• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    use of a cannabidiol (cbd) in combination with an antiepileptic drug (aed) that acts through a gaba receptor agonist. the present invention relates to the use of cannabidiol (cbd) in the treatment of patients with childhood-onset epilepsy who are simultaneously taking one or more antiepileptic drugs acting via a gaba receptor agonist. preferably, aed is stiripentol. preferably, the cbd used is in the form of a highly purified cannabis extract such that the cbd is present in more than 98% of the total extract (w / w) and the other components of the extract are distinguished. specifically, the cannabinoid tetrahydrocannabinol (thc) was removed substantially up to a maximum level of 0.15% (w / w) and the prophylactic cbd analog, cannabidivarin (cbdv), is present in amounts of up to 1%. alternatively, the cbd can be a synthetically produced cbd.
    公开号:BR112020015018A2
    申请号:R112020015018-5
    申请日:2019-01-22
    公开日:2021-01-19
    发明作者:Geoffrey Guy；Volker Knappertz；Benjamin Whalley
    申请人:GW Research Limited；
    IPC主号:
    专利说明:

    [001] [001] The present invention relates to the use of cannabidiol (CBD) in the treatment of patients with childhood-onset epilepsy who are simultaneously taking one or more antiepileptic drugs acting through a GABA receptor agonist. Preferably, the AED is stiripentol.
    [002] [002] Preferably, the CBD used is in the form of a highly purified cannabis extract such that CBD is present in more than 98% of the total extract (w / w) and the other components of the extract are distinguished. Specifically, the cannabinoid tetrahydrocannabinol (THC) was removed substantially up to a maximum level of 0.15% (w / w) and the prophylactic CBD analog, cannabidivarin (CBDV), is present in amounts of up to 1%. Alternatively, the CBD can be a synthetically produced CBD. BACKGROUND OF THE INVENTION
    [003] [003] Epilepsy occurs in approximately 1% of the world population (Thurman et al., 2011), of which 70% are able to adequately control their symptoms with the available antiepileptic drugs (AEDs). However, 30% of this group of patients (Eadie et al., 2012) are unable to achieve seizure control with the AEDs that are available and, thus, are known to have intractable epilepsy or “treatment-resistant epilepsy” (TRE) .
    [004] [004] Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as “failure to respond to an adequate clinical trial with two AEDs tolerated and appropriately used (either as monotherapy or in combination) for
    [005] [005] Individuals who develop epilepsy during the first few years of life are often difficult to treat and are thus often referred to as treatment-resistant. Children who suffer frequent seizures in childhood often have neurological damage, which can cause many cognitive, behavioral and motor delays.
    [006] [006] Childhood-onset 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 adult epileptics per population.
    [007] [007] When a child or young adult has a seizure, investigations are usually carried out to ascertain the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, so diagnosis for these children can take some time.
    [008] [008] The main symptom of epilepsy is repeated seizures. To determine the type of epilepsy or the epileptic syndrome that a patient suffers from, an investigation is carried out into the type of seizures that the patient is experiencing. Clinical observations and electroencephalography (EEG) examinations are conducted, and the type (s) of seizures and / are classified according to the ILAE classification described below.
    [009] [009] The International Classification of Seizure Types proposed by ILAE was adopted in 1981 and a proposed revision was published by ILAE in 2010 and has not yet replaced the 1981 classification. The 2010 terminology revision proposal includes changes proposed to replace terminology from partial to focal. In addition, the term “simple partial seizure” has been replaced by the term “focal seizure in which there is no impairment of perception / responsiveness” and the term
    [0010] [0010] Generalized seizures, in which the seizure originates somewhere in a network and quickly involves networks distributed bilaterally, can be divided into six subtypes: Tonic-clonic seizures (great evil); absence crises (small mal); clonic seizures; tonic crises; atonic and myoclonic crises.
    [0011] [0011] Focal (partial) seizures, when the seizure originates within networks limited to a single hemisphere, are also divided into subcategories. Here, the seizure is distinguished according to one or more characteristics of the crisis, including aura, motor, autonomic and perception / responsiveness. When a seizure starts as a localized crisis with rapid evolution for distribution in bilateral networks, this seizure is known as a bilateral seizure crisis, which is the terminology proposed to replace Crises with Secondary Generalization (generalized crises that evolved from focal crises and no longer remain localized ).
    [0012] [0012] Epileptic syndromes are often manifested by many different types of seizures and the identification of the types of seizures that a patient is suffering from is important, as many of the standard AEDs target treatment or are effective only against a given type / subtype convulsion.
    [0013] [0013] One of such syndromes of childhood epilepsy is Lennox-Gastaut syndrome (SLG). SLG is a severe form of epilepsy, in which seizures usually begin before the age of 4 years. The types of seizures, which vary between patients, include tonic (body stiffening, eye deviation upward, dilated pupils and altered breathing patterns), atonic (momentary loss of muscle tone and consciousness, causing sudden falls), atypical (stare) and myoclonic absence
    [0014] [0014] Seizures in SLG are often described as "falling crises". Such fall crises are defined as an attack or outbreak (atonic, tonic or tonic-clonic) involving the entire body, the trunk or the head that led or could have led to a fall, injury, falling into a chain or causing the patient hit his head on a surface.
    [0015] [0015] Most patients with SLG experience some degree of impairment of intellectual function or information processing, along with developmental delay and behavioral disorders.
    [0016] [0016] SLG can be caused by malformations in the brain, perinatal asphyxia, severe head trauma, infection in the central nervous system and hereditary degenerative or metabolic conditions. In 30-35% of cases, no cause can be found.
    [0017] [0017] First-line treatment for seizures, including the treatment of seizures in patients with SLG, typically comprises a broad-spectrum AED, such as sodium valproate often in combination with rufinamide or lamotrigine. Other AEDs that can be considered include felbamate, clobazam and topiramate.
    [0018] [0018] Another epilepsy syndrome in childhood is Dravet's syndrome. The onset of Dravet's syndrome almost always occurs during the first year of life with clonic and tonic-clonic seizures in previously healthy infants with normal development (Dravet, 2011). Symptoms peak at about five months of age. Other seizures develop between one and four years of age, such as prolonged focal cognitive seizures and brief absences.
    [0019] [0019] In the diagnosis of Dravet's syndrome, both focal and generalized seizures are considered mandatory, patients with
    [0020] [0020] Seizures progress to more frequent and resistant to treatment, meaning that seizures do not respond well to treatment. They also tend to be prolonged, lasting more than 5 minutes. Prolonged seizures can lead to status epilepticus, which is a seizure lasting more than 30 minutes, or seizures that occur in clusters (salvages), one after the other.
    [0021] [0021] The prognosis is poor and approximately 14% of children die during a seizure, due to infection, or suddenly due to uncertain causes, often due to relentless neurological decline. Patients develop intellectual disabilities and continuous seizures throughout life. Intellectual impairment varies from severe, in 50% of patients, to moderate and mild intellectual disability, each representing 25% of cases.
    [0022] [0022] There is currently no FDA approved treatment specifically indicated for Dravet's syndrome. The standard of care usually involves a combination of the following anticonvulsants: clobazam, clonazepam, levetiracetam, topiramate and valproic acid.
    [0023] [0023] Stiripentol is approved in Europe for the treatment of Dravet syndrome in conjunction with clobazam and valproic acid. In the United States, stiripentol obtained the Orphan Drug Designation for the treatment of Dravet's syndrome in 2008; however, the drug is not approved by the FDA.
    [0024] [0024] Potent sodium channel blockers, used to treat epilepsy, actually increase the frequency of seizures in patients with Dravet's syndrome. The most common are phenytoin, carbamazepine, lamotrigine and rufinamide.
    [0025] [0025] Treatment may also include a ketogenic diet and physical and nerve stimulation. In addition to anticonvulsant drugs, many patients with Dravet's syndrome are treated with antipsychotic drugs, stimulants and drugs to treat insomnia.
    [0026] [0026] Common AEDs defined by their mechanisms of action are described in the following tables: Table 1. Examples of narrow spectrum AEDs narrow spectrum AED Mechanism Indication Phenytoin Sodium channel Partial complex 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 Gabapentina Calcium channel Partial seizures Mixed seizures Pregabalin Calcium adjuvant therapy for partial seizures with or without secondary generalization Lacoste channel Adjuvant therapy for partial seizures Vigabatrin GABA receptor agonist Secondary generalized tonic-clonic seizures Partial seizures due to West syndrome Table 2. Examples of AEDs broad spectrum AED broad mechanism Spectrum indication Valproic acid GABA / Sodium channel o 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
    [0027] [0027] The present invention demonstrates that patients with treatment-resistant childhood onset epilepsy have a low rate of seizure reduction response when treated with the stiripentol antiepileptic drug. In addition, it has been found that the effectiveness of treatment with stiripentol is further reduced when combined with the antiepileptic drug clobazam. However, surprisingly, when cannabinoid cannabidiol (CBD) is supplied in combination with stiripentol or with stiripentol and clobazam, there is a significant and beneficial increase in the response rate in relation to the ability of drugs to reduce
    [0028] [0028] Such an increase in effectiveness by adding CBD is unexpected, especially in view of the data showing a decrease in effectiveness when stiripentol is combined with clobazam. BRIEF SUMMARY OF THE INVENTION
    [0029] [0029] According to a first aspect of the present invention, cannabidiol (CBD) is provided for use in reducing seizures in treatment-resistant epilepsy, in which CBD is administered in combination with an antiepileptic drug (AED) that acts through of GABA receptor agonist.
    [0030] [0030] Preferably, the AED that acts through the GABA receptor agonist is stiripentol.
    [0031] [0031] In an additional embodiment, CBD is administered in combination with stiripentol and clobazam.
    [0032] [0032] Preferably, the CBD is in the form of a highly purified Cannabis extract that comprises at least 98% (w / w) CBD and comprises less than 0.15% THC and up to 1% CBDV.
    [0033] [0033] Alternatively, CBD is present as a synthetic compound.
    [0034] [0034] Preferably, the dose of CBD is below 50 mg / kg / day. More preferably, the dose of CBD is greater than 10 mg / kg / day, more preferably, the dose is CBD is greater than 20 mg / kg / day.
    [0035] [0035] Preferably, treatment-resistant epilepsy is Lennox-Gastaut syndrome or Dravet syndrome.
    [0036] [0036] According to a second aspect of the present invention, a method is provided for the treatment of treatment-resistant epilepsy, in which CBD is administered to an individual in need of it in combination with stiripentol (STP).
    [0037] [0037] Preferably, the individual is a human.
    [0038] [0038] Definitions of some of the terms used to describe the invention are detailed below:
    [0039] [0039] The cannabinoids described in the present patent application are listed below, along with their standard abbreviations. Table 4. Cannabinoids and their abbreviations CBD Cannabidiol CBDA Cannabidiolic acid CBDV Cannabidivarin CBDVA Cannabidivarinic acid THC Tetrahydrocannabinol
    [0040] [0040] The table above is not complete and simply details the cannabinoids that are identified in this patent application for reference. To date, more than 60 different cannabinoids have been identified, and these cannabinoids can be divided into different groups as follows: Phytocannabinoids; Endocannabinoids and synthetic cannabinoids
    [0041] [0041] "Phytocannabinoids" are cannabinoids that originate in nature and can be found in the Cannabis plant. Phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
    [0042] [0042] "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 extracted together with the cannabinoids have been substantially removed, such that the highly purified cannabinoid is greater than or equal to 98% (w / w) pure.
    [0043] [0043] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid type structure and are produced using chemical means rather than by the plant.
    [0044] [0044] Phytocannabinoids can be obtained in neutral form (were decarboxylated) or in the form of carboxylic acid 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 to undergo decarboxylation and result in the neutral form.
    [0045] [0045] "Treatment-resistant epilepsy" (TRE) or "intractable epilepsy" is defined, according to the 2009 ILAE guidance, as epilepsy that is not adequately controlled by clinical trial with one or more AEDs. Treatment-resistant epilepsies, such as Dravet's syndrome or Lennox-Gastaut syndrome, are childhood epilepsies that are difficult to treat. Often the treatment of seizures in patients with these syndromes involves the use of adjuvant therapy, for example, treatment with more than one antiepileptic drug simultaneously.
    [0046] [0046] “Childhood epilepsy” refers to the many syndromes
    [0047] [0047] The production of the highly purified cannabidiol extract (> 98% w / w) is described below, which has a known and constant composition and was used in the Examples below.
    [0048] [0048] Briefly, the active ingredient used is an extract, obtained by liquid carbon dioxide, containing chemotypes of Cannabis sativa L. with a high content of CBD, which was further purified by a method of crystallization in solvent to produce CBD. The crystallization process specifically removes other cannabinoids and plant components to produce more than 98% CBD. Although CBD is highly purified because it was produced from a Cannabis plant rather than synthetically, there are a small number of other cannabinoids that are produced and extracted simultaneously with CBD. Details of these cannabinoids and the amounts in which they are present in the drug are as described in Table 5 below. Table 5: Composition of highly purified CBD extract Cannabinoid CBD concentration> 98% w / w CBDA NMT 0.15% w / w CBDV NMT 1.0% w / w ∆9 THC NMT 0.15% w / w CBD- C4 NMT 0.5% w / w> - greater than NMT - no more than EXAMPLE 1: DRUG INTERACTION BETWEEN CANABIDIOL
    [0049] [0049] The effectiveness of CBD for the adjuvant treatment of seizures associated with Dravet's syndrome has been demonstrated in a single trial in patients aged 2-18 years. After a baseline period of 4 weeks, patients were randomized to receive CBD 20 mg / kg / day (n = 61) or placebo (n = 59). CBD or placebo was added to your ongoing antiepileptic treatment, which remained stable throughout the study's treatment period.
    [0050] [0050] All patients were diagnosed with treatment-resistant Dravet's syndrome and seizures were inadequately controlled with one or more antiepileptic drugs (AEDs) simultaneously, with or without vagal nerve stimulation or ketogenic diet.
    [0051] [0051] Seizure counts were reported daily using an Interactive Voice Response System. Seizure seizures were defined as all atonic, tonic, clonic and tonic-clonic seizures that could be counted. The primary endpoint of effectiveness was the percentage change from baseline in seizures.
    [0052] [0052] At baseline, the characteristics of the disease state were comparable between groups, with 72.5% reporting an increase in seizure frequency with previous treatment and 15% never experiencing a reduction in seizure frequency with previous medications.
    [0053] [0053] During a baseline period of 4 weeks, patients were required to have had at least 4 seizures (tonic-clonic, clonic, tonic or atonic) while on stable therapy with AED. Patients had previously failed with a median of 4 previous AEDs, and 93% were taking 2 or more concurrent AEDs during the trial. The most commonly used concomitant AEDs (> 25% of patients) were clobazam, valproate, stiripentol, levetiracetam and topiramate.
    [0054] [0054] The median percentage change from baseline in the reduction of seizures in Dravet's syndrome for the CBD group 20 mg / kg / day was statistically higher than that obtained with placebo (p = 0.0123).
    [0055] [0055] After the trial, statistical analysis was performed on the various groups of patients to determine if there was an interaction between any of the concomitant AEDs that the patients were taking. Data for the interaction between CBD and stiripentol (STP) are described below. Results
    [0056] [0056] Table 6 below describes the percentage of patients who experienced a 50% reduction in seizures over the treatment period. Table 6: Interaction between CBD and other AEDs Combination of AEDs Percentage of patients with seizure reduction greater than 50% Stiripentol 14% Stiripentol + Clobazam 8% Stiripentol + CBD 43% Stiripentol + Clobazam + CBD 26%
    [0057] [0057] As shown, 14% of patients who were taking stiripentol and placebo achieved a greater than 50% reduction in the number of seizures compared to the number recorded during the baseline 4-week registration period.
    [0058] [0058] Surprisingly, there was a reduction in effectiveness in patients who were taking stiripentol and clobazam, in which only 8% of these patients experienced a reduction of over 50% in seizures compared to the baseline rate.
    [0059] [0059] In the groups taking the CBD test compound, there was an increase in effectiveness in both groups. It was found that 43% of patients using stiripentol and CBD achieved a reduction of more than 50% in seizures, while 26% of patients taking stiripentol, clobazam and CBD obtained a reduction of more than 50% in seizures.
    [0060] [0060] The increase in efficacy caused by the addition of CBD to the AED stiripentol provides a useful combination therapy.
    [0061] [0061] In addition, those patients who are already taking a combination of stiripentol and clobazam may benefit from the inclusion of CBD as an adjunct therapy, since such inclusion has been shown to reduce the number of seizures.
    [0062] [0062] As can be seen in Table 3, stiripentol and clobazam are AEDs commonly used in childhood epileptic syndromes and, in addition, they act by reinforcing gamma-aminobutyric acid (GABA) -A receptor agonists.
    [0063] [0063] Stiripentol is a positive allosteric modulator of GABA-A receptors in the brain that increases the duration of opening of the channel when it binds to a site other than the benzodiazepine binding site. Reduced synaptosomal absorption of GABA and / or inhibition of GABA transaminase may also explain the role of stiripentol in reducing seizures.
    [0064] [0064] Clobazam binds at distinct binding sites at the postsynaptic GABA receptor. These GABA receptors are at various locations in the CNS (Limbic system, reticular formation) and clobazam increases the time during which the receptor is open. As a result, hyperpolarization and membrane stabilization occurs, since the post-synaptic inhibitory effect of GABA is enhanced.
    [0065] [0065] The combination of CBD with AEDs that act as GABA receptor agonists may therefore prove to be of particular benefit in the treatment of childhood epileptic syndromes. EXAMPLE 2: DRUG INTERACTION BETWEEN CANABIDIOL (CBD) AND STYLIPENTOL (STP) IN HEALTHY VOLUNTEERS
    [0066] [0066] As part of an open, fixed-sequence clinical trial in healthy volunteers, the primary objective was to investigate the impact of CBD (750
    [0067] [0067] The plasma concentrations of the analytes were determined using validated bioanalytical methods. A secondary objective was to assess the safety and tolerability of CBD when co-administered with STP.
    [0068] [0068] When CBD was combined with STP (12 subjects), there was an increase of 1.28 to 1.55 times in the exposure (Cmax and AUCtau). Co-administration of STP with CBD had no effect on CBD exposure; however, STP reduced exposure to 7-OH-CBD and 7-COOH-CBD by 29% and 13%, respectively.
    [0069] [0069] The most common adverse event (AE) was diarrhea, none of the effects observed on exposure to analytes was likely to be of clinical relevance or correlated with the incidence or severity of AEs. Conclusions
    [0070] [0070] The data above demonstrate that the combination of CBD with STP provides a safe and effective combined treatment option.
    权利要求:
    Claims (11)
    [1]
    1. Use of a cannabidiol (CBD) in combination with an antiepileptic drug (AED) that acts by means of a GABA receptor agonist, characterized by the fact that it is for the manufacture of a drug for the reduction of seizures in treatment-resistant epilepsy.
    [2]
    2. Use according to claim 1, characterized by the fact that the AED that acts through the GABA receptor agonist is stiripentol.
    [3]
    Use according to claim 1 or 2, characterized by the fact that CBD is present in combination with stiripentol and clobazam.
    [4]
    Use according to any one of claims 1 to 3, characterized by the fact that the CBD is in the form of a highly purified Cannabis extract that comprises at least 98% (w / w) CBD.
    [5]
    5. Use according to claim 4, characterized by the fact that the highly purified extract comprises less than 0.15% THC.
    [6]
    6. Use according to claim 4, characterized by the fact that the extract still comprises up to 1% CBDV.
    [7]
    7. Use according to claim 1, characterized by the fact that CBD is present as a synthetic compound.
    [8]
    Use according to any one of claims 1 to 7, characterized by the fact that the dose of CBD is below 50 mg / kg / day.
    [9]
    Use according to any one of claims 1 to 8, characterized by the fact that the dose of CBD is above 10 mg / kg / day.
    [10]
    Use according to any one of claims 1 to 9, characterized by the fact that the dose of CBD is above 20 mg / kg / day.
    [11]
    11. Use according to any one of claims 1 to 10, characterized by the fact that treatment-resistant epilepsy is Lennox-Gastaut Syndrome or Dravet Syndrome.
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    GB202002754D0|2020-02-27|2020-04-15|Gw Res Ltd|Methods of treating tuberous sclerosis complex with cannabidiol and everolimus|
    GB2597299A|2020-07-20|2022-01-26|Gw Res Ltd|Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to structural abnormalities of the brain|
    GB2597300A|2020-07-20|2022-01-26|Gw Res Ltd|Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to structural abnormalities of the brain|
    GB2597297A|2020-07-20|2022-01-26|Gw Res Ltd|Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to structural abnormalities of the brain|
    GB2597282A|2020-07-20|2022-01-26|Gw Res Ltd|Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to genetic abnormalities|
    GB2597308A|2020-07-20|2022-01-26|Gw Res Ltd|Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to structural abnormalities of the brain|
    GB2597283A|2020-07-20|2022-01-26|Gw Res Ltd|Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to structural abnormalities of the brain|
    法律状态:
    2021-12-14| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    GB1801158.5|2018-01-24|
    GB1801158.5A|GB2572737A|2018-01-24|2018-01-24|Use of cannabinoids in the treatment of epilepsy|
    PCT/GB2019/050174|WO2019145700A1|2018-01-24|2019-01-22|Use of cannabinoids in the treatment of epilepsy|
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