Use of cannabinoids in treatment of epilepsy

Abstract

To provide the use of cannabidiol (CBD) for treatment of atonic seizures.SOLUTION: Specifically, the CBD appears particularly effective in reducing atonic seizures in patients suffering with etiologies that include Lennox-Gastaut syndrome, tuberous sclerosis, Dravet syndrome, Doose syndrome, Aicardi syndrome, CDKL5 and Dup15q in comparison to other seizure types. The disclosure further relates to the use of CBD in combination with one or more anti-epileptic drugs (AEDs).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the use of cannabidiol (CBD) in the treatment of atonic seizures. In one embodiment, patients suffering from atonic seizures are children and young adults. CBD appears to be particularly effective in reducing atonic seizures in patients with etiologies including Lennox-Gastaut syndrome, tuberous sclerosis, Dravet syndrome, Doose syndrome, Aicardi syndrome, CDKL5, and Dup15q, compared to other seizure types.

[0002] In these patients, treatment with CBD reduced the occurrence of atonic seizures by more than 50% in a high proportion, i.e., 63% of patients, which was surprising considering that in all treated subjects, the proportion of patients benefiting from a reduction in the total number of seizures of more than 50% was significantly lower (46%).

[0003] Preferably, the CBD used is in the form of a highly purified cannabis extract in which the CBD is present at more than 98% (w / w) of the total extract and the other components of the extract are characterized below: In particular, the cannabinoid tetrahydrocannabinol (THC) has been substantially removed to a level of 0.15% (w / w) or less, and the propyl analogue of CBD, cannabidivarin (CBDV), is present in an amount of up to 1%. Alternatively, the CBD can be synthetically produced CBD.

[0004] In use, CBD can be given simultaneously with one or more other antiepileptic drugs (AEDs). Alternatively, CBD can be formulated to be administered separately, subsequently, or simultaneously with one or more AEDs, or the combination can be provided in a single dosage form. When CBD is formulated to be administered separately, subsequently, or simultaneously, it can be provided as a kit or with instructions for administration of the component or components in the indicated manner. It can also be used as the sole drug therapy, i.e., as a monotherapy. [Background technology]

[0005] Epilepsy affects approximately 1% of the population worldwide (Thurman et al., 2011), of whom 70% can adequately control their symptoms with available antiepileptic drugs (AEDs). However, 30% of this patient population (Eadie et al., 2012) are unable to achieve seizure freedom with available AEDs and are therefore referred to as suffering from refractory epilepsy, or "treatment-resistant epilepsy" (TRE).

[0006] Refractory, or treatment-resistant, epilepsy is defined by the International League Against Epilepsy (ILAE) as "the absence of two accepted and appropriately selected and used AEDs to achieve sustained freedom from seizures." was defined in 2009 as “failure of an adequate trial of a regimen (whether as monotherapy or in combination)” ( Kwan et al., 2009 ).

[0007] Individuals who develop epilepsy in the first few years of life are often difficult to treat and are therefore often referred to as treatment-resistant. Children who experience frequent seizures during early childhood are often left with neurological disabilities that can cause cognitive, behavioral, and motor delays.

[0008] Infant epilepsy is a relatively common neurological disorder in children and young adults, with an incidence of approximately 700 per 100,000, which is twice the prevalence of adults with epilepsy per population.

[0009] When children and young adults exhibit seizures, tests are usually done to determine the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, so a diagnosis in these children can take some time.

[0010] The main symptom of epilepsy is recurrent seizures. To determine the type of epilepsy or epileptic syndrome a patient suffers from, an examination is performed to determine the type of seizures the patient is experiencing. Clinical observations and electroencephalography (EEG) are performed and the seizure type is classified according to the ILEA classification described below and shown in Figure 1.

[0011] 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, but the 1981 classification has not yet been discarded. Figure 1 has been modified from the 2010 proposal for revised terminology to include the proposed change to replace partial with focal. In addition, the term "simple partial seizures" has been replaced by the term "focal seizures with unimpaired awareness / responsiveness," and the term "complex partial seizures" has been replaced by the term "focal seizures with impaired awareness / responsiveness."

[0012] From Figure 1, it can be seen that generalized seizures, in which seizures arise within a bilaterally distributed network and spread rapidly throughout the network, can be divided into six subtypes: tonic-clonic (grand mal), absence (petit mal), clonic, tonic, atonic, and myoclonic.

[0013] Focal (partial) seizures, where the seizures occur within a network restricted to only one cerebral hemisphere, are also divided into subcategories. In this case, the seizures are characterized according to one or more seizure features, including aura, motor, autonomic, and consciousness / response. If a seizure begins as a focal seizure and rapidly evolves to become distributed within a network on both sides, it is known as a bilateral convulsive seizure. This is the terminology proposed to be replaced by secondary generalized seizures (generalized seizures that evolve from focal seizures and are no longer focal).

[0014] Focal seizures in which the subject's awareness / responsiveness is altered are referred to as focal seizures with impairment, and focal seizures in which the subject's awareness or responsiveness is not impaired are referred to as focal seizures without impairment.

[0015] Atonic attacks involve a loss of muscle tone causing the person to fall. These are sometimes called "fall attacks" and are generally brief (less than 15 seconds). Atonic attacks can occur without warning while standing, sitting, or walking, and the patient often suffers from trauma due to the fall.

[0016] Atonic seizures are often associated with Lennox-Gastaut syndrome, but may also occur or be a symptom of other types of epilepsy syndromes, including tuberous sclerosis complex, Dravet syndrome, Doose syndrome, Aicardi syndrome, CDKL5, and Dup15q.

[0017] It is important to identify the type of seizure a patient suffers from, as epilepsy syndromes often present with many different types of seizures and many standard AEDs are targeted or only effective at treating a given seizure type / subtype.

[0018] One such childhood epilepsy syndrome is Lennox-Gastaut syndrome. Lennox-Gastaut syndrome is a severe form of epilepsy. Seizures generally begin before age 4. The seizure types, which vary among patients, include tonic (rigidity of the body, upward eye roll, dilated pupils, and changes in breathing patterns), atonic (brief loss of muscle tone and sensation, causing sudden falls), atypical absence (staring spells), and myoclonic (sudden muscle jerks) seizures. There may be periods of frequent seizures mixed with brief periods of relative seizure freedom.

[0019] In addition to developmental delay, most children with Lennox-Gastaut syndrome experience some degree of impairment in intellectual functioning and information processing, as well as behavioral problems.

[0020] Lennox-Gastaut syndrome may be caused by brain malformations, perinatal asphyxia, severe head injury, central nervous system infections, and inherited degenerative or metabolic diseases. In 30-35% of cases, no cause can be found.

[0021] First-line treatment for atonic seizures, including those in patients with Lennox-Gastaut syndrome, generally includes broad-spectrum AEDs, such as sodium valproate, often in combination with lamotrigine. Other AEDs that may be considered include rufinamide, felbamate, clobazam, and topiramate.

[0022] AEDs such as carbamezapine, gabapentin, oxcarbazepine, pregabalin, tiagabineor, and vigabatrin are contraindicated in atonic seizures.

[0023] Common AEDs, defined by their mechanism of action, are shown in the table below.

[0024] [Table 1]

[0025] [Table 2]

[0026] [Table 3]

[0027] From these listings we can see that there is only one drug currently approved for the treatment of atonic seizures, namely clonazepam, which works via a GABA mechanism.

[0028] Over the past 40 years, there have been multiple animal and human studies on the use of cannabidiol (CBD), a non-psychoactive cannabinoid, for the treatment of seizures.

[0029] A 1978 study gave four adult patients 200 mg / day of pure CBD. Two of the four patients became seizure-free, while the rest experienced no change in seizure frequency (Mechoulam and Carlini, 1978).

[0030] Cunha et al. reported that administration of CBD to eight adult patients with generalized epilepsy resulted in a significant reduction in seizures in four of the patients (Cunha et al., 1980), and Consroe et al. (1982) determined that CBD could prevent seizures in mice following administration of convulsant drugs or electrical currents.

[0031] In contrast to the above studies, an open-label study reported that 200 mg / day of pure CBD was ineffective in controlling seizures in 12 hospitalized adult patients (Ames and Cridland, 1986).

[0032] All of the above studies focused on treating subjects suffering from generalized epilepsy and did not consider the treatment of specific seizure subtypes.

[0033] More recently, WO 2011 / 001169 describes the use of CBD in the treatment of focal seizures, WO 2012 / 093255 describes the use of CBD in combination with standard antiepileptic drugs in the treatment of epilepsy, and WO 2013 / 045891 describes a composition comprising CBD and CBDV for use in the treatment of epilepsy.

[0034] In November 2013, the company GW Pharmaceuticals issued a press release stating that CBD had received orphan drug designation and that it was intended to treat Dravet syndrome. The company issued a further press release in February 2014 stating that CBD had also received orphan drug designation and that it was intended to treat Lennox-Gastaut syndrome.

[0035] Again, the rationale was to treat a disease different from the type of seizures the subject was experiencing.

[0036] In addition, it has been suggested that CBD-rich cannabis may be effective in treating epilepsy: a case study reported in 2005 showed that a child with Lennox-Gastaut syndrome showed improvement in seizure frequency after treatment with CBD in an oily solution (Pelliccia et al., 2005).

[0037] Porter and Jacobson (2013) reported a parent survey conducted through a Facebook group investigating the use of CBD-rich cannabis for children with treatment-resistant epilepsy. They found that 16 of the 19 parents surveyed reported that their child's epilepsy had improved. The children surveyed in this report had all consumed cannabis purportedly containing high concentrations of CBD, but for many of these cases, the amount of CBD present and the amount of other components, including THC, was unknown. In reality, the CBD levels ranged from 0.5 to 28.6 mg / kg / day (in these extracts tested), while THC levels of around 0.8 mg / kg / day were reported. There is concern that children with TRE were given cannabis extracts containing THC, a convulsant-inducing agent (Consroe et al., 1977), at potentially psychoactive doses of 0.8 mg / kg / day.

[0038] Furthermore, a research paper published in June 2014 described the use of a high-CBD strain for the treatment of patients with Dravet syndrome, stating that the treatment reduced the frequency of their seizures (Maa et al., 2014).

[0039] Literature published after the priority application was filed discloses the use of CBD in the treatment of refractory epilepsy in the treatment of tuberous sclerosis in patients with the onset of focal seizures ( Geffrey et al., 2014 ). Summary of the Invention [Problem to be solved by the invention]

[0040] There has been renewed interest in the potential of cannabis and cannabinoids, including CBD, for the treatment of epilepsy, but to date there is little real-world data demonstrating efficacy in patients.

[0041] The applicant found that CBD was significantly effective in reducing a high proportion of atonic seizures, i.e., in 63% of patients, the occurrence of atonic seizures by more than 50%. In comparison, in all treated subjects, the proportion of patients benefiting from a reduction in the total number of seizures of more than 50% was significantly lower (46%).

[0042] In addition, it is noteworthy that the patients treated were refractory to existing AEDs, making these figures even more remarkable. [Means for solving the problem]

[0043] According to a first aspect of the present invention there is provided a method for treating atonic seizures using cannabidiol ( CBD) will be provided.

[0044] Preferably, the atonic seizures are treatment-resistant.

[0045] Preferably, the atonic seizures are associated with Lennox-Gastaut syndrome, tuberous sclerosis, Dravet syndrome, Doose syndrome, Aicardi syndrome, CDKL5, or Dup15q.

[0046] In one embodiment, CBD is used in combination with one or more concomitant antiepileptic drugs (AEDs).

[0047] In a further embodiment, the CBD is present as a highly purified cannabis extract containing at least 95% (w / w) CBD, more preferably 98% (w / w) CBD. Preferably, the extract contains less than 0.15% THC. More preferably, the extract further contains up to 1% CBDV.

[0048] In an alternative embodiment, the CBD is present as a synthetic compound.

[0049] In further embodiments of the invention, the one or more AEDs are selected from the group consisting of clobazam, clonazepam, levetiracetam, topiramate, stiripentol, phenobarbital, lacosamide, valproic acid, zonisamide, perampanel, and fosphenytoin.

[0050] Preferably, the number of different antiepileptic drugs used in combination with CBD is reduced. Alternatively, the dose of the one or more antiepileptic drugs used in combination with CBD is reduced.

[0051] Preferably, the dose of CBD is greater than 5 mg / kg / day.

[0052] According to a second aspect of the present invention, there is provided a method of treating atonic seizures comprising administering cannabidiol (CBD) to a subject.

[0053] According to a third aspect of the present invention there is provided a composition for use in treating atonic seizures characterised by atonic seizures comprising cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavouring.

[0054] Preferably, the solvent is sesame oil, the co-solvent is ethanol, the sweetener is sucralose, the flavor is strawberry flavor, and the CBD is present in a concentration of 25 mg / ml to 100 mg / ml.

[0055] More preferably, the composition comprises cannabidiol (CBD) in a concentration of 25-100 mg / ml, ethanol in a concentration of 79 mg / ml, sucralose in a concentration of 0.5 mg / ml, strawberry flavoring in a concentration of 0.2 mg / ml, and sesame in an amount up to 1.0 ml.

[0056] definition Definitions of some of the terms used to describe this invention are set out below.

[0057] The cannabinoids mentioned in this application are listed below with their standard abbreviations.

[0058] [Table 4]

[0059] The above table is not exhaustive, but merely details the cannabinoids identified for reference in this application. To date, over 60 different cannabinoids have been identified, which can be divided into different groups: phytocannabinoids, endocannabinoids, and synthetic cannabinoids (which can be novel cannabinoids, or synthetically produced phytocannabinoids or endocannabinoids).

[0060] "Phytocannabinoids" are naturally occurring cannabinoids that can be found in the cannabis plant. Phytocannabinoids can be isolated from the plant to produce highly purified extracts, or they can be synthetically replicated.

[0061] "Highly purified cannabinoids" are those extracted from the cannabis plant and highly purified. "Cannabinoids" is defined as cannabinoids that have been purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed such that the extracted cannabinoids are at least 95% (w / w) pure.

[0062] A "synthetic cannabinoid" is a compound that has the structure of a cannabinoid or a structure similar to a cannabinoid, and is produced using chemical means rather than from the plant.

[0063] Plant cannabinoids can be obtained either in neutral (decarboxylated) or carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will decarboxylate most of the carboxylic acid form to the neutral form.

[0064] "Treatment-resistant epilepsy" (TRE) or "refractory epilepsy" is defined by the 2009 ILAE guidance as epilepsy that is not adequately controlled by a trial of one or more AEDs.

[0065] "Childhood epilepsy" refers to many different syndromes and genetic mutations that may result in childhood epilepsy. Some examples of these are Dravet syndrome, myoclonic-absence epilepsy, Lennox-Gastaut syndrome, generalized seizures of unknown etiology, CDKL5 mutations, Aicardi syndrome, bilateral polymicrogyria, Dup15q, SNAP25, and febrile infection-associated epilepsy syndrome (FIRES), benign rolandic epilepsy, juvenile myoclonic epilepsy, infantile spasms (West syndrome), and Landau-Kleffner syndrome. As there are many different childhood epilepsies, the above list is non-exhaustive.

[0066] An "atonic seizure" is defined as a convulsive type epileptic seizure that causes the muscles to relax and the patient to flop or fall.

[0067] "Mixed seizures" are defined as the presence of both generalized and focal seizures in the same patient.

[0068] The terms "50% responder" and "50% reduction in seizures" are both terms used in clinical trials. In this application, the terms define the proportion of subjects who experience a 50% or greater reduction in the number of seizures during treatment with CBD compared to the number of seizures experienced during the baseline period before CBD administration. [Brief description of the drawings]

[0069] [Figure 1] The ILAE proposal for a revised terminology for the codification of seizures and epilepsy in 2010 is presented. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] Preparation of highly purified CBD extracts The Examples below describe the production of a highly purified (>98% w / w) cannabidiol extract of known and consistent composition that was used in an expanded access trial.

[0071] In summary, the drug substance used in this clinical trial is a liquid carbon dioxide extract of a CBD-rich species of the cannabis plant (Cannabis sativa L.) that is further purified to obtain CBD by solvent crystallization, which specifically removes other cannabinoids and plant components to obtain greater than 95% (w / w), typically greater than 98% (w / w) CBD.

[0072] Cannabis sativa L. plants are grown, harvested, processed and extracted from plant material. The product (intermediate) is taken out and then purified by crystallization to obtain CBD (active pharmaceutical ingredient).

[0073] This plant starting material is called the botanical raw material (BRM), its plant extract is the intermediate, and its active pharmaceutical ingredient (API) is CBD, the drug substance.

[0074] Both the plant starting material and the plant extract are controlled by specifications. The specifications for the drug substance are shown in Table 5 below.

[0075] [Table 5]

[0076] The resulting CBD drug substance is greater than 98% pure. Other cannabinoids that may occur in the extract are CBDA, CBDV, CBD-C4, and THC.

[0077] Distinct chemical species of the cannabis plant (Cannabis sativa L.) have been processed to maximize the output of specific chemical constituents, or cannabinoids. One plant primarily yields CBD. Only the (-) trans isomer occurs naturally, and the stereochemistry of CBD is not further affected during purification.

[0078] Intermediate production The overall steps for producing the intermediate plant extract are as follows: 1) Growth 2) Decarboxylation 3) First extraction (using liquid CO2) 4) Second extraction ("dewaxing" using ethanol) 5) Filtration 6) Evaporation It is.

[0079] The high CBD chemical variety was grown, harvested, dried, and stored in a drying room until needed. The botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm sieve. The ground BRM was stored in a freezer for up to 3 months prior to extraction.

[0080] Decarboxylation of CBDA to CBD was carried out using a large Heraeus tray oven. The batch size for decarboxylation in the Heraeus is approximately 15 kg. The trays were placed in the oven and heated to 105° C. The BRM took 96.25 minutes to reach 105° C. and was held at 105° C. for 15 minutes. The oven was then set to 150° C. The BRM took 75.7 minutes to reach 150° C. and was held at 150° C. for 130 minutes. Total time in the oven was 380 minutes, including 45 minutes cooling and 15 minutes venting.

[0081] A first extraction was carried out using liquid CO2 at 60 bar / 10°C to remove the botanical drug substance (BDS) which was used for crystallisation to produce the test material.

[0082] The crude CBD, BDS, was dewaxed in a second extraction under standard conditions (2 volumes of ethanol at -20°C for approximately 50 hours). The precipitated wax was removed by filtration and the solvent was evaporated using a rotary evaporator (water bath max. 60°C) to give BDS.

[0083] API Production The manufacturing steps for producing the drug substance from the intermediate plant extract include: 1) C5~C 12 Crystallization using linear or branched alkanes 2) Filtration 3) C5~C 12 Optional recrystallization from linear or branched alkanes 4) Vacuum drying It is.

[0084] The intermediate plant extract (12 kg) produced using the above methodology was added to a 30 liter stainless steel vessel containing C5-C 12 Dispersed in linear or branched alkane (9000 ml, 0.75 aliquots).

[0085] The mixture was stirred by hand to break up any lumps, and then the sealed container was placed in a freezer for approximately 48 hours.

[0086] The crystals were isolated by vacuum filtration and cooled to 5°C. 12 The drug substance was washed with aliquots of linear or branched alkanes (total 12000 ml) and dried at 60° C. under a vacuum of <10 mb until dry before being submitted for analysis. The dried product was placed in a pharmaceutical stainless steel container with FDA food grade approved silicone seal and clamp - Store in a freezer at 20°C.

[0087] Pharmaceutical production The medication is provided as an oral solution. The oral solution offerings contain 25mg / ml or 100mg / ml of CBD with excipients sesame oil, ethanol, sucralose, and flavorings. These two product strengths are available to allow for titration over a wide dose range.

[0088] The 25 mg / ml solution is suitable for lower doses and the 100 mg / ml solution is suitable for higher doses.

[0089] The formulation of this drug is as shown in Table 6 below.

[0090] [Table 6]

[0091] The drug substance CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.

[0092] Sweeteners and fruit flavors are needed to improve the palatability of the sesame oil solution.

[0093] Ethanol is necessary to solubilize the sweeteners and flavoring agents.

[0094] The composition can be approximately uniform, meaning that the functional ingredients can differ from the quantitative composition specified in Table 6 by amounts up to 10%. EXAMPLES

[0095] Example 1 below describes the use of a highly purified cannabis extract containing cannabidiol (CBD) in an expanded access treatment program in children with TRE.

[0096] Example 1: Efficacy of cannabidiol in reducing atonic seizures in children and young adults with treatment-refractory epilepsy material and method Of 137 children and young adults with severe treatment-resistant epilepsy (TRE) of childhood onset, 27 had epilepsy characterized by atonic seizures. These subjects were tested with a highly purified extract of cannabidiol (CBD) obtained from the cannabis plant. All subjects showed atonic seizures, often in addition to other seizures. Participation in this study The individuals were part of CBD's expanded access compassionate use program.

[0097] The epilepsy syndromes suffered by these patients were Lennox-Gastaut syndrome, tuberous sclerosis complex, Dravet syndrome, Doose syndrome, Aicardi syndrome, CDKL5, and Dup15q.

[0098] All patients entered a 4-week baseline period in which a parent / caregiver kept a diary of anticipated seizures and recorded all countable seizure types.

[0099] Patients were then given 5 mg / kg / day of a highly purified CBD extract (>98% w / w CBD) of known, consistent composition dissolved in sesame oil in addition to their baseline antiepileptic drug (AED) regimen.

[0100] The daily dose was gradually increased in increments of 2-5 mg / kg until intolerance occurred or a maximum dose of 25 mg / kg / day was reached.

[0101] Patients were examined at regular intervals of 2 to 4 weeks. Laboratory tests of blood, liver, and kidney function and levels of concomitant AEDs were performed at baseline and after 4 weeks of CBD treatment.

[0102] All patients were taking at least two concomitant antiepileptic drugs. These included clobazam, levetiracetam, topiramate, stiripentol, phenobarbital, lacosamide, valproic acid, and zonisamide. The mean number of concomitant antiepileptic drugs taken was 2.7. The majority were taking either clobazam and / or valproic acid.

[0103] result Twenty-seven children and young adults, all of whom had atonic seizures, were treated with CBD for at least 12 weeks.

[0104] The profile of 50% responders based on 12 weeks of treatment is summarized in Table 7 below.

[0105] [Table 7]

[0106] Table 7 shows that after 3 months of treatment, 63% of patients showed a notable >50% reduction in atonic seizures, and these data indicate that CBD is highly effective in reducing this type of seizure.

[0107] conclusion These data show that CBD significantly reduces the number of atonic seizures in a high proportion of patients who do not respond satisfactorily to existing AEDs.

[0108] It was surprising that such a large number of this treatment-resistant patient group were able to benefit. Notable was the fact that almost two-thirds of these patients (63%) benefited from at least a 50% reduction in the number of atonic seizures they suffered. Furthermore, when these data are compared with other subtypes of generalized seizures, it is clearly seen that CBD was able to selectively reduce the occurrence of atonic seizures. Table 8 below details these results.

[0109] [Table 8]

[0110] From Table 8, when comparing the number of recorded atonic seizures with other generalized seizure types such as tonic seizures (49% of patients experienced a greater than 50% reduction in seizures), tonic-clonic seizures (43% of patients experienced a greater than 50% reduction in seizures), and myoclonic seizures (43% of patients experienced a greater than 50% reduction in seizures), it is quite surprising that almost two-thirds (63%) of the patients who were experiencing atonic seizures showed a greater than 50% reduction in the number of seizures that occurred.

[0111] 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. Geffrey A,Pollack S,Paolini J,Bruno P,Thiele E(2014)“Cannabidiol(CBD)treatment for refractory epilepsy in Tuberous Sclerosis Complex(TSC).”American Epilepsy Society Annual Meeting.5-9 December 2014. Kwan P,Arzimanoglou A,Berg AT,Brodie MJ,Hauser WA,Mathern G,Moshe 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. Maa E and Figi P(2014).“The case for medical marijuana in epilepsy”,Epilepsia 55(6):783-786 Mechoulam R and Carlini EA(1978).“Toward drugs derived from cannabis.”Die naturwissenschaften 65:174-9. Pelliccia A,Grassi G,Romano A,Crocchialo P(2005).“Treatment with CBD in oily solution of drug resistant paediatric epilepsies”.Congress of Cannabis and the Cannabinoids,Leiden,The Netherlands.International Association for Cannabis as a Medicine.p14. 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;Selass ie,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

Claims

1. A composition comprising cannabidiol (CBD) for use in the treatment of generalized seizures, selected from one or more of the subtypes of seizures: astonic, tonic, tonic-clonic, myoclonus, and absence seizures.

2. The composition according to claim 1, wherein the seizure is resistant to treatment.

3. The composition according to claim 1 or 2, wherein the CBD is for use in combination with one or more associated antiepileptic drugs (AEDs).

4. The composition according to any one of claims 1 to 3, wherein the CBD is present as a highly purified cannabis extract containing at least 95% (w / w) CBD.

5. The composition according to claim 4, wherein the extract contains less than 0.15% THC.

6. The composition according to claim 4 or 5, wherein the extract further comprises up to 1% CBDV.

7. The composition according to claim 1, wherein the CBD is present as a synthetic compound.

8. The composition according to claim 3, wherein one or more AEDs are selected from the group consisting of clobazam, clonazepam, levetiracetam, topiramate, stiripentol, phenobarbital, lacosamide, valproic acid, zonisamide, perampanel, and fosphenytoin.

9. The composition according to any one of claims 1 to 8, wherein the number of different antiepileptic drugs used in combination with the CBD is reduced.

10. The composition according to any one of claims 1 to 9, wherein the dose of the one or more antiepileptic drugs used in combination with the CBD is reduced.

11. The composition according to any one of claims 1 to 10, wherein the dose of CBD exceeds 5 mg / kg / day.

12. The composition according to any one of claims 1 to 11, further comprising a solvent, an auxiliary solvent, a sweetener, and a flavoring agent.

13. The composition according to claim 12, wherein the solvent is sesame oil.

14. The composition according to claim 12, wherein the auxiliary solvent is ethanol.

15. The composition according to claim 12, wherein the sweetener is sucralose.

16. The composition according to claim 12, wherein the CBD is present at a concentration of 25 mg / ml to 100 mg / ml.