USE OF CANNABINOIDS IN THE TREATMENT OF EPILEPSY

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of epilepsy which results from mutation of the KCNT1 gene. The CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised. In particular the cannabinoid tetrahydrocannabinol (THC) is present in an amount of from 0.02 to 0.1% (w/w). In an alternative embodiment the CBD may be in a synthetic form. In use the CBD may also be used concomitantly with one or more other anti-epileptic drugs (AED). The CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dosage form. Where the CBD is formulated for administration separately, sequentially or simultaneously it may be provided as a kit or together with instructions to administer the one or more components in the manner indicated. It may also be used as the sole medication, i.e. as a monotherapy.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

10. (canceled)

11. (canceled)

12. A method of treating a subject in need thereof diagnosed with epilepsy associated with KCNT1 mutation comprising administering cannabidiol (CBD) to a subject.

13. The method of claim 1, wherein treating reduces non-seizure symptoms in epilepsy associated with KCNT1 mutation.

14. The method of claim 1, wherein the epilepsy associated with KCNT1 mutation is Epilepsy of Infancy with Migrating Focal Seizures (EIMFS).

15. The method of claim 1, wherein the epilepsy is a treatment resistant epilepsy (TRE).

16. The method of claim 1, comprising administering one or more concomitant anti-epileptic drugs (AED).

17. The method of claim 1, wherein the CBD is present as a highly purified extract of cannabis which comprises at least 98% (w/w) CBD.

18. The method of claim 17, wherein the extract comprises up to 0.1% (w/w) tetrahydrocannabinol (THC).

19. The method of claim 17, wherein the THC is present at a concentration of between 0.02 and 0.1% (w/w).

20. The method of claim 17, wherein the extract comprises up to 1% (w/w) cannabidivarin (CBDV).

21. The method of claim 1, wherein the CBD is present as a synthetic compound.

22. The method of claim 1, wherein CBD is administered at a dose ranging from 5 to 50 mg/kg/day.

23. The method of claim 17, wherein the extract comprises 0.2-0.8% (w/w) cannabidivarin (CBDV), 0.3-0.4% (w/w) cannabidiol-C4 (CBD-C4), 0.1-0.15% (w/w) cannabidiol-C1 (CBD-C1), and 0.02-0.1% (w/w) tetrahydrocannabinol (THC).

24. The method of claim 1, wherein CBD is administered in a formulation comprising ethanol, sucralose, strawberry flavoring, and sesame oil.

25. The method of claim 24, wherein the formulation comprises 25 mg/mL or 100 mg/mL CBD, 79 mg/mL ethanol, 0.5 mg/mL sucralose, and 0.2 mg/mL strawberry flavoring.

Description

DETAILED DESCRIPTION

Preparation of Highly Purified CBD Extract

[0058] The following describes the production of the highly-purified (>98% w/w) cannabidiol extract of botanical origin which has a known and constant composition was used in the Examples below.

[0059] In summary the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 98% CBD. Although the CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small amount of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as follows:

TABLE-US-00002 Cannabinoid Concentration CBDV  0.2-0.8% (w/w) CBD-C4  0.3-0.4% (w/w) CBD-C1 0.1-0.15% (w/w) Δ.sup.9 THC 0.02-0.1% (w/w)

Production of the Drug Product

[0060] The drug product is presented as an oral solution. The oral solution presentation contains 25 mg/ml or 100 mg/ml CBD, with the excipients sesame oil, ethanol, sucralose and flavouring. Two product strengths are available to allow dose titration across a wide dose range.

[0061] The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at higher doses.

[0062] The drug product formulation is as described below:

TABLE-US-00003 Qualitative Reference to Component Composition Function Quality Standard Cannabidiol (CBD) 25 mg/ml or Active In-house 100 mg/ml Anhydrous ethanol 79.0 mg/ml Excipient Ph. Eur. Sucralose  0.5 mg/ml Sweetener In-house Strawberry  0.2 mg/ml Flavouring In-house flavouring Sesame oil q.s to 1.0 ml Excipient Ph. Eur.

[0063] The drug substance, CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.

[0064] A sweetener and fruit flavouring are required to improve palatability of the sesame oil solution.

[0065] Ethanol was required to solubilize the sweetener and the flavouring.

[0066] The composition can be substantially equivalent, by which is meant the functional ingredients can vary from the qualitative composition specified above by an amount of up to 10%.

[0067] Example 1 below describes the use of a highly purified cannabis extract comprising cannabidiol (CBD). Cannabidiol is the most abundant non-psychoactive cannabinoid in the selected chemovar. Previous studies in animals have demonstrated that CBD has anticonvulsant efficacy in multiple species and models.

[0068] Example 1 describes a case study of a child with a KCNT1 mutation that was provided highly purified cannabidiol as part of an expanded access treatment program of children with refractory epilepsy.

Example 1: Efficacy of Cannabidiol in Reducing Seizure Frequency, Seizure Severity and Other Symptoms in Children and Young Adults with Epilepsy Associated with KCNT1 Mutation

Materials and Methods

[0069] The child was aged three years and 11 months when he was enrolled in an expanded access compassionate use program for CBD. The patient was diagnosed with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS). The diagnosis by clinical and EEG criteria was corroborated by genetic testing which showed a mutation in the KCNT1 gene.

[0070] This subject was treated with a highly purified extract of cannabidiol (CBD) obtained from a cannabis plant. Seizure frequency and severity was documented in seizure diaries at baseline (4-week pre-treatment period) and over the treatment period. At each visit quality of life changes, including mood, behaviour, and cognitive function were recorded in addition to global impression of change using a numerical scale.

[0071] The patient first presented with seizures on the first day of life. He experienced on average 14 seizures per day. The types of seizure that occurred were motor arrest; asymmetric tonic; clonic extremity movements, irregular breathing and cyanosis. The patient also had a profound developmental delay with a Developmental Quotient (DQ) score of less than 25.

[0072] The patient had tried and failed seven different anti-epileptic drugs and at the time of treatment and continued on the ketogenic diet however his seizures remained refractory.

[0073] Pharmaceutical-grade plant-derived CBD oral solution was gradually titrated by 2 to 5 mg/kg increments up to a maximum dose of 25 mg/kg/day.

[0074] The patient was seen at regular intervals of 2-4 weeks. Laboratory testing for hematologic, liver, kidney function and concomitant AED levels was performed at baseline, and after every 4 weeks of CBD therapy.

[0075] The patient was treated for over three years and remains on treatment currently.

Results

[0076] Over the initial 12 weeks of the treatment period the overall seizure frequency increased by 13% compared to baseline. The patient was unable to reach the maximum dose of 25 mg/kg/day over the initial 12 week period due to experiencing somnolence when the CBD was titrated too quickly.

[0077] After 16 weeks of treatment the patient was able to reach a dose of 25 mg/kg/day without side effects and at this dose experienced a 12% reduction in overall seizure frequency.

[0078] The patient also experienced a clinically meaningful reduction in seizure severity. There was a 93% reduction in Type C seizures which were characterised by irregular breathing, cyanosis and clonic extremity movements. There was also a 48% reduction in Type D seizures which are the most severe type of seizures and are characterised by asymmetric tonic seizures.

[0079] In addition to the reduction in seizure frequency and severity the caregivers of the patient documented that treatment with the highly purified extract of CBD made a noticeable difference to his demeanour. After 6 months of treatment, he was described as more interactive and had attained new milestones including babbling, smiling, and fixing.

CONCLUSIONS

[0080] These data indicate that CBD is effective in the treatment of epilepsy associated with KCNT1 mutations.

[0081] It is surprising that in this very intractable patient there was a reduction in both the frequency and the severity of seizures which has been accompanied by an improvement in developmental milestones.

REFERENCES

[0082] Ames F R and Cridland S (1986). “Anticonvulsant effects of cannabidiol.” S Afr Med J 69:14. [0083] 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 [0084] Consroe P, Benedicto M A, Leite J R, Carlini E A, Mechoulam R. (1982). “Effects of cannabidiol on behavioural seizures caused by convulsant drugs or current in mice.” Eur J Pharmaco. 83: 293-8 [0085] Cunha J M, Carlini E A, Pereira A E, Ramos O L, Pimental C, Gagliardi R et al. (1980). “Chronic administration of cannabidiol to healthy volunteers and epileptic patient.” Pharmacology. 21:175-85 [0086] Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011 April; 52 Suppl 2:3-9. [0087] Eadie, M J (December 2012). “Shortcomings in the current treatment of epilepsy.” Expert Review of Neurotherapeutics 12 (12): 1419-27. [0088] Kwan P, Arzimanoglou A, Berg A T, Brodie M J, Hauser W A, Mathern G, Moshé S L, 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. [0089] Mechoulam R and Carlini E A (1978). “Toward drugs derived from cannabis.” Die naturwissenschaften 65:174-9. [0090] Porter B E, 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 [0091] Press C A, Knupp K G and Chapman K E (2015) “Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy”. Epilepsy and Behaviour. 45.49-52. [0092] Thurman, D J; Beghi, E; Begley, C E; Berg, A T; Buchhalter, J R; Ding, D; Hesdorffer, D C; Hauser, W A; Kazis, L; Kobau, R; Kroner, B; Labiner, D; Liow, K; Logroscino, G; Medina, M T; Newton, C R; Parko, K; Paschal, A; Preux, P M; Sander, J W; Selassie, A; Theodore, W; Tomson, T; Wiebe, S; ILAE Commission on, Epidemiology (September 2011). “Standards for epidemiologic studies and surveillance of epilepsy.” Epilepsia. 52 Suppl 7: 2-26