Use Of Cannabidiol In The Treatment Of Epilepsy

  • Published: Jan 12, 2017
  • Earliest Priority: Jun 17 2014
  • Family: 37
  • Cited Works: 0
  • Cited by: 0
  • Cites: 0
  • Additional Info: Full text
This following text has been automatically extracted from the original PDF supplied by the patent office.  Please refer to the original PDF document to view the text in its original format.
AU 2015275887 A1
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) 
(19) World Intellectual Property 
Organization 
International Bureau 
(10) International Publication Number 
(43) International Publication Date W O 2015/193668 A1 
23 December 2015 (23.12.2015) W I P 0 I P C T 
(51) International Patent Classification: Comprehensive Epilepsy Center, 223 East 34th Street, 
A61K31/05 (2006.01) A61K31/496 (2006.01) New York, New York NY 10016 (US). SCHILLER, 
A61K31/195 (2006.01) A61K31/53 (2006.01) Dominic; Equipped 4 (IP) Limited, 47 Hamilton Square, 
A61K 31/20 (2006.01) A61K31/551 (2006.01) Birkenhead Merseyside CH41 5AR (GB).  
A61K31/27(2006.01) A61K31/5513 (2006.01) (74) Agent: HGF LIMITED; 4th Floor, Merchant Exchange, A61K 31/352 (2006.01) A61K 31/5517(2006.01) 17-19 Whitworth Street West, Manchester M1 5WG (GB).  A61K31/4015 (2006.01) A61K31/7048 (2006.01) 
A61K31/4166 (2006.01) A61P 25/10 (2006.01) (81) Designated States (unless otherwise indicated, for every 
A61K 31/423 (2006.01) kind of national protection available): AE, AG, AL, AM, 
(21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 
PCT/GB2015/051776 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 
DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, 
(22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 
17 June 2015 (17.06.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 
(25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 
(26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 
TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.  
(30) Priority Data: 
1410771.8 17 June 2014 (17.06.2014) GB (84) Designated States (unless otherwise indicated, for every 
kind of regional protection available): ARIPO (BW, GH, (71) Applicant: GW PHARMA LIMITED [GB/GB]; Sover- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 
eign House, Vision Park, Chivers Way, Histon, Cambridge TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 
Cambridgeshire CB24 9BZ (GB). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 
(72) Inventors: GUY, Geoffrey; GW Pharma Limited, Sover- DK, EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 
eign House, Vision Park, Chivers Way, Histon Cambridge LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 
Cambridgeshire CB24 9BZ (GB). WRIGHT, Stephen; SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 
GW Pharma Limited, Sovereign House, Vision Park, GW, KM, ML, MR, NE, SN, TD, TG).  
Chivers Way, Histon Cambridge Cambridgeshire CB24 Declarations under Rule 4.17: 
9BZ (GB). MEAD, Alice; GW Pharma Limited, Sovereign 
House, Vision Park, Chivers Way, Histon Cambridge Cam- - of inventorship (Rule 4.17(iv)) 
bridgeshire CB24 9BZ (GB). CHEETHAM, Emma; GW Published: 
Pharma Limited, Sovereign House, Vision Park, Chivers 
Way, Histon Cambridge Cambridgeshire CB24 9BZ (GB). with international search report (Art. 21(3)) 
DEVINSKY, Orrin; Department of Neurology, NYU 
(54) Title: USE OF CANNABIDIOL IN THE TREATMENT OF EPILEPSY 
(57) Abstract: The present disclosurerelates to the use of cannabidiol (CBD) in the treatment of absence seizures. In particular, the 
f4 disclosure relates to the use of CBD for reducing absence seizures in patients suffering withetiologies that include: Lennox-Gastaut 
Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; CDKL5; Dup15q;, Jeavons syndrome; Myoclonic 
Absence Epilepsy;Neuronal ceroid lipofuscinoses(NCL) and brain abnormalities. The disclosure further relates to the use of CBD in 
combination with one or more anti-epileptic drugs (AEDs).

WO 2015/193668 PCT/GB2015/051776 
1 
USE OF CANNABIDIOL IN THE TREATMENT OF EPILEPSY 
FIELD OF THE INVENTION 
[0001] The present invention relates to the use of cannabidiol (CBD) in the treatment of 
absence seizures. In one embodiment the patients suffering from absence seizures are 
children and young adults. CBD appears particularly effective in reducing absence seizures in 
patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis 
Complex; Dravet Syndrome; Doose Syndrome; CDKL5; Dupl5q; , Jeavons syndrome; 
Myoclonic Absence Epilepsy; Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities in 
comparison to other seizure types.  
[0002] Significantly CBD proved very effective in treating a sub-type of absence seizures, 
namely myoclonic absence seizures. The etiologies of patients which suffer from myoclonic 
absence seizures include Doose Syndrome, Jeavons syndrome and Myoclonic Absence 
Epilepsy syndrome.  
[0003] In these patients treatment with CBD reduced the occurrence of absence seizures 
or myoclonic absence seizures by greater than 50% in a large proportion of patients, 64% and 
75% respectively. This was surprising given that the proportion of patients benefitting from a 
greater than 50% reduction in total seizures was significantly less, (46%), in all subjects 
treated.  
[0004] Preferably the CBD used is in the form of a highly purified extract of cannabis such 
that the CBD is present at greater than 98% of the total extract (w/w) and the other 
components of the extract are characterised. In particular the cannabinoid 
tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% 
(w/w) and the propyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts of up to 
1%. Alternatively, the CBD may be a synthetically produced CBD.  
[0005] In use the CBD may be used concomitantly with one or more other anti-epileptic 
drugs (AED). When used in combination with another AED the CBD may be formulated for 
administration separately, sequentially or simultaneously with the one or more AED or the 
combination may be provided in a single dosage form. Where the CBD is formulated for 
administration separately, sequentially or simultaneously it may be provided as a kit or together 
with instructions to administer the one or more components in the manner indicated. It may 
also be used as the sole medication, i.e. as a monotherapy.

WO 2015/193668 PCT/GB2015/051776 
2 
BACKGROUND TO THE INVENTION 
[0006] Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 
2011) of which 70% are able to adequately control their symptoms with the available existing 
anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie et al., 2012), are unable 
to obtain seizure freedom from the AED that are available and as such are termed as suffering 
from intractable or "treatment-resistant epilepsy" (TRE).  
[0007] Intractable or treatment-resistant epilepsy was defined in 2009 by the International 
League Against Epilepsy (I LAE) as "failure of adequate trials of two tolerated and appropriately 
chosen and used AED schedules (whether as monotherapies or in combination) to achieve 
sustained seizure freedom" (Kwan et al., 2009).  
[0008] Individuals who develop epilepsy during the first few years of life are often difficult 
to treat and as such are often termed treatment-resistant. Children who undergo frequent 
seizures in childhood are often left with neurological damage which can cause cognitive, 
behavioral and motor delays.  
[0009] Childhood epilepsy is a relatively common neurological disorder in children and 
young adults with a prevalence of approximately 700 per 100,000. This is twice the number of 
epileptic adults per population.  
[0010] When a child or young adult presents with a seizure, investigations are normally 
undertaken in order to investigate the cause. Childhood epilepsy can be caused by many 
different syndromes and genetic mutations and as such diagnosis for these children may take 
some time.  
[0011] The main symptom of epilepsy is repeated seizures. In order to determine the type 
of epilepsy or the epileptic syndrome that a patient is suffering from, an investigation into the 
type of seizures that the patient is experiencing is undertaken. Clinical observations and 
electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified 
according to the ILAE classification described below and in Figure 1.  
[0012] The International classification of seizure types proposed by the ILAE was adopted 
in 1981 and a revised proposal was published by the ILAE in 2010 and has not yet 
superseded the 1981 classification. Figure 1 is adapted from the 2010 proposal for revised 
terminology and includes the proposed changes to replace the terminology of partial with focal.  
In addition the term "simple partial seizure" has been replaced by the term "focal seizure where 
awareness / responsiveness is not impaired" and the term "complex partial seizure" has been 
replaced by the term "focal seizure where awareness / consciousness is impaired".  
[0013] From Figure 1 it can be seen that Generalised seizures, where the seizure arises 
within and rapidly engages bilaterally distributed networks, can be split into six subtypes:

WO 2015/193668 PCT/GB2015/051776 
3 
Tonic-Clonic (grand mal) seizures; Absence (petit mal) Seizures; Clonic Seizures; Tonic 
Seizures; Atonic Seizures and Myoclonic Seizures.  
[0014] Focal (partial) seizures where the seizure originates within networks limited to only 
one hemisphere, are also split into sub-categories. Here the seizure is characterized according 
to one or more features of the seizure, including aura, motor, autonomic and awareness / 
responsiveness. Where a seizure begins as a localized seizure and rapidly evolves to be 
distributed within bilateral networks this seizure is known as a Bilateral convulsive seizure, 
which is the proposed terminology to replace Secondary Generalised Seizures (generalized 
seizures that have evolved from focal seizures and are no longer remain localized).  
[0015] Absence seizures can occur as Typical absence seizures; Atypical absence 
seizures or Absence seizures with special features such as Myoclonic absence and Eyelid 
myoclonia.  
[0016] Typical absence seizures are generalized seizures with a sudden onset and offset 
of altered awareness. The altered awareness can vary in severity dependent on the specific 
syndrome that the patient is suffering from. Clonic movements of the eyelids, head, eyebrows, 
chin perioral or other facial parts can occur, whereas myoclonus of limbs only occurs rarely. In 
addition, absence status epilepticus can also occur.  
[0017] Atypical absence seizures have a less sudden onset and offset of loss of 
awareness than occurs in typical absence seizures. They are associates with other features 
such as loss of muscle tone of the head, trunk or limbs and subtle myoclonic jerks. A loss of 
awareness is usually minimal.  
[0018] Myoclonic absence seizures present with bilateral rhythmic myoclonic jerks of the 
shoulders and arms. There is tonic abduction which results in progressive lifting of the arms 
during the seizure. Seizures last between 10 and 60 seconds and there may be a complete 
loss of awareness.  
[0019] Eyelid myoclonia are absence seizures which are accompanied by brief repetitive 
myoclonic jerks of the eyelids with simultaneous upward deviation of the eyeballs and 
extension of the head. Seizures are typically brief and multiple seizures can occur on a daily 
basis. Awareness is mostly retained.  
[0020] Absence seizures may occur in epilepsy syndromes including: Lennox-Gastaut 
Syndrome; Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet Syndrome; 
Doose Syndrome; CDKL5; Dupl5q; Jeavons Syndrome; Myoclonic Absence Epilepsy; 
Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities.  
[0021] Epileptic syndromes often present with many different types of seizure and 
identifying the types of seizure that a patient is suffering from is important as many of the

WO 2015/193668 PCT/GB2015/051776 
4 
standard AED's are targeted to treat or are only effective against a given seizure type / sub
type.  
[0022] The first line treatment for absence seizures usually comprises a broad spectrum 
AED, such as sodium valproate, lamotrigine or ethosuximide. A combination of these 
medicaments may be required in order to treat absence seizures.  
[0023] Common AED defined by their mechanisms of action are described in the following 
tables: 
[0024] Table 1. Examples of narrow spectrum AED 
Narrow-spectrum AED Mechanism Indication 
Phenytoin Sodium channel Complex partial 
Tonic-clonic 
Phenobarbital GABA / Calcium channel Partial seizures 
Tonic-clonic 
Carbamazepine Sodium channel Partial seizures 
Tonic-clonic 
Mixed seizures 
Oxcarbazepine Sodium channel Partial seizures 
Tonic-clonic 
Mixed seizures 
Gabapentin Calcium channel Partial seizures 
Mixed seizures 
Pregabalin Calcium channel Adjunct therapy for partial 
seizures with or without 
secondary generalisation 
Lacosamide Sodium channel Adjunct therapy for partial 
seizures 
Vigabatrin GABA Secondarily generalized 
tonic-clonic seizures 
Partial seizures 
Infantile spasms due to West 
syndrome

WO 2015/193668 PCT/GB2015/051776 
[0025] Table 2. Examples of broad spectrum AED 
Broad-spectrum AED Mechanism Indication 
Valproic acid GABA / Sodium channel First-line treatment for tonic
clonic seizures, absence 
seizures and myoclonic 
seizures 
Second-line treatment for 
partial seizures and infantile 
spasms.  
Intravenous use in status 
epilepticus 
Lamotrigine Sodium channel Partial seizures 
Tonic-clonic 
Seizures associated with 
Lennox-Gastaut syndrome 
Ethosuximide Calcium channel Absence seizures 
Topiramate GABA / Sodium channel Seizures associated with 
Lennox-Gastaut syndrome 
Zonisamide GABA / Calcium /Sodium Adjunctive therapy in adults 
channel with partial-onset seizures 
Infantile spasm 
Mixed seizure 
Lennox-Gastaut syndrome 
Myoclonic 
Generalised tonic-clonic 
seizure 
Levetiracetam Calcium channel Partial seizures 
Adjunctive therapy for partial, 
myoclonic and tonic-clonic 
seizures 
Clonazepam GABA Typical and atypical absences 
Infantile myoclonic

WO 2015/193668 PCT/GB2015/051776 
6 
Myoclonic seizures 
Akinetic seizures 
Rufinamide Sodium channel Adjunctive treatment of partial 
seizures associated with 
Lennox-Gastaut syndrome 
[0026] Table 3. Examples of AED used specifically in childhood epilepsy 
AED Mechanism Indication 
Clobazam GABA Adjunctive therapy in complex 
partial seizures 
Status epilepticus 
Myoclonic 
Myoclonic-absent 
Simple partial 
Complex partial 
Absence seizures 
Lennox-Gastaut syndrome 
Stiripentol GABA Severe myoclonic epilepsy in 
infancy (Dravet syndrome) 
[0027] From these tables it can be seen that the three AED that are used as first line 
treatments for absence seizures, namely: sodium valproate, lamotrigine or ethosuximide are 
GABA/sodium channel, sodium channel and calcium channel drugs respectively.  
[0028] It can also be seen from these tables that other AED are approved for use in 
absence seizures, these include clonazepam and clobazam, both of which work by a GABA 
mechanism.  
[0029] Over the past forty years there have been a number of animal studies on the use 
of the non-psychoactive cannabinoid cannabidiol (CBD) to treat seizures. For example, 
Consroe et al., (1982) determined that CBD was able to prevent seizures in mice after 
administration of pro-convulsant drugs or an electric current.  
[0030] Studies in epileptic adults have also occurred in the past forty years with CBD.  
Cunha et al. reported that administration of CBD to eight adult patients with generalized 
epilepsy resulted in a marked reduction of seizures in 4 of the patients (Cunha et al., 1980).

WO 2015/193668 PCT/GB2015/051776 
7 
[0031] A study in 1978 provided 200 mg/day of pure CBD to four adult patients, two of the 
four patients became seizure free, whereas in the remainder seizure frequency was 
unchanged (Mechoulam and Carlini, 1978).  
[0032] In contrast to the studies described above, an open label study reported that 200 
mg / day of pure CBD was ineffective in controlling seizures in twelve institutionalized adult 
patients (Ames and Cridland, 1986).  
[0033] In the past forty years of research there have been over thirty drugs approved for 
the treatment of epilepsy none of which are cannabinoids. Indeed, there appears to have been 
a prejudice against cannabinoids, possibly due to the scheduled nature of these compounds 
and / or the fact that THC, which is a known psychoactive, has been ascribed as a pro
convulsant (Consroe et al., 1977).  
[0034] A paper published recently suggested that cannabidiol-enriched cannabis may be 
efficacious in the treatment of epilepsy. Porter and Jacobson (2013) report on a parent survey 
conducted via a Facebook group which explored the use of cannabis which was enriched with 
CBD in children with treatment-resistant epilepsy. It was found that sixteen of the 19 parents 
surveyed reported an improvement in their child's epilepsy. The children surveyed for this 
paper were all taking cannabis that was purported to contain CBD in a high concentration 
although the amount of CBD present and the other constituents including THC were not known 
for many of the cases. Indeed, whilst CBD levels ranged from 0.5 to 28.6 mg/kg/day (in those 
extracts tested), THC levels as high as 0.8 mg/kg/day were reported.  
[0035] Providing children with TRE with a cannabis extract that comprises THC, which has 
been described as a pro-convulsant (Consroe et al., 1977), at a potentially psychoactive dose 
of 0.8 mg/kg/day, is a concern and as such there is a need to determine whether CBD is in fact 
efficacious.  
[0036] In November 2013 the company GW Pharmaceuticals made a press release to 
state that they were intending to treat Dravet Syndrome with CBD as it had received orphan 
drug designation.  
[0037] To date there have been no controlled trials of CBD in children and young adults 
with intractable epilepsy.  
BRIEF SUMMARY OF THE DISCLOSURE 
[0038] In accordance with a first aspect of the present invention there is provided 
cannabidiol (CED) for use in the treatment of epilepsy, wherein the epilepsy is characterised 
by absence seizures.  
[0039] In one embodiment the epilepsy is a childhood epilepsy.

WO 2015/193668 PCT/GB2015/051776 
8 
[0040] In one embodiment the absence seizures are myoclonic absence seizures.  
[0041] Surprisingly, the CBD has been shown to be particularly effective in subjects with 
epilepsy which is treatment-resistant.  
[0042] In a further embodiment the CBD is for use in combination with one or more 
concomitant anti-epileptic drugs (AED).  
[0043] Preferably the absence seizures to be treated are in patients diagnosed with: 
Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet 
Syndrome; Doose Syndrome; Jeavons Syndrome; CDKL5; Dupl5q; Neuronal ceroid 
lipofuscinoses (NCL) and brain abnormalities.  
[0044] Most preferably the treatment-resistant epilepsy is one of: Lennox-Gastaut 
Syndrome; Dravet Syndrome and Myoclonic Absence Epilepsy.  
[0045] In a further embodiment the CBD is present as a highly purified extract of cannabis 
which comprises at least 98% (w/w) CBD. Preferably the extract comprises less than 0.15% 
THC. More preferably the extract further comprises up to 1% CBDV.  
[0046] In an alternative embodiment the CBD is present as a synthetic compound.  
[0047] In a further embodiment of the invention the one or more AED is selected from the 
group consisting of: clobazam, clonazepam, clorazepate, desmethylclobazam, diazepam, 
ethosuximide, felbamate, gabapentin, ketogenic diet, lacosamide, lamotrigine, levetiracetam, 
lorazepam, midazolam, N-desmethylclobazam, nordiazepam, phenytoin, stiripentol, 
topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.  
[0048] Preferably the one or more AED is selected from the group consisting of sodium 
valproate; lamotrigine; ethosuximide; clobazam and clonazepam.  
[0049] Preferably the number of different anti-epileptic drugs that are used in combination 
with the CBD is reduced. Alternatively the dose of anti-epileptic drugs that are used in 
combination with the CBD is reduced.  
[0050] There are many side effects associated with the commonly used AED which 
include dizziness, blurred vision, nausea, respiratory system depression, tiredness, 
headaches, and other motor side effects on the central nervous system. These side effects are 
particularly common as higher doses or combinations of numerous AED are used. As such 
there is a need for an alternative medication that is able to reduce the numbers of seizures 
whilst at the same time exhibiting a safe side effect profile.  
[0051] Preferably the dose of CBD is greater than 5 mg/kg/day. Thus for a 15 kg patient a 
dose of greater than 75mg of CBD per day would be provided. Doses greater than 5mg/kg/day

WO 2015/193668 PCT/GB2015/051776 
9 
such as greater than 10/mg/kg/day, greater than 15 mg/kg/day, greater than 20mg/kg/day and 
greater than 25 mg/kg/day are also envisaged to be effective.  
[0052] Preferably the epilepsy is childhood epilepsy.  
[0053] In accordance with a second aspect of the present invention there is provided a 
method of treating epilepsy comprising administering cannabidiol (CBD) to a subject, wherein 
the epilepsy is characterised by absence seizures.  
[0054] Preferably the subject is a human, typically a patient that is suffering from epilepsy 
characterised by absence seizures.  
[0055] In accordance with a third aspect of the present invention there is provided a 
composition for use in the treatment of epilepsy characterised by absence seizures comprising 
cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavouring.  
[0056] Preferably the solvent is sesame oil, the co-solvent is ethanol, the sweetener is 
sucralose, the flavouring is strawberry flavour and the CBD is present at a concentration of 
between 25/mg/ml and 100 mg/ml, namely 50mg/ml and 75 mg/ml.  
[0057] More preferably the composition comprises cannabidiol (CBD) at a concentration of 
between 25 to 100 mg/ml, ethanol at a concentration of 79 mg/ml, sucralose at a concentration 
of 0.5 mg/ml, strawberry flavouring at a concentration of 0.2 mg/ml and sesame oil q.s. to 
1.0ml.  
[0058] It is envisaged that the composition be administered as an oral liquid solution.  
Other modes of administration including solids, semi-solids, gels, sprays, aerosols, inhalers, 
vaporisers, enemas and suppositories are alternative administration forms. Such medicaments 
could be administered via the oral, buccal, sublingual, respiratory, nasal and distal rectum 
route.  
DEFINITIONS 
[0059] Definitions of some of the terms used to describe the invention are detailed below: 
[0060] The cannabinoids described in the present application are listed below along with their 
standard abbreviations.  
Table 4. Cannabinoids and their abbreviations

WO 2015/193668 PCT/GB2015/051776 
CBD Cannabidiol 
OH 
CBDA Cannabidiolic acid 
CBDVA Cannabidivarin d 
OH H 
CBDVA Cannabidivarinicai 
HH 
THC Tetrahydrocannabinol 
[0061] The table above is not exhaustive and merely details the cannabinoids which are 
identified in the present application for reference. So far over 60 different cannabinoids have 
been identified and these cannabinoids can be split into different groups as follows: 
Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel 
cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).  
[0062] "Phytocannabinoids" are cannabinoids that originate from nature and can be found in 
the cannabis plant. The phytocannabinoids can be isolated from plants to produce a highly 
purified extract or can be reproduced synthetically.

WO 2015/193668 PCT/GB2015/051776 
11 
[0063] "Highly purified cannabinoid extracts" are defined as cannabinoids that have been 
extracted from the cannabis plant and purified to the extent that other cannabinoids and non
cannabinoid components that are co-extracted with the cannabinoids have been substantially 
removed, such that the highly purified cannabinoid is greater than or equal to 98% (w/w) pure.  
[0064] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid-like 
structure and are manufactured using chemical means rather than by the plant.  
[0065] Phytocannabinoids can be obtained 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 
decarboxylate into the neutral form.  
[0066] "Treatment-resistant epilepsy" (TRE) or "intractable epilepsy" is defined as per the 
ILAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more 
AED.  
[0067] "Childhood epilepsy" refers to the many different syndromes and genetic mutations 
that can occur to cause epilepsy in childhood. Examples of some of these are as follows: 
Dravet Syndrome; Myoclonic-Absence Epilepsy; Lennox-Gastaut syndrome; Generalized 
Epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria; 
Dupl5q; SNAP25; and febrile infection related epilepsy syndrome (FIRES); benign rolandic 
epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau-Kleffner 
syndrome. The list above is non-exhaustive as many different childhood epilepsies exist.  
[0068] "Absence Seizures" are defined as a generalised type of epileptic seizure which 
causes a loss of awareness often accompanied by myoclonic jerks.  
[0069] "Myoclonic Absence Seizures" are defined as a sub-type of absence seizures which 
present with bilateral myoclonic jerks of the arms and shoulders.  
[0070] "Mixed seizures" are defined as the existence of both generalised and focal seizures 
in the same patient.  
[0071] The terms "50% responder" and "50% reduction in seizure" are both terms used in 
clinical studies. In the present application the terms define the percentage of subjects that 
experienced a greater than or equal to 50% reduction in the number of seizures during 
treatment with CBD in comparison to the number experienced during the baseline period 
before the CBD was administered.

WO 2015/193668 PCT/GB2015/051776 
12 
DETAILED DESCRIPTION 
PREPARATION OF HIGHLY PURIFIED CBD EXTRACT 
[0072] The following describes the production of the highly-purified (>98% w/w) 
cannabidiol extract which has a known and constant composition which was used for the 
expanded access trials described in the Examples below.  
[0073] In summary the drug substance used in the trials is a liquid carbon dioxide extract 
of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a 
solvent crystallization method to yield CBD. The crystallisation process specifically removes 
other cannabinoids and plant components to yield greater than 98% CBD.  
[0074] The Cannabis sativa L. plants are grown, harvested, and processed to produce a 
botanical extract (intermediate) and then purified by crystallization to yield the CBD (drug 
substance).  
[0075] The plant starting material is referred to as Botanical Raw Material (BRM); the 
botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, 
the drug substance.  
[0076] Both the botanical starting material and the botanical extract are controlled by 
specifications. The drug substance specification is described in Table 5 below.  
Table 5. CBD Specification 
Test Test Method Limits 
Appearance Visual Off-white / pale yellow crystals 
Identification A HPLC-UV Retention time of major peak 
corresponds to certified CBD 
Reference Standard 
Identification B GC-FID/MS Retention time and mass spectrum 
of major peak corresponds to 
certified CBD Reference Standard 
Identification C FT-IR Conforms to reference spectrum for 
certified CBD Reference Standard 
Identification D Melting Point 65 - 670 C 
Identification E Specific Optical Conforms with certified CBD 
Rotation Reference Standard; -1100 to -1400 
(in 95% ethanol) 
Total Purity Calculation > 98.0% 
Chromatographic Purity HPLC-UV > 98.0% 
1 
Chromatographic Purity GC-FID/MS > 98.0 % 
2 
Other Cannabinoids: HPLC-UV 
- CBDA

WO 2015/193668 PCT/GB2015/051776 
13 
Test Test Method Limits 
- CBDV NMT 0.15% w/w 
- A9 THC NMT 1.0% w/w 
- CBD-C4 NMT 0.15% w/w 
NMT 0.5% w/w 
Residual Solvents: GC 
- Alkane NMT 0.5% w/w 
- Ethanol NMT 0.5% w/w 
Residual Water Karl Fischer NMT 1.0% w/w 
NMT- Not more than 
[0077] The purity of the CBD drug substance achieved is greater than 98%. The other 
cannabinoids which may occur in the extract are: CBDA, CBDV, CBD-C4 and THC.  
[0078] Distinct chemotypes of Cannabis sativa L. plant have been produced to maximize 
the output of the specific chemical constituents, the cannabinoids. One type of plant produces 
predominantly CBD. Only the (-)-trans isomer occurs naturally. Furthermore during purification 
the stereochemistry of CBD is not affected.  
Production of the Intermediate 
[0079] An overview of the steps to produce a botanical extract, the intermediate, are as 
follows: 
1. Growing 
2. Decarboxylation 
3. Extraction No.1 - using liquid C02 
4. Extraction No.2 - 'winterization' using ethanol 
5. Filtration 
6. Evaporation 
[0080] High CBD chemovars were grown, harvested and dried and stored in a dry room 
until required. The botanical raw material (BRM) was finely chopped using an Apex mill fitted 
with a 1mm screen. The milled BRM was stored in a freezer for up to 3 months prior to 
extraction.  
[0081] Decarboxylation of CBDA to CBD was carried out using a large Heraeus tray oven.  
The decarboxylation batch size in the Heraeus is approximately 15 Kg. Trays were placed in 
the oven and heated to 1050C; the BRM took 96.25 minutes to reach 105 *C. Held at 1050C for 
Minutes. Oven then set to 1500 C.; the BRM took 75.7 minutes to reach 150*C; BRM held at 
1500C for 130 Minutes. Total time in the oven was 380 Minutes, including 45 minutes cooling 
and 15 Minutes venting.  
[0082] Extraction No 1 was performed using liquid CO 2 at 60 bar / 100 C to produce 
botanical drug substance (BDS).

WO 2015/193668 PCT/GB2015/051776 
14 
[0083] The crude CBD BDS was winterised in Extraction No 2 under standard conditions 
(2 volumes of ethanol at minus 20'C for around 50 hours). The precipitated waxes were 
removed by filtration and the solvent evaporated using the rotary evaporator (water bath up to 
600C) to yield the BDS, which was then used for crystallisation to produce the test material..  
Production of the Drug Substance 
[0084] The manufacturing steps to produce the drug substance from the intermediate 
botanical extract are as follows: 
1. Crystallization using C5-C12 straight chain or branched alkane 
2. Filtration 
3. Optional recrystallization from C5-C12 straight chain or branched alkane 
4. Vacuum drying 
[0085] Intermediate botanical extract (12kg) produced using the methodology above was 
dispersed in C5-C12 straight chain or branched alkane (9000 ml, 0.75 vols) in a 30 litre 
stainless steel vessel.  
[0086] The mixture was manually agitated to break up any lumps and the sealed container 
then placed in a freezer for approximately 48 hours.  
[0087] The crystals were isolated by vacuum filtration, washed with aliquots of cold C5
C12 straight chain or branched alkane (total 12000 ml), and dried under a vacuum of < 10mb 
at a temperature of 600 C until dry before submitting the drug substance for analysis.  
[0088] The dried product was stored in a freezer at minus 20 0C in a pharmaceutical grade 
stainless steel container, with FDA food grade approved silicone seal and clamps.  
Production of the Drug Product 
[0089] The drug product is presented as an oral solution. The oral solution presentation 
contains 25mg/ml or 100mg/ml CBD, with the excipients sesame oil, ethanol, sweetener and 
flavouring. Two product strengths are available to allow dose titration across a wide dose 
range.  
[0090] The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at 
higher doses.  
[0091] The drug product formulation is as described in Table 6 below: 
Table 6. Drug Product specification 
Component Qualitative Function Reference to 
Composition Quality Standard 
Cannabidiol (CBD) 25 mg/ml or 100 mg/ml Active In-house

WO 2015/193668 PCT/GB2015/051776 
Anhydrous ethanol 79.0 mg/ml* Excipient Ph.Eur.  
Sucralose 0.5 mg/ml Sweetener In-house 
Strawberry 0.2 mg/ml Flavouring In-house 
flavouring 
Sesame oil q.s to 1.0 ml Excipient Ph.Eur.  
[0092] The drug substance, CBD is insoluble in water. Sesame oil was selected as an 
excipient to solubilize the drug substance.  
[0093] A sweetener and fruit flavouring are required to improve palatability of the sesame 
oil solution.  
[0094] Ethanol was required to solubilize the sweetener and the flavouring.  
[0095] The composition can be substantially equivalent, by which is meant the functional 
ingredients can vary from the qualitative composition specified in Table 6 by an amount of up 
to 10%.  
[0096] Example 1 below describes the use of a highly purified cannabis extract comprising 
cannabidiol (CED). Cannabidiol is the most abundant non-psychoactive cannabinoid in the 
selected chemovar. Previous studies in animals have demonstrated that CBD has 
anticonvulsant efficacy in multiple species and models.  
[0097] Example 1 describes data produced in an expanded access treatment program in 
children with TRE.  
EXAMPLE 1: EFFICACY OF CANNABIDIOL REDUCING ABSENCE SEIZURES IN CHILDREN 
AND YOUNG ADULTS WITH INTRACTABLE EPILEPSY 
Materials and Methods 
[0098] Of 137 children and young adults with severe, childhood onset treatment-resistant 
epilepsy (TRE), forty-two suffered from epilepsy that was characterised by absence seizures.  
These subjects were tested with a highly purified extract of cannabidiol (CED) obtained from a 
cannabis plant. All subjects presented with absence type seizures, often in addition to other 
generalised and / or focal seizures. The participants in the study were part of an expanded 
access compassionate use program for CD.

WO 2015/193668 PCT/GB2015/051776 
16 
[0099] The epileptic syndromes that these patients suffered from were as follows: Lennox
Gastaut Syndrome; Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet 
Syndrome; Doose Syndrome; Jeavons Syndrome; CDKL5; Dupl5q; Neuronal ceroid 
lipofuscinoses (NCL) and brain abnormalities.  
[00100] Seizure types experienced by these patients included: tonic, clonic, tonic-clonic, 
myoclonic, atonic, absence, myoclonic-absence, focal seizures without impairment, focal 
seizures with impairment and focal seizures evolving to bilateral convulsive seizures.  
[00101] All patients entered a baseline period of 4 weeks when parents/caregivers kept 
prospective seizure diaries, noting all countable seizure types.  
[00102] The patients then received a highly purified CBD extract (greater than 98% CBD 
w/w) in sesame oil, of known and constant composition, at a dose of 5 mg/kg/day in addition to 
their baseline anti-epileptic drug (AED) regimen.  
[00103] The daily dose was gradually increased by 2 to 5mg/kg increments until 
intolerance occurred or a maximum dose of 25 mg/kg/day was achieved.  
[00104] Patients were seen at regular intervals of 2-4 weeks. Laboratory testing for 
hematologic, liver, kidney function, and concomitant AED levels was performed at baseline, 
and after every 4 weeks of CBD therapy.  
[00105] The patients on the study were all taking at least one concomitant AED. These 
included clobazam, clonazepam, clorazepate, desmethylclobazam, diazepam, ethosuximide, 
felbamate, gabapentin, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, 
midazolam, N-desmethylclobazam, nordiazepam, phenytoin, stiripentol, topiramate, trazodone, 
vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.  
Results 
[00106] Of the 42 children and young adult patients who received treatment with CBD, 
there were 28 patients who received treatment for at least 12 weeks of treatment all of whom 
suffered from absence type seizures.  
[00107] A summary of the 50% responders, based on 12 weeks of treatment are 
summarized in Table 7 below.  
Table 7. Summary of 50% responders after 12 weeks of treatment 
Absence seizures Total seizures 
(n=28) (n=137) 
> 50% reduction in 64% (n=18) 46% (n=63) 
seizures

WO 2015/193668 PCT/GB2015/051776 
17 
< 50% reduction in 36% (n=10) 54% (n=74) 
seizures 
[00108] Table 7 shows that after 3 months of therapy, a remarkable 64% of patients had an 
equal to or greater than >50% reduction in absence seizures, these data infer that the CBD is 
very effective at reducing this type of seizure.  
Conclusions 
[00109] These data indicate that CBD significantly reduces the number of absence type 
seizures in a high proportion of patients that do not respond well to existing AED.  
[00110] It was surprising that in this group of patients which are treatment-resistant such a 
high number were able to gain an effect. The fact that nearly two thirds of the patients (64%) 
benefitted from at least a fifty percent reduction in the number of absence seizures that they 
suffered from was remarkable.  
EXAMPLE 2: EFFICACY OF CANNABIDIOL REDUCING MYOCLONIC ABSENCE SEIZURES IN 
CHILDREN AND YOUNG ADULTS WITH INTRACTABLE EPILEPSY 
Materials and Methods 
[00111] Of 137 children and young adults with severe, childhood onset treatment-resistant 
epilepsy (TRE), ten suffered from epilepsy that was characterised by myoclonic absence 
seizures. These subjects were tested with a highly purified extract of cannabidiol (CD) 
obtained from a cannabis plant. All subjects presented with myoclonic absence type seizures, 
often in addition to other generalised and / or focal seizures. The participants in the study were 
part of an expanded access compassionate use program for CD.  
[00112] The epileptic syndromes that these patients suffered from were as follows: 
Myoclonic Absence Epilepsy; Doose Syndrome; and epilepsy of unknown cause.  
[00113] All patients entered a baseline period of 4 weeks when parents/caregivers kept 
prospective seizure diaries, noting all countable seizure types.  
[00114] The patients then received a highly purified CBD extract (greater than 98% CBD 
w/w) in sesame oil, of known and constant composition, at a dose of 5 mg/kg/day in addition to 
their baseline anti-epileptic drug (AED) regimen.

WO 2015/193668 PCT/GB2015/051776 
18 
[00115] The daily dose was gradually increased by 2 to 5mg/kg increments until 
intolerance occurred or a maximum dose of 25 mg/kg/day was achieved.  
[00116] Patients were seen at regular intervals of 2-4 weeks. Laboratory testing for 
hematologic, liver, kidney function, and concomitant AED levels was performed at baseline, 
and after every 4 weeks of CBD therapy.  
[00117] The patients on the study were all taking at least one concomitant AED. These 
included clobazam, clonazepam, clorazepate, diazepam, ethosuximide, ketogenic diet, 
lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, and valproic acid.  
Results 
[00118] Of the 10 children and young adult patients who received treatment with CBD, 
there were 8 patients who received treatment for at least 12 weeks of treatment all of whom 
suffered from myoclonic absence type seizures.  
[00119] A summary of the 50% responders, based on 12 weeks of treatment are 
summarized in Table 8 below.  
Table 8. Summary of 50% responders after 12 weeks of treatment 
Myoclonic absence Total seizures 
seizures (n=137) 
(n=10) 
> 50% reduction in 75% (n=6) 46% (n=63) 
seizures 
< 50% reduction in 25% (n=2) 54% (n=74) 
seizures 
[00120] Table 8 shows that after 3 months of therapy, a remarkable 75% of patients had an 
equal to or greater than >50% reduction in absence seizures, these data infer that the CBD is 
very effective at reducing this type of seizure.  
Conclusions 
[00121] These data indicate that CBD significantly reduces the number of myoclonic 
absence seizures in a high proportion of patients that do not respond well to existing AED.  
[00122] It was surprising that in this group of patients which are treatment-resistant such a 
high number were able to gain an effect. The fact that nearly three quarters of the patients 
(75%) benefitted from at least a fifty percent reduction in the number of myoclonic absence 
seizures that they suffered from was remarkable.

WO 2015/193668 PCT/GB2015/051776 
19 
References: 
Ames FR and Cridland S (1986). "Anticonvulsant effects of cannabidiol." S Afr Med J 69:14.  
Consroe P, Martin P, Eisenstein D. (1977). "Anticonvulsant drug antagonism of delta-9
tetrahydrocannabinol induced seizures in rabbits." Res Commun Chem Pathol Pharmacol.  
16:1-13 
Consroe P, Benedicto MA, Leite JR, Carlini EA, Mechoulam R. (1982). "Effects of cannabidiol 
on behavioural seizures caused by convulsant drugs or current in mice." Eur J Pharmaco. 83: 
293-8 
Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimental C, Gagliardi R et al. (1980). "Chronic 
administration of cannabidiol to healthy volunteers and epileptic patient." Pharmacology.  
21:175-85 
Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011 Apr;52 Suppl 2:3-9.  
Eadie, MJ (December 2012). "Shortcomings in the current treatment of epilepsy." Expert 
Review of Neurotherapeutics 12 (12): 1419-27.  
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, Mathern G, Mosh6 SL, Perucca E, 
Wiebe S, French J. (2009) "Definition of drug resistant epilepsy: Consensus proposal by the 
ad hoc Task Force of the ILAE Commission on Therapeutic Strategies." Epilepsia.  
Mechoulam R and Carlini EA (1978). "Toward drugs derived from cannabis." Die 
naturwissenschaften 65:174-9.  
Porter BE, Jacobson C (December 2013). "Report of a parent survey of cannabidiol-enriched 
cannabis use in paediatric treatment resistant epilepsy" Epilepsy Behaviour. 29(3) 574-7 
Thurman, DJ; Beghi, E; Begley, CE; Berg, AT; Buchhalter, JR; Ding, D; Hesdorffer, DC; 
Hauser, WA; Kazis, L; Kobau, R; Kroner, B; Labiner, D; Liow, K; Logroscino, G; Medina, MT; 
Newton, CR; Parko, K; Paschal, A; Preux, PM; Sander, JW; Selassie, A; Theodore, W; 
Tomson, T; Wiebe, S; ILAE Commission on, Epidemiology (September 2011). "Standards for 
epidemiologic studies and surveillance of epilepsy." Epilepsia. 52 Suppl 7: 2-26

WO 2015/193668 PCT/GB2015/051776 
CLAIMS 
1. Cannabidiol (CBD) for use in the treatment of epilepsy, wherein the epilepsy is 
characterised by absence seizures.  
2. CBD for use according to claim 1, wherein the absence seizures are myoclonic 
absence seizures.  
3. Cannabidiol (CBD) for use according to claim 1 or claim 2, wherein the epilepsy is 
treatment-resistant epilepsy (TRE).  
4. CBD for use according to any of the preceding claims, wherein the CBD is for use in 
combination with one or more concomitant anti-epileptic drugs (AED).  
5. CBD for use according to any of the preceding claims, wherein the absence seizures to 
be treated are in subjects diagnosed with: Lennox-Gastaut Syndrome; Myoclonic 
Absence Epilepsy; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; 
Jeavons Syndrome; CDKL5; Dupl5q; Neuronal ceroid lipofuscinoses (NCL) and brain 
abnormalities.  
6. CBD for use according to claim 5, wherein the subject is diagnosed with Lennox
Gastaut Syndrome.  
7. CBD for use according to claim 5, wherein the subject is diagnosed with Dravet 
Syndrome.  
8. CBD for use according to claim 5, wherein the subject is diagnosed with Myoclonic 
Absence Epilepsy.  
9. CBD for use according to any of the preceding claims, wherein the CBD is present as a 
highly purified extract of cannabis which comprises at least 98% (w/w) CBD.  
10. CBD for use according to claim 9 wherein the extract comprises less than 0.15% THC.  
11. CBD for use according to claim 9 or 10 wherein the extract further comprises up to 1% 
CBDV.  
12. CBD for use according to any of the preceding claims, where in the CBD is present as 
a synthetic compound.

WO 2015/193668 PCT/GB2015/051776 
21 
13. CBD for use according to claim 4, wherein the one or more AED is selected from the 
group consisting of: clobazam, clonazepam, clorazepate, desmethylclobazam, 
diazepam, ethosuximide, felbamate, gabapentin, ketogenic diet, lacosamide, 
lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, 
nordiazepam, phenytoin, stiripentol, topiramate, trazodone, vagus nerve stimulation, 
valproic acid, vigabatrin, and zonisamide.  
14. CBD for use according to claim 13, wherein the one or more AED is selected from the 
group consisting of: sodium valproate; lamotrigine; ethosuximide; clobazam; and 
clonazepam.  
15. CBD for use according to any of the preceding claims, wherein the number of different 
anti-epileptic drugs that are used in combination with the CBD is reduced.  
16. CBD for use according to any of the preceding claims, wherein the dose of anti
epileptic drugs that are used in combination with the CBD is reduced.  
17. CBD for use according to any of the preceding claims, wherein the dose of CBD is 
greater than 5 mg/kg/day.  
18. CBD for use according to any of the preceding claims, wherein the epilepsy is 
childhood epilepsy.  
19. A method of treating epilepsy comprising administering cannabidiol (CBD) to a subject, 
wherein the epilepsy is characterised by absence seizures.  
20. A composition for use in the treatment of epilepsy characterised by absence seizures 
comprising cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavouring.  
21. A composition according to claim 20, wherein the solvent is sesame oil.  
22. A composition according to claim 20, wherein the co-solvent is ethanol.  
23. A composition according to claim 20, wherein the sweetener is sucralose.  
24. A composition according to claim 20, wherein the flavouring is strawberry flavour.

WO 2015/193668 PCT/GB2015/051776 
22 
25. A composition according to claim 20, wherein the CBD is present at a concentration of 
between 25/mg/ml and 100 mg/ml.  
26. A composition according to any of claims 14 to 19, which comprises cannabidiol (CBD) 
at a concentration substantially of between 25 to 100 mg/ml, ethanol at a concentration 
substantially of 79 mg/ml, sucralose at a concentration substantially of 0.5 mg/ml, 
strawberry flavouring at a concentration substantially of 0.2 mg/ml and sesame q.s. to 
1.0ml.  

Sign in to the Lens

Feedback