT/GBZOO8/001837 describes the production of a ‘zero
cannabinoid’ plant. These plants were produced by selective breeding to produce a Cannabis
sativa L plant that contained a generally qualitatively similar terpene e as a Cannabis
sativa L plant that produced inoids yet it was devoid of any cannabinoids. These plants
can be used to produce cannabinoid-free plant extracts which are useful control plants in
experiments and al trials. A breakdown of the terpene profile produced in the plants can be
found in the table below. The primary rpenes and sesquiterpene are highlighted in bold.
Table 5.1 Monoterpene amount by percentage of total terpene fraction and ranges
Amount Range Range Range
Monoterpenes (% 0f (1 10%) (i 25%) (i 50%)
terpene
fraction)
Pinene (alpha & beta) m 26.41 — 32.27 22.01 — 36.68 14.67 — 44.01
Myrcene m21.95 — 36.58 14.63 — 43.89
Limonene 4.79 — 5.85 3.99 — 6.65 2.66 — 7.98
Linalol 4.05 — 4.95 3.38 — 5.63 2.25 — 6.75
Verbenol (cis & trans) 3.11 — 3.80 2.59 — 4.31 1.73 — 5.18
Total 71.87
The monoterpene containing fraction comprises approximately 65-79% (w/w) of the
total terpene fraction.
Table 5.2 Monoterpene amount by percentage of monoterpenes
Amount
Monoterpenes (41 0f
monoterpene
fraction)
Pinene (alpha & beta)
Myrcene
Limonene
Linalol
Table 5.3 Sesquiterpene amount by percentage of total terpene fraction and ranges
Amount Range Range Range
terpenes (% 0f (1 10%) (i 25%) (i 50%)
terpene
fraction)
Caryophyllenes (t & oxide) 10.89 9.80 — 11.98 8.17 — 13.61
Bergotamene 2.51 2.26 — 2.76 1.88 — 3.14 1.26 — 3.77
Farnesene (Z,E & alpha) 3.43 3.09 — 3.77 2.57 — 4.29 1.72 — 5.15
Humulene (& epoxide II) 5.04 4.54 — 5.54 3.78 — 6.30 2.52 — 7.56
delta guaiene 2.40 2.16 — 2.64 1.80 — 3.00 1.20 — 3.60
Bisabolene 3.85 3.47 — 4.24 2.89 — 4.81 1.93 — 5.78
Total
The sesquiterpene containing fraction comprises imately 25-31% (w/w) of the
total terpene fraction.
Table 5.4 Sesquiterpene amount by percentage of sesquiterpenes
Amount
Sesquiterpenes (°/_° 0f
erpene
Caryophyllenes (t & oxide) 38.73
Farnesene (Z,E & alpha)
Humulene (& epOXIde ll)
delta guaIene
The amount of the principle sesquiterpene caryophylene in the sesquiterpene fraction
as a percentage of the sesquiterpene fraction is approximately 35-43% (w/w). The
sesquiterpene on also has a secondary sesquiterpene humulene which is present at
approximately 16-20% (w/w) of the sesquiterpene fraction.
Comparative Example 6
Use of CBDV (+l+) BDS in the PTZ model of generalised es
This comparative e was previously presented in GB1005364.3 (unpublished)
patent ation and is included here for representative purposes.
Methodology as described in Example 1.
CBDV (+/+) BDS was administered at four doses that yielded a dose of CBDV of 50
and 100 mg/kg. Table 6.1 below details the data obtained.
Table 5.1
CBDV (+l+) BDS Mortality (%)
(mg/k9)
0 26.3
16.7
] As can be seen the CBDV (+/+) BDS exhibited a trend to decrease seizure-related
mortality.
References
ALGER, B. E. (2006) Not too excited? Thank your endocannabinoids. Neuron, 51, 393-5.
AMES FR. (1986) Anticonvulsant effect of cannabidiol. South African Medical Journal 69:14.
AVOLI, M., LOUVEL, J., PUMAIN, R. & KOHLING, R. (2005) Cellular and molecular
mechanisms of epilepsy in the human brain. Prog Neurobiol.
BOSTANCI, M. O. & BAGIRICI, F. (2006) The effects of octanol on penicillin induced
epileptiform activity in rats: an in vivo study. Epilepsy Res, 71, 188-94.
BRUST, J. C., NG, S. K., HAUSER, A. W. & SUSSER, M. (1992) Marijuana use and the risk of
new onset seizures. Trans Am Clin ClimatolAssoc, 103, .
CONSROE, P.F., WOOD, G.C. & BUCHSBAUM, H. (1975) Anticonvulsant Nature of Marihuana
Smoking. J.American MedicalAssociation 234 306-307
CUNHA, J. M., CARLINI, E. A., PEREIRA, A. E., RAMOS, O. L., EL, C., GAGLIARDI,
R., SANVITO, W. L., LANDER, N. & MECHOULAM, R. (1980) Chronic administration of
cannabidiol to y volunteers and epileptic patients. Pharmacology, 21, .
DAVIS, M. |., RONESI, J. & LOVINGER, D. M. (2003) A Predominant Role for Inhibition of the
Adenylate Cyclase/Protein Kinase A Pathway in ERK Activation by Cannabinoid Receptor 1 in
N1E-115 Neuroblastoma Cells. J.Biol. Chem, 278, 48973-48980.
DREIFUSS, F. E., BANCAUD, J., HENRIKSEN, O., RUBIO-DONNADIEU, F.PENRY, J. K. &
SEINO, M. (1981) Proposal for revised clinical and electroencephalographic fication of
epileptic seizures. Epilepsia, 22, 489-501.
FERDINAND, R. F., VAN DER ENDE, J., BONGERS, I., SELTEN, J. P., K, A. &
VERHULST, F. C. (2005) Cannabis--psychosis pathway independent of other types of
psychopathology. Schizophr Res, 79, 289-95.
FISHER, R. S., VICKREY, B. G., GIBSON, P., HERMANN, B., PENOVICH, P., R, A.
& WALKER, S. (2000) The impact of epilepsy from the patient's perspective I. Descriptions and
subjective perceptions. Epilepsy Res, 41, 39-51.
GASTAUT, H. (1970) Clinical and Electroencephalographical fication of Epileptic
Seizures. Epilepsia, 11, 102-112.
LUTZ, B. (2004) On-demand activation of the endocannabinoid system in the control of
neuronal excitability and epileptiform seizures. Biochem col, 68, 1691-8.
MACKIE, K. (2006) Cannabinoid receptors as eutic targets. Annu Rev Pharmacol
Toxicol, 46, 101-22.
MCCORMICK, D. A. & RAS, D. (2001) On the ar and network bases of epileptic
seizures. Annu Rev Physiol, 63, 815-46.
MERLIS, J. K. (1970) Proposal for an International Classification of the Epilepsies. Epilepsia,
11, 114-119.
NG et al. (1990) t drug use and the risk of new-onset seizures, American Journal of
Epidemiology 132: 47-57.
OBAY, B. D., TASDEMIR, E., TUMER, C., BILGIN, H. M. & SERMET, A. (2007) Antiepileptic
40 s of ghrelin on pentylenetetrazole-induced seizures in rats. Peptides, 28, .
PEREIRA, M. B., S, R. L., ASSIS, M. A., SILVA, R. F., ES, M. M., FREITAS,
R. M. & TAKAHASHI, R. N. (2007) Study pharmacologic of the GABAergic and glutamatergic
drugs on seizures and status ticus induced by pilocarpine in adult Wistar rats. Neurosci
Lett, 419, 253-7.
E R. G., (2000) inoid receptor ligands: clinical and neuropharmacological
considerations, relevant to future drug discovery and development. Exp. Opin. Invest. Drugs
9(7).-
RAUCA, c., WISWEDEL, |., ZERBE, R., KEILHOFF, G. & KRUG, M. (2004) The role of
superoxide dismutase and alpha-tocopherol in the development of seizures and ng
induced by pentylenetetrazol - influence of the radical scavenger phenyl-N-tert-butyl
nitrone. Brain Res, 1009, 203-12.
SANDER, J. W. (2003) The epidemiology of epilepsy ted. Curr Opin Neurol, 16, 165-70.
SWANN, J. W. (2004) The effects of seizures on the connectivity and circuitry of the developing
brain. Ment Retard Dev Disabil Res Rev, 10, 96-100.
TREMBLY B. SHERMAN M. (1990) Double-blind clinical study of cannabidiol as a secondary
anticonvulsant. Marijuana ’90 International ence on Cannabis and Cannabinoids.
Kolympari, Crete, July 8-11, 1990.
WINGERCHUK, D. (2004) Cannabis for medical purposes: cultivating science, weeding out the
fiction. Lancet, 364, 315-6.
26—NDU-22113 16:46 FROM HGF MPINCHESTER TEI EF'D MUNICH P.Ei4/|Zl'?
PCT/GB 2012/052 284 — 26—11—2013
Claims (5)
- CLAIMS 1. A ition comprising the phytocannabinoids cannabidivarin (CBDV) and cannabidicl (CED). abSent of the cannabinoids tetrahydrocannabivarin (THCV) and tetrahydrocannabinol (THC). for use in the treatment of epilepsy.
- 2. A composition as claimed in claim 1, wherein the epilepsy to be treated is generalised seizure.
- 3. A composition as claimed in claim 1 or claim 2, further comprising one or more excipients.
- 4. A composition as claimed in any of the ing claims. which further comprises at least one non—cannabinoid component of cannabis.
- 5. A composition as claimed in claim 4. wherein the at least one non-cannabinoid ent of cannabis is or ses a terpene. B. A composition as d in any of the ing claims. wherein the phytocannabinoids comprise. or consist essentially of CBDV. CBD and one or more cannabichromene type compounds. 7'. A composition as claimed in claim 6, n the one or more cannabichromene type compounds is nnnabichromene propyl variant (CBCV) and I or cannaoichrornene (CBC). 8. A composition as claimed in any of the preceding claims. wherein the CEDV and GED are present in a ratio of from 7:1 to 1:2 CBD)_ 9. A composition as claimed in claim 8, wherein the CBDV and GED are present in a ratio of from 5.1 to 1:1 (CBDV:CBD). 10. A composition as claimed in claim 8 or claim 9. wherein the CBDV and GED are present in a ratio of 4.5:1 to 2:1 (CBDV:CBD). 11. A unit dose of a composition as claimed in any of the preceding claims, comprising from 500 to 2000 mg CBDV. 12. A unit dose of a composition as claimed in claim 11. comprising trom 100 to 600 mg CBD. Duration: 26.11 .2013 17:31 :17 - 2013 17:32:53. This page 4 of 7 1AM EN DED SH EET317;32;16 Received at the EPO on Nov 26, 2013 17:32:53. Page 4 of 7 26—Nov—2213 16:46 FRDM HEF MRNCHESTER To EPD MUNICH ? PCT/GB
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1116789.7A GB2495118B (en) | 2011-09-29 | 2011-09-29 | A pharmaceutical composition comprising the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) |
GB1116789.7 | 2011-09-29 | ||
PCT/GB2012/052284 WO2013045891A1 (en) | 2011-09-29 | 2012-09-14 | A pharmaceutical composition comprising the phytocannabinoids cannabidivarin (cbdv) and cannabidiol (cbd) |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ622424A NZ622424A (en) | 2015-10-30 |
NZ622424B2 true NZ622424B2 (en) | 2016-02-02 |
Family
ID=
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