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US-12616705-B2 - Use of cannabinoids in the treatment of Angelman syndrome

US12616705B2US 12616705 B2US12616705 B2US 12616705B2US-12616705-B2

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of Angelman syndrome (AS). CBD has been shown to be particularly effective in improving anxiety in rodent models of AS. The CBD is preferably substantially pure. It may take the form of a highly purified extract of cannabis such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised. Alternatively, the CBD is synthetically produced. Alternatively, the CBD may be used as a botanical drug substance (BDS) from a cannabis plant in which CBD is the predominant cannabinoid. The CBD may also be present in combination with other cannabinoids and non-cannabinoid components such as terpenes. In use the CBD may be used concomitantly with one or more other medicaments. Alternatively, the CBD may be formulated for administration separately, sequentially or simultaneously with one or more medicaments or the combination may be provided in a single dosage form. Where the CBD is formulated for administration separately, sequentially or simultaneously it may be provided as a kit or together with instructions to administer the one or more components in the manner indicated. It may also be used as the sole medication, i.e. as a monotherapy.

Inventors

  • Geoffrey Guy
  • Stephen Wright
  • James Brodie
  • Marie WOOLLEY-ROBERTS
  • Livio LUONGO

Assignees

  • JAZZ PHARMACEUTICALS RESEARCH UK LIMITED

Dates

Publication Date
20260505
Application Date
20230502
Priority Date
20161216

Claims (15)

  1. 1 . A method for treating Angelman syndrome, comprising orally administering to a subject in need thereof a therapeutically effective amount of a cannabidiol (CBD) drug substance, wherein the CBD drug substance comprises at least 98% (w/w) CBD and the CBD is administered at a dose of at least 20 mg/kg/day.
  2. 2 . The method of claim 1 , wherein the CBD drug substance is administered in combination with one or more concomitant medications.
  3. 3 . The method of claim 1 , wherein the CBD drug substance is administered in combination with at least one anti-epileptic drug (AED).
  4. 4 . The method of claim 1 , wherein the CBD drug substance is an extract of cannabis.
  5. 5 . The method of claim 4 , wherein the extract comprises less than 0.15% THC.
  6. 6 . The method of claim 1 , wherein the CBD is a synthetic compound.
  7. 7 . The method of claim 1 , further comprising treating a movement disorder.
  8. 8 . The method of claim 1 , further comprising treating cognitive dysfunction.
  9. 9 . The method of claim 1 , wherein the CBD drug substance comprises greater than 98.5% (w/w) CBD.
  10. 10 . The method of claim 9 , wherein the CBD is an extract of cannabis.
  11. 11 . The method of claim 9 , wherein the CBD is a synthetic compound.
  12. 12 . The method of claim 1 , wherein the CBD drug substance comprises greater than 99% (w/w) CBD.
  13. 13 . The method of claim 12 , wherein the CBD is an extract of cannabis.
  14. 14 . The method of claim 13 , wherein the extract comprises less than 0.15% THC.
  15. 15 . The method of claim 1 , wherein the treating Angelman syndrome comprises treating anxiety in Angelman syndrome.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation of application Ser. No. 16/467,639 filed Jun. 7, 2019, now U.S. Pat. No. 11,679,087, which claims the benefit of International PCT Application No. PCT/GB2017/053735 filed Dec. 13, 2017; and Great Britain Application No. 1621480.1 filed Dec. 16, 2016; all of which are incorporated herein by reference to their entirety. FIELD OF THE INVENTION The present invention relates to the use of cannabidiol (CBD) in the treatment of Angelman syndrome (AS). The CBD is preferably substantially pure. It may take the form of a highly purified extract of cannabis such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised. Alternatively, the CBD is synthetically produced. In a further alternative the CBD may be used as a botanical drug substance (BDS) from a cannabis plant in which CBD is the predominant cannabinoid. In such an embodiment the CBD may be present in combination with other cannabinoids and non-cannabinoid components such as terpenes. In use the CBD may be used concomitantly with one or more other medicaments. Alternatively the CBD may be formulated for administration separately, sequentially or simultaneously with one or more medicaments or the combination may be provided in a single dosage form. Where the CBD is formulated for administration separately, sequentially or simultaneously it may be provided as a kit or together with instructions to administer the one or more components in the manner indicated. It may also be used as the sole medication, i.e. as a monotherapy. BACKGROUND TO THE INVENTION Angelman syndrome (AS) occurs in approximately 1 in 12,000 to 15,000 individuals and is caused by abnormalities on chromosome 15. Individuals with AS typically show severe to profound learning disability, significant difficulties with mobility and communication in addition to seizures. It has been suggested that between 50% and 80% of individuals with AS meet the criteria for autism spectrum disorder. Typical characteristics of Angelman syndrome include: delayed development which is usually noticeable from 6-12 months of age; severe language impairment with little or no speech; movement and balance problems (ataxia); frequent seizures (epilepsy) in around 85% of cases; a small head size (microcephaly); sociable behaviour with frequent smiling. A genetic anomaly responsible for AS occurs by chance around the time of conception. The UBE3A gene is either absent or malfunctions. A child usually inherits one copy of the UBE3A gene from each parent. Both copies are switched on (active) in most of the body's tissues. However, in certain areas of the brain, only the gene inherited from the mother is active. In most cases of AS (about 70%), the child's maternal copy of the UBE3A gene is missing, which means there's no active copy of the UBE3A gene in the child's brain. Testing compounds for their effectiveness on signs and symptoms of Angelman syndrome is challenging given that this disorder has so many different affected symptom domains. The UBE3A mouse model is used to evaluate a compounds effectiveness in the treatment of AS. This model has been shown to recapitulate many of the phenotypic features of AS, including motor dysfunction, increased seizure susceptibility, and hippocampal-dependent learning and memory deficits in mice with the knockout gene. The NOR test is used to evaluate cognition, particularly recognition memory, in rodent models of CNS disorders, such as Angelman syndrome. The test is based on the tendency of rodents to spend more time exploring a novel object than a familiar one. The choice to explore the novel object reflects the use of learning and recognition memory. The NOR test is conducted in an open field arena with two different kinds of objects. Both objects are generally consistent in height and volume, but are different in shape and appearance. During habituation, the animals are allowed to explore an empty arena. Twenty-four hours after habituation, the animals are exposed to the familiar arena with two identical objects placed at an equal distance. The next day, the mice are allowed to explore the open field in the presence of the familiar object and a novel object to test short-term and long-term recognition memory. The time spent exploring each object and the discrimination index percentage is recorded. This test is useful for assessing cognitive dysfunction in rodent models of AS. There is no specific therapy for Angelman syndrome. Medication is usually required to control seizures. Physical and occupational therapies, communication therapy, and behavioral therapies are also important. The endocannabinoid system has been linked to physiological progression of autism spectrum disorders, possibly implicating CB1 and CB2 receptors. The phytocannabinoids are known to interact with the endocannabinoid system. The phytocannabinoid tetrahydrocannabi