Use of Cannabidiol in the Treatment of Epilepsy

Abstract

A novel composition useful for treating epilepsy, particularly absence seizures, is provided. The present invention provides a composition comprising (i) cannabidiol (CBD) at a concentration of 22.5-110 mg / ml, (ii) ethanol at a concentration of 71.1-86.9 mg / ml, (iii) a sweetener at a concentration of 0.45-0.55 mg / ml, (iv) a flavoring at a concentration of 0.18-0.22 mg / ml, and (v) sesame oil in an amount sufficient to make a volume of 0.95-1.1 ml. The sweetener is preferably sucralose, and the flavoring is preferably strawberry flavor.

Description

Technical Field

[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 is considered particularly effective in reducing absence seizures in patients suffering from Lennox-Gastaut syndrome, tuberous sclerosis complex, Doose syndrome, CDKL5, Dup15q, Jeavons syndrome, myoclonic absence epilepsy, neuronal ceroid lipofuscinosis (NCL) and brain abnormalities, as compared to other seizure

[0002] types. Significantly, CBD has been shown to be very effective in treating a subtype of absence seizures, namely myoclonic absence seizures. The etiologies of patients suffering 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 64% and 75% respectively, and by more than 50% in the majority of patients. This was surprising considering that the proportion of patients receiving the benefit of a greater than 50% reduction in total seizures in all treated subjects was significantly lower (46%).

[0004] Preferably, the CBD used is in the form of a high-purity extract of cannabis such that the CBD is present at greater than 98% (w / w) of the total extract and the other constituents of the extract are characterized. Specifically, the cannabinoid Substantially removed to levels below 0.15% (w / w), and cannabidiol (CBDV), a propyl analogue of CBD, is present in amounts up to 1%. Alternatively, CBD may be synthetically produced CBD. In use, CBD can be used in combination with one or more other anti - epileptic drugs (AEDs). When used in combination with another AED, CBD can be formulated for administration separately, sequentially, or simultaneously with one or more AEDs, or the combination can be provided in a single - dose form. When CBD is formulated for separate, sequential, or simultaneous administration, CBD can be provided as a kit for administering one or more components as directed, or together with instructions. CBD can also be used as monotherapy, i.e., single - drug therapy.

[0005]

Background Art

[0006] Epilepsy occurs in approximately 1% of the world's population (Thurman et al., 2011), and 70% of those can have their symptoms adequately controlled using available existing anti - epileptic drugs (AEDs). However, 30% of this patient group (Eadie et al., 2012) cannot achieve seizure freedom with available AEDs and are thus said to suffer from intractable or "treatment - resistant epilepsy" (TRE). Intractable or treatment - resistant epilepsy was defined by the International League Against Epilepsy (ILAE) in 2009 as "the failure to achieve sustained seizure freedom using (either as monotherapy or combination therapy),

[0007] Even if appropriately selected and used, the proper trial of two AED schedules with high tolerance was defined as "failure" (Kwan et al., 2009).

[0008] Individuals who develop epilepsy during the first few years of life often have difficult-to-treat epilepsy and are therefore often referred to as treatment-resistant. Children who experience frequent seizures in childhood often have neurological disorders that can cause cognitive,

[0009] Childhood epilepsy is a relatively common neurological disorder with a prevalence of approximately 700 per 100,000 in children and young adults. This is twice the number of adults with epilepsy per capita.

[0010] When a child or young adult has a seizure, an investigation is usually conducted to determine the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, so it may take some time to diagnose these children.

[0011] The main symptom of epilepsy is repeated seizures. To determine the type of epilepsy the patient has or the epilepsy syndrome, an investigation of the type of seizure the patient is experiencing is conducted. Clinical observations and electroencephalogram (EEG) tests are performed, and the type(s) of seizure(s) 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 revision was issued by the ILAE in 2010 but has not yet replaced the 1981 classification. Figure 1 is compiled from the 2010 proposal for revised terminology and is part Include the proposed changes to replace the terminology of partial seizures with focal seizures. In addition, the term "simple partial seizure" is replaced with the term "focal seizure without impairment of awareness / reduced responsiveness", and the term "complex partial seizure" is replaced with "focal seizure with impairment of awareness / consciousness".

[0013] From Figure 1, it can be seen that generalized seizures occurring within the bilateral distributed network and rapidly involving that network can be divided into six subtypes: tonic-clonic (grand mal) seizures, absence (petit mal) seizures, clonic seizures, tonic seizures, atonic seizures, and myoclonic seizures.

[0014] Focal (partial) seizures that originate within the network and are limited to only one cerebral hemisphere can also be divided into subcategories. Here, the seizure is characterized according to one or more characteristics of the seizure, including aura, motor, autonomic, and awareness / reactivity. If the seizure begins as a focal seizure and rapidly progresses and spreads within the bilateral network, this seizure is known as a bilateral convulsive seizure, which is a proposed terminology to replace secondary generalized seizures (generalized seizures that have progressed from focal seizures and are no longer focal).

[0015]

[0016] Absence seizures can occur as typical absence seizures, atypical absence seizures, or absence seizures with special characteristics such as myoclonic absence and eyelid myoclonia

[0016] Typical absence seizures are generalized seizures that are accompanied by a sudden onset and recovery of changes in consciousness. The changes in consciousness can vary in severity depending on the specific syndrome the patient is suffering from. Clonic movements may occur in the eyelids, head, eyebrows, jaw , around the mouth, or other parts of the face, while myoclonus of the hands and feet ​Absence status epilepticus occurs extremely rarely.

[0017] The sudden onset and recovery of loss of consciousness in atypical absence seizures is different from that in typical absence seizures. These include loss of muscle tone in the head, trunk, or limbs, and fine myocardial infarction. It is associated with other characteristics such as knee spasms. Loss of consciousness is usually minimal.

[0018] Myoclonic absence seizures are characterized by bilateral rhythmic myoclonic jerks of the shoulders and arms. The attack is followed by a progressive arm elevation followed by a rigid abduction. The attack lasts 10 to 60 seconds and is followed by complete consciousness. Total loss may occur.

[0019] Eyelid myoclonia is characterized by brief eyelid contractions accompanied by simultaneous upward deviation of both eyes and extension of the head. These are absence seizures that occur in association with recurrent myoclonic jerks of the brain. Seizures typically last for a short period of time. Multiple seizures may occur regularly. Consciousness is usually preserved.

[0020] Absence seizures include those in Lennox-Gastaut syndrome, myoclonic absence epilepsy, and tuberous sclerosis complex. Complex, Dravet syndrome, Douce syndrome, CDKL5, Dup15q, Jevons syndrome , myoclonic absence epilepsy, neuronal ceroid lipofuscinosis (NCL), and brain abnormalities. This may occur in meta-epilepsy syndromes.

[0021] Epilepsy syndromes often present with many different types of seizures, and the seizures that patients suffer from Identifying the type of This is important because it is only effective against the seizure type / subtype.

[0022] The primary treatment for absence seizures usually includes broad-spectrum AEDs such as sodium valproate, lamotrigine or ethosuximide. Combinations of these drugs may be required to treat absence seizures.

[0023] General AEDs defined by their mechanism of action are described in the following table.

[0024]

Table 1

[0025]

Table 2

[0026]

Table 3

[0027] From these tables, it can be seen that the three AEDs used as primary treatment for absence seizures, namely sodium valproate, lamotrigine or ethosuximide, are GABA / sodium channel, sodium channel and calcium channel drugs respectively.

[0028] From these tables, it can also be seen that other AEDs are approved for use in absence seizures, and these AEDs include clonazepam and clobazam, both of which are also known to act via the GABA mechanism.

[0029] Over the past 40 years, numerous animal experiments have been conducted on the use of cannabidiol (CBD), a non-psychoactive cannabinoid, to treat seizures. For example, Con ​​Sroe et al. (1982) found that CBD could prevent seizures in mice after administration of convulsant drugs or application of electric current. Studies using CBD in adults with epilepsy have also been conducted over the past 40 years. Cunha et al. reported that administration of CBD to 8 adult patients with generalized epilepsy resulted in a significant reduction in seizures in 4 of the patients (Cunha et al., 1980).

[0030] In a 1978 study where 4 adult patients were provided with 200 mg / day of pure CBD, seizures disappeared in 2 of the 4 patients, while there was no change in the seizure frequency of the remaining 2 patients (Mechoulam and Carlini, 1978). In contrast to the above studies, non - blinded trials reported that 200 mg / day of pure CBD was not effective in controlling seizures in 12 adult patients housed in a facility (Ames and Cridland, 1986). Over the past 40 - year investigation, more than 30 drugs have been approved for the treatment of epilepsy, but none of them are cannabinoids. In fact, there seems to be a preconception against cannabinoids, perhaps due to the designated nature of these compounds and / or the fact that THC, a known psychoactive substance, has been regarded as a convulsant (Consroe et al., 1977). Recent published papers have shown that cannabis rich in cannabidiol is effective in the treatment of epilepsy.

[0031] 4 people of adult patients were given 200mg / day of pure CBD in the 1978 study, seizures disappeared in 2 of the 4 patients, while the remaining 2 patients had no change in seizure frequency (Mechoulam and Carlini, 1978). Of the 4 patients, seizures disappeared in 2, while there was no change in the seizure frequency of the remaining 2 (Mechoulam and Carlini, 1978). In contrast to the above studies, non - blinded trials reported that 200mg / day of pure CBD was not effective in controlling seizures in 12 adult patients housed in a facility (Ames and Cridland, 1986).

[0032] In contrast to the above - mentioned studies, non - blinded trials reported that 200 mg / day of pure CBD was not effective in controlling seizures in 12 adult patients housed in a facility. In fact, there seems to be a preconception against cannabinoids, perhaps due to the designated nature of these compounds and / or the fact that THC, a known psychoactive substance, has been regarded as a convulsant (Consroe et al., 1977). Recent published papers have shown that cannabis rich in cannabidiol is effective in the treatment of epilepsy.

[0033] Over the past 40 years of investigation, more than 30 drugs have been approved for the treatment of epilepsy, but none of them are cannabinoids. In fact, there seems to be a preconception against cannabinoids, perhaps due to the designated nature of these compounds and / or the fact that THC, a known psychoactive substance, has been regarded as a convulsant (Consroe et al., 1977). And / or the fact that THC, a known psychoactive substance, has been regarded as a convulsant (Consroe et al., 1977), there seems to be a preconception against cannabinoids. Consroe et al. (1977), there seems to be a preconception against cannabinoids. Recent published papers have shown that cannabis rich in cannabidiol is effective in the treatment of epilepsy.

[0034] Recent published papers have shown that cannabis rich in cannabidiol is effective in the treatment of epilepsy. suggested that it might be effective. Porter and Jacobson (2013 year) reported a parent - targeted survey conducted via a Facebook group that investigated the use of CBD - fortified cannabis in children with treatment - resistant epilepsy . Of the 19 parents surveyed, 16 reported an improvement in their children's epilepsy . All of the children investigated for this paper had ingested cannabis that was reported to contain high concentrations of CBD, although the amounts of other components, including the amount of CBD present and THC, were often unknown . In fact, the CBD levels ranged from 0.5 - 28 .6 mg / kg / day (in these extracts tested), while the THC levels were reported to be as high as 0.8 mg / kg / day . Providing children with TRE who have ingested cannabis extracts containing THC, which is described as a convulsant (Consroe et al., 1977), at potentially psychoactive doses of 0.8 mg / kg / day is a concern, and thus there is a need to determine whether CBD is actually effective

[0035] . In November 2013, GW Pharmaceuticals issued a press release stating its intention to treat Dravet syndrome with CBD, as CBD had received orphan drug designation .

[0036] To date, no controlled clinical trials of CBD in children and young adults with intractable epilepsy have been conducted .

[0037]

SUMMARY OF THE INVENTION

[0038] ​​​According to a first aspect of the present invention, cannabidiol (CBD) is provided for use in the treatment of epilepsy characterized by absence seizures. In one embodiment, the epilepsy is childhood epilepsy.

[0039] In one embodiment, the absence seizure is a myoclonic absence seizure.

[0040] Surprisingly, CBD has been shown to be particularly effective in subjects suffering from treatment-resistant epilepsy.

[0041] In a further embodiment, CBD is used in combination with one or more concomitant anti-epileptic drugs (AEDs). Preferably, the absence seizures to be treated are in patients diagnosed with Lennox-Gastaut syndrome, myoclonic absence epilepsy, tuberous sclerosis complex, Doose syndrome, Dravet syndrome, Jeavons syndrome, CDKL5, Dup15q, neuronal ceroid lipofuscinosis (NCL) and brain abnormalities.

[0042] Most preferably, the treatment-resistant epilepsy is one of Lennox-Gastaut syndrome, Dravet syndrome and myoclonic absence epilepsy. In a further embodiment, CBD is present as a high-purity extract of cannabis containing at least 98% (w / w) CBD. Preferably, the extract contains less than 0.15% THC. More preferably, the extract further contains up to 1% CBDV.

[0043]

[0044]

[0045]

[0046] In an alternative embodiment, CBD is present as a synthetic compound. In an alternative embodiment, CBD is present as a synthetic compound. Preferably, the extract contains less than 0.15% THC.

[0046]

[0047] In a further embodiment of the present invention, one or more AEDs are 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, selected from the group consisting of.

[0048] Preferably, one or more AEDs are selected from the group consisting of sodium valproate, lamotrigine, ethosuximide clobazam and clonazepam.

[0049] Preferably, the number of different anti-epileptic drugs used in combination with CBD is reduced . Alternatively, the dose of anti-epileptic drug used in combination with CBD is reduced.

[0050] There are many side effects associated with commonly used AEDs, including dizziness, blurred vision, nausea, respiratory depression, fatigue, headache and other motor side effects on the central nervous system. These side effects are especially common when high doses or combinations of multiple AEDs are used . Thus, there is a need for alternative drug therapies that can reduce the number of seizures while simultaneously exhibiting a safe side effect profile .

[0051] Preferably, the dose of CBD is more than 5 mg / kg / day. Thus, for a 15 kg patient , a dose of CBD exceeding 75 mg per day is provided. For example, 10 / mg Greater than 5 mg / kg / day, greater than 15 mg / kg / day, greater than 20 mg / kg / day, and greater than 25 mg / kg / day, such as doses exceeding 5 mg / kg / day, are also assumed to be effective.

[0052] Preferably, the epilepsy is childhood epilepsy.

[0053] According to a second aspect of the present invention, there is provided a method of treating epilepsy, which comprises administering cannabidiol (CBD) to a subject, wherein the epilepsy is characterized by absence seizures.

[0054] Preferably, the subject is a human, typically a patient suffering from epilepsy characterized by absence seizures.

[0055] According to a third aspect of the present invention, there is provided a composition for use in the treatment of epilepsy characterized by absence seizures, which comprises cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavoring agent.

[0056] Preferably, the solvent is sesame oil, the co-solvent is ethanol, the sweetener is sucralose, the flavoring agent is strawberry flavor, and CBD is present at a concentration between 25 mg / ml and 100 mg / ml, i.e., between 50 mg / ml and 75 mg / ml.

[0057] More preferably, the composition comprises cannabidiol (CBD) at a concentration between 25 mg / ml and 100 mg / ml, ethanol at a concentration of 79 mg / ml, sucralose at a concentration of 0.5 mg / ml, strawberry flavor at a concentration of 0.2 mg / ml, and an appropriate amount of sesame oil to make 1.0 ml.

[0058] The composition is expected to be administered as an oral liquid solution. Other forms of administration, including solids, semi-solids, gels, sprays, aerosols, inhalers, nebulizers, suppositories, and enemas, are alternative forms of administration. Such drugs can be administered via the oral, buccal, sublingual, respiratory, nasal, and distal rectal routes.

[0059] [Definitions] Some of the terms used to describe the present invention are defined in detail below.

[0060] The cannabinoids described in this application are listed below along with their common abbreviations.

[0061] [Table 4]

[0062] The above table is not exhaustive and merely details the cannabinoids identified in this application for reference. To date, over 60 different cannabinoids have been identified, and these can be divided into different groups (phytocannabinoids; endocannabinoids and synthetic cannabinoids (which can be novel cannabinoids or phytocannabinoids or endocannabinoids produced by synthesis)).

[0063] "Phytocannabinoids" are naturally occurring cannabinoids that can be found in the cannabis plant. Phytocannabinoids can be isolated from plants to produce high-purity extracts or replicated synthetically.

[0064] "High-purity cannabinoid extract" is extracted from the cannabis plant and its high-purity cann​​​​​​​​​ The cannabinoid is refined to such an extent that other cannabinoids and non-cannabinoid components co-extracted with the cannabinoid are substantially removed so that the cannabinoid has a purity of 98% (w / w) or higher. It is defined as a cannabinoid produced by such refining.

[0065] A "synthetic cannabinoid" is a compound having a cannabinoid or cannabinoid-like structure and is produced by using chemical means rather than by a plant.

[0066] Phytocannabinoids can be obtained in the neutral (decarboxylated form) or in the carboxylic acid form depending on the method used for extracting the cannabinoid. For example, by heating the carboxylic acid form, most of the carboxyl groups of the carboxylic acid form are removed and it is known to become the neutral form.

[0067] "Treatment-resistant epilepsy" (TRE) or "intractable epilepsy" is defined by the 2009 ILAE guidance as epilepsy that is not adequately controlled by trials of one or more AEDs.

[0068] "Childhood epilepsy" refers to many different syndromes and genetic mutations that can cause epilepsy in childhood. Some examples of these are Dravet syndrome, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome, idiopathic general epilepsy, CDKL5 mutations, Aicardi syndrome, bilateral polymicrogyria, Dup15q, SNAP25, and febrile infection-related epilepsy syndrome (FIRES), benign Rolandic epilepsy, juvenile myoclonic epilepsy, infantile spasms (West syndrome), as well as Landau-Kleffner syndrome. As described above, The enumeration is non-exhaustive as there are many different childhood epilepsies.

[0069] "Absence seizures" are defined as the general type of seizure that causes loss of consciousness, often accompanied by myoclonic jerks. It is defined as the general type of seizure that causes loss of consciousness, often accompanied by myoclonic jerks.

[0070] "Myoclonic absence seizures" are defined as a subtype of absence seizures that exhibit bilateral myoclonic jerks of the arms and shoulders. It is defined as a subtype of absence seizures that exhibit bilateral myoclonic jerks of the arms and shoulders.

[0071] "Mixed seizures" are defined as those in which both general seizures and focal seizures are present in the same patient. It is defined as those in which both general seizures and focal seizures are present in the same patient.

[0072] The terms "50% responder" and "50% reduction in seizures" are both terms used in clinical research. In this application, these terms define the proportion of subjects who experienced a reduction of more than 50% in the number of seizures during treatment with CBD, compared to the number of seizures experienced during the baseline period before CBD was administered. The terms "50% responder" and "50% reduction in seizures" are both terms used in clinical research. In this application, these terms define the proportion of subjects who experienced a reduction of more than 50% in the number of seizures during treatment with CBD, compared to the number of seizures experienced during the baseline period before CBD was administered. The terms "50% responder" and "50% reduction in seizures" are both terms used in clinical research. In this application, these terms define the proportion of subjects who experienced a reduction of more than 50% in the number of seizures during treatment with CBD, compared to the number of seizures experienced during the baseline period before CBD was administered. The terms "50% responder" and "50% reduction in seizures" are both terms used in clinical research. In this application, these terms define the proportion of subjects who experienced a reduction of more than 50% in the number of seizures during treatment with CBD, compared to the number of seizures experienced during the baseline period before CBD was administered.

Brief Description of the Drawings

[0073]

Figure 1

Modes for Carrying Out the Invention

[0074] <Preparation of High-Purity CBD Extract> The following describes the preparation of a high-purity (over 98% w / w) cannabidiol extract with a known and constant composition, used in the expanded access trial described in the following examples. The following describes the preparation of a high-purity (over 98% w / w) cannabidiol extract with a known and constant composition, used in the expanded access trial described in the following examples.

[0075] In summary, the drug substance used in the trial was further purified by solvent crystallization to obtain CBD, from Cannabis sativa L. In summary, the drug substance used in the trial was further purified by solvent crystallization to obtain CBD, from Cannabis sativa L. It is a liquid carbon dioxide extract of high CBD-containing chemical species. The crystallization process specifically removes other cannabinoids and plant components to obtain more than 98% CBD yielded.

[0076] Cannabis sativa L. plants are cultivated, harvested, and processed to produce a plant extract (intermediate) which is then purified by crystallization to obtain CBD (bulk drug).

[0077] The plant starting material is referred to as plant raw material (BRM), the plant extract is an intermediate, and the active pharmaceutical ingredient (API) is the bulk drug CBD.

[0078] Both the plant starting material and the plant extract are controlled by specifications. The specifications of the bulk drug are described in Table 5 below.

[0079]

Table 5

[0080] The purity of the CBD bulk drug achieved is more than 98%. Other cannabinoids that may occur in the extract are CBDA, CBDV, CBD-C4, and THC.

[0081] Different chemical species of Cannabis sativa L. plants are produced to maximize the production of cannabinoids, which are specific chemical components. One type of the plant mainly produces CBD. Only (-)-trans monomers occur naturally. Furthermore, the stereochemistry of CBD is not affected during purification.

[0082] <Preparation of Intermediate> An overview of the steps for preparing the intermediate, which is a plant extract, is shown below. 1. Cultivation 2. Decarboxylation 3. Extraction No. 1 - Using liquid CO2 4. Extraction No. 2 - "Debloating" using ethanol 5. Filtration 6. Evaporation

[0083] Cultivated, harvested, and dried the high-CBD chemical type, and stored it in a drying chamber until it reached the desired state done. The plant raw material (BRM) was finely ground using an Apex mill equipped with a 1-mm screen. The ground BRM was stored in a freezer for up to 3 months before extraction

[0084] The decarboxylation of CBDA to CBD was carried out using a large-capacity Heraeus tray oven The decarboxylation batch size of Heraeus is approximately 15 kg. The tray was placed in the oven and heated to 105°C, which took 96.25 minutes for the BRM to reach 105°C It was held at 105°C for 15 minutes. Then, the oven was set to 150°C. The BRM took 75.7 minutes to reach 150°C, and the BRM was held at 150°C for 130 minutes . The total time in the oven was 380 minutes, including 45 minutes for cooling and 15 minutes for degassing

[0085] Performed Extraction No. 1 using liquid CO2 at 60 bar / 10°C to produce the plant crude drug (BDS )

[0086] The BDS of crude CBD was debloated in Extraction No. 2 under standard conditions (at approximately -20°C for 50 hours, 2 vol of ethanol ol). The precipitated wax was removed by filtration, and the solvent was evaporated using a rotary evaporator (water bath at a maximum of 60°C) to obtain BDS, which was then used for crystallization to produce the test material

[0087] <Production of the crude drug> The manufacturing steps for preparing the active ingredient from the intermediate plant extract are as follows : 1. Crystallization using a straight-chain or branched C5-C12 alkane 2. Filtration 3. Optional recrystallization from a straight-chain or branched C5-C12 alkane 4. Vacuum drying

[0088] The intermediate plant extract (12 kg) prepared using the above means was dispersed in a straight-chain or branched C5-C12 alkane (9000 ml, 0.75 vol) in a 30-liter stainless-steel vessel .

[0089] The mixture was manually stirred until all lumps were broken, and then the sealed vessel was placed in a freezer for 48 hours

[0090] The crystals were isolated by vacuum filtration, washed with a defined quantity of cooled straight-chain or branched C5-C12 alkane (total 12000 ml), and dried under vacuum at a temperature of 60 °C above 10 mbar before the active ingredient was submitted for analysis

[0091] The dried product was stored in a freezer at -20 °C in a pharmaceutical-grade stainless-steel vessel equipped with an FDA food-grade approved silicone seal and clamp

[0092] <Manufacture of the formulation> The formulation is presented as an oral solution. The presented oral solution contains 25 mg / ml or 100 mg / ml of CBD together with the excipients sesame oil, ethanol, sweeteners and flavorings Two product strengths are available with incremental dosing possible over a wide dosage range

[0093] ​​​​​​​ A 25 mg / ml solution is appropriate as a low dose, and a 100 mg / ml solution is appropriate as a high dose.

[0094] The pharmaceutical formulation is as described in Table 6 below.

[0095]

Table 6

[0096] The active ingredient CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the active ingredient.

[0097] Sweeteners and fruit flavorings are necessary to improve the taste of the sesame oil solution.

[0098] Ethanol was necessary to solubilize the sweeteners and flavorings.

[0099] The composition can be made substantially equivalent, meaning that the functional components can be varied by up to 10% in amount from the qualitative composition specified in Table 6.

[0100] Example 1 below describes the use of a high-purity cannabis extract containing cannabidiol (CBD). Cannabidiol is the most abundant non-psychoactive cannabinoid in the selected chemotype. Previous studies in animals have demonstrated that CBD has an anticonvulsant effect on a number of species and models.

[0101] Example 1 describes data generated in an expanded access treatment program in children with TRE.

Example

[0102] <Efficacy of Cannabidiol in Reducing Atonic Seizures in Children and Young Adults with Refractory Epilepsy > [Materials and Methods] Thirteen children and young adults with severe treatment-resistant epilepsy (TRE) with childhood onset Of these, 42 had epilepsy characterized by atonic seizures. These subjects were tested using a high-purity extract of cannabidiol (CBD) obtained from the cannabis plant All subjects had atonic seizures, often in addition to other generalized and / or focal seizures Participants in this study were part of an expanded access compassionate use program for CBD.

[0103] The epilepsy syndromes these patients had were Lennox-Gastaut syndrome, myoclonic astatic epilepsy, tuberous sclerosis complex, Doose syndrome, Dravet syndrome, Jeavons syndrome CDKL5, Dup15q, neuronal ceroid lipofuscinosis (NCL) and brain abnormalities were.

[0104] The seizure types these patients experienced were tonic, atonic, tonic-atonic, myoclonic, drop, atonic, myoclonic atonic, focal seizures without impairment, focal seizures with impairment and focal seizures progressing to bilateral clonic seizures.

[0105] All patients entered a 4-week baseline period, during which parents / caregivers noted all possible seizure types and kept a log of predicted seizures.

[0106] Subsequently, patients were given, in addition to their baseline antiepileptic drug (AED) regimen, a known single Received a high-purity CBD extract (CBD > 98% (w / w)) in sesame oil at a dose of 5 mg / kg / day of a defined composition. (w / w) CBD)

[0107] The daily dose was gradually increased in increments of 2 - 5 mg / kg until intolerance occurred or the maximum dose reached 25 mg / kg / day. Patients were examined at regular intervals of 2 - 4 weeks. Clinical tests for blood, liver, and kidney function as well as for concomitant AED levels were performed at baseline and 4 weeks after each cycle of CBD therapy.

[0108] All patients in this study were taking at least one concomitant AED. These AEDs 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. to concomitant AED levels were performed at baseline and 4 weeks after each cycle of CBD therapy.

[0109] All patients in this study were taking at least one concomitant AED. These AEDs 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. D as 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. to concomitant AED levels were performed at baseline and 4 weeks after each cycle of CBD therapy. to concomitant AED levels were performed at baseline and 4 weeks after each cycle of CBD therapy. to concomitant AED levels were performed at baseline and 4 weeks after each cycle of CBD therapy. to concomitant AED levels were performed at baseline and 4 weeks after each cycle of CBD therapy.

[0110] [Results] Of the 42 children and young adult patients who received treatment with CBD, 28 patients received treatment for at least 12 weeks, all of whom had absence seizures. Of the 42 children and young adult patients who received treatment with CBD, 28 patients received treatment for at least 12 weeks, all of whom had absence seizures.

[0111] The profiles of 50% responders based on 12 weeks of treatment are summarized in Table 7 below.

[0112] [Table 7] ​

[0113] Table 7 shows that, after 3 months of treatment, notably, absence seizures were reduced by more than 50% in 64% of the patients, suggesting from this data that CBD is highly effective in reducing this type of seizure.

[0114] [Conclusion] These data indicate that CBD significantly reduces the frequency of absence seizures at a high rate in patients who do not respond well to existing AEDs.

[0115] It was surprising that such a large number of treatment-resistant patients in this group were able to benefit. The fact that nearly two-thirds (64%) of the patients received the benefit of having at least a 50% reduction in the frequency of the absence seizures they were suffering from was notable. [Example]

[0116] [Efficacy of Cannabidiol in Reducing Myoclonic Absence Seizures in Children and Young Adults with Refractory Epilepsy] [Materials and Methods] Of 137 children and young adults with severe treatment-resistant epilepsy (TRE) presenting in childhood, 10 had epilepsy characterized by myoclonic absence seizures. These subjects were tested with a high-purity extract of cannabidiol (CBD) obtained from the cannabis plant. All subjects presented with myoclonic absence seizures, often in addition to other generalized and / or focal seizures. Participants in this study were part of an expanded access compassionate use program for CBD.

[0117] ​​​​​​​The epilepsy syndromes these patients suffered from were myoclonic astatic epilepsy, Doose syndrome, and epilepsy of uncertain cause.

[0118] All patients entered a 4-week baseline period, during which parents / carers paid attention to all accountable seizure types and kept a log of predicted seizures.

[0119] Subsequently, in addition to their baseline antiepileptic drug (AED) regimen, patients received a high-purity CBD extract (CBD > 98% (w / w)) in sesame oil at a dose of 5 mg / kg / day of a known and fixed composition. (w / w) CBD)

[0120] The daily dose was gradually increased in increments of 2 - 5 mg / kg until intolerance occurred or the maximum dose reached 25 mg / kg / day.

[0121] Patients were examined at regular intervals of 2 - 4 weeks. Clinical tests for blood, liver, and kidney function and concomitant AED levels were performed at baseline and after every 4 weeks of CBD therapy.

[0122] All patients in this study were taking at least one concomitant AED. These AEDs included clobazam, clonazepam, chlormezanone, diazepam, ethosuximide, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, and valproic acid.

[0123] [Results] Of the 10 pediatric and young adult patients treated with CBD, 8 patients received at least 12 weeks of treatment, all of whom suffered from myoclonic astatic seizures. ​​​​​

[0124] The outline of 50% responders based on 12 weeks of treatment is summarized in Table 8 below.

[0125] [Table 8]

[0126] Table 8 shows that after 3 months of therapy, notably, the absence seizures of 75% of patients were reduced by more than 50%. From this data, it is inferred that CBD is very effective in reducing this type of seizure.

[0127] [Conclusion] These data indicate that CBD significantly reduces the frequency of myoclonic absence seizures in a high proportion of patients who do not respond well to existing AEDs.

[0128] It was surprising that such a large number of patients in this group of treatment-resistant patients were able to benefit. The fact that nearly three-quarters (75%) of the patients received the benefit that the frequency of myoclonic absence seizures they suffered from was reduced by at least 50% was remarkable.

[0129] [References] [Table 9] ​​​​​

Claims

**Claim 1** An orally administrable composition comprising: (i) cannabidiol (CBD) at a concentration of 22.5 to 110 mg / ml; (ii) ethanol at a concentration of 71.1 to 86.9 mg / ml; (iii) a sweetener at a concentration of 0.45 to 0.55 mg / ml; (iv) a flavorant at a concentration of 0.18 to 0.22 mg / ml; and (v) sesame oil in an amount such that the total volume of the composition is 0.95 to 1.1 ml. **Claim 2** The orally administrable composition according to claim 1, consisting of (i) cannabidiol (CBD) at a concentration of 22.5 to 110 mg / ml; (ii) ethanol at a concentration of 71.1 to 86.9 mg / ml; (iii) a sweetener at a concentration of 0.45 to 0.55 mg / ml; (iv) a flavorant at a concentration of 0.18 to 0.22 mg / ml; and (v) an appropriate amount of sesame oil to make the total volume of the composition 0.95 to 1.1 ml. **Claim 3** The orally administrable composition according to claim 1 or 2, wherein the CBD is present at a concentration of 25 to 100 mg / ml. **Claim 4** The orally administrable composition according to any one of claims 1 to 3, wherein the ethanol is present at a concentration of 79 mg / ml. **Claim 5** The orally administrable composition according to any one of claims 1 to 4, wherein the sweetener is present at a concentration of 0.5 mg / ml. **Claim 6** The orally administrable composition according to any one of claims 1 to 5, wherein the sweetener is sucralose. **Claim 7** The orally administrable composition according to any one of claims 1 to 6, wherein the flavorant is present at a concentration of 0.2 mg / ml. **Claim 8** The orally administrable composition according to any one of claims 1 to 7, wherein the flavorant is strawberry flavor. **Claim 9** The orally administrable composition according to any one of claims 1 to 8, wherein the amount of sesame oil present in the composition is an amount such that the total volume of the composition is 1.0 ml.

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