USE OF CANNABIDIOL IN THE TREATMENT OF EPILEPSY

Abstract

The present disclosure relates to the use of cannabidiol (CBD) for the reduction of seizure frequency in the treatment of “treatment-resistant epilepsy” (TRE). In particular, the disclosure relates to the use of CBD of treating TRE when the TRE is Lennox-Gastaut syndrome; Dravet syndrome; or Acardi syndrome.

Claims

1. A method of reducing convulsive seizure frequency in a patient with a treatment-resistant epilepsy, which is Lennox-Gastaut syndrome, comprising administering to the patient in need thereof cannabidiol (CBD), wherein the CBD has a purity of at least 98% (w/w) CBD and comprises not more than 0.15% (w/w) Δ9-tetrahydrocannabinol (THC), wherein the dose of the CBD ranges from 5-25 mg/kg/day.

2. A method of treating seizures in a subject having Aicardi Syndrome, comprising administering to the subject in need thereof cannabidiol (CBD), wherein the CBD has a purity of at least 95 (w/w), and the dose of CBD ranges from about 5-25 mg/kg/day.

3. The method of claim 2, wherein the seizures are convulsive seizures.

4. The method of claim 2, wherein the seizures are focal seizures with impairment.

5. The method of claim 2, wherein the seizures are infantile spasms.

6. The method of claim 2, wherein the seizures are treatment resistant.

7. The method of claim 2, wherein the CBD is a highly purified extract of cannabis which has a purity of at least 98% (w/w).

8. The method of claim 7, wherein the extract comprises less than 0.15% tetrahydrocannabinol (THC).

9. The method of claim 7, wherein the extract further comprises up to 1% cannabidivarin (CBDV).

10. The method of claim 2, wherein the CBD is present as a synthetic compound.

11. The method of claim 2, wherein the dose of the CBD is 10 mg/kg/day.

12. The method of claim 2, wherein the dose of the CBD is 12 mg/kg/day.

13. The method of claim 2, wherein the dose of the CBD is 14 mg/kg/day.

14. The method of claim 2, wherein the dose of CBD is 15 mg/kg/day.

15. The method of claim 2, wherein the dose of the CBD is 16 mg/kg/day.

16. The method of claim 2, wherein the dose of the CBD is 18 mg/kg/day.

17. The method of claim 2, wherein the dose of the CBD is 20 mg/kg/day.

18. The method of claim 24, wherein the CBD is administered as a composition, comprising cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavoring.

19. The method of claim 18, wherein the solvent is sesame oil.

20. The method of claim 18, wherein the co-solvent is ethanol.

21. The method of claim 18, wherein the sweetener is sucralose.

22. The method of claim 18, wherein the CBD is present at a concentration of ranging from about 25 mg/ml and to about 100 mg/ml.

23. The method of claim 2, wherein the patient is administered a starting dose of 5 mg/kg/day, and then the dose is increased by about 2-5 mg/kg up to a maximum of 25 mg/kg/day.

24. The method of claim 23, wherein the dose of the CBD is increased up to 10 mg/kg/day.

25. The method of claim 23, wherein the dose of the CBD is increased up to 12 mg/kg/day.

26. The method of claim 23, wherein the dose of the CBD is increased up to 14 mg/kg/day.

27. The method of claim 23, wherein the dose of CBD is increased up to 15 mg/kg/day.

28. The method of claim 23, wherein the dose of the CBD is increased up to 16 mg/kg/day.

29. The method of claim 23, wherein the dose of the CBD is increased up to 18 mg/kg/day.

30. The method of claim 23, wherein the dose of the CBD is increased up to 20 mg/kg/day.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 shows the ILAE proposal for revised terminology for organization of seizures and epilepsies in 2010.

DEFINITIONS

[0048] Definitions of some of the terms used to describe the invention are detailed below:

[0049] The cannabinoids described in the present application are listed below along with their standard abbreviations.

TABLE-US-00004 TABLE 4 Cannabinoid and their abbreviations CBD Cannabidiol [00001] CBDA Cannabidiolic acid [00002] CBDV Cannabidivarin [00003] CBDVA Cannabidivarinic acid [00004] THC Tetrahydrocannabinol [00005]

[0050] The table above is not exhaustive and merely details the cannabinoids which are identified in the present application for reference. So far over 60 different cannabinoids have been identified and these cannabinoids can be split into different groups as follows: Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).

[0051] “Phytocannabinoids” are cannabinoids that originate from nature and can be found in the cannabis plant. The phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.

[0052] “Highly purified cannabinoids” 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 co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.

[0053] “Synthetic cannabinoids” are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.

[0054] Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form 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 form to decarboxylate into the neutral form.

[0055] “Treatment-resistant epilepsy” (TRE) or “intractable epilepsy” is defined as per the ILAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.

[0056] “Childhood epilepsy” refers to the many different syndromes and genetic mutations that can occur to cause epilepsy in childhood. Examples of some of these are as follows: Tuberous Sclerosis Complex; Dravet Syndrome; Myoclonic-Absence Epilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria; Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau-Kleffner syndrome. The list above is non-exhaustive as many different childhood epilepsies exist.

[0057] Focal Seizures” are defined as seizures which originate within networks limited to only one hemisphere. What happens during the seizure depends on where in the brain the seizure happens and what that part of the brain normally does.

[0058] “Focal seizure where awareness/consciousness are impaired” has replaced the term “complex partial seizure”. These seizures usually start in a small area of the temporal lobe or frontal lobe of the brain and involve other areas of the brain within the same hemisphere that affect alertness and awareness. Most subjects experience automatisms during a focal seizure with impaired consciousness.

[0059] “Convulsive seizures” are clonic, tonic, tonic-clonic, atonic and focal secondary generalized seizures.

[0060] “Infantile spasms” are also known as epileptic spasms, juvenile spasms, and West syndrome. These are an epileptic disorder found in infants. Infantile spasms usually occur between the third and the twelfth month of life and commonly manifest around the fifth month.

[0061] “Mixed seizures” are defined as the existence of both generalised and focal seizures in the same patient.

[0062] The terms “50% responder” and “50% reduction in seizure” are both terms used in clinical studies. In the present application the terms define the percentage of subjects that experienced a greater than or equal to 50% reduction in the total number of seizures during treatment with CBD in comparison to the number experienced during the baseline period before the CBD was administered.

DETAILED DESCRIPTION

Preparation of Highly Purified CBD Extract

[0063] The following describes the production of the highly-purified (>98% w/w) cannabidiol extract which has a known and constant composition which was used for the expanded access trials described in Examples below.

[0064] In summary the drug substance used in the trials 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 95% CBD w/w, typically greater than 98% w/w.

[0065] The Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (drug substance).

[0066] The plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.

[0067] Both the botanical starting material and the botanical extract are controlled by specifications. The drug substance specification is described in Table 5 below.

TABLE-US-00005 TABLE 5 CBD Specification Test Test Method Limits Appearance Visual Off-white/pale yellow crystals Identification A HPLC-UV Retention time of major peak corresponds to certified CBD Reference Standard Identification B GC-FID/MS Retention time and mass spectrum of major peak corresponds to certified CBD Reference Standard Identification C FT-IR Conforms to reference spectrum for certified CBD Reference Standard Identification D Melting 65-67° C. Point Identification E Specific Conforms with certified CBD Optical Reference Standard; −110° Rotation to −140° (in 95% ethanol) Total Purity Calculation ≥98.0% Chromatographic Purity HPLC-UV ≥98.0% 1 Chromatographic Purity GC-FID/MS ≥98.0% 2 Other Cannabinoids: HPLC-UV CBDA NMT 0.15% w/w CBDV NMT 1.0% w/w Δ.sup.9 THC NMT 0.15% w/w CBD-C4 NMT 0.5% w/w Residual Solvents: GC Alkane NMT 0.5% w/w Ethanol NMT 0.5% w/w Residual Water Karl Fischer NMT 1.0% w/w NMT—Not more than

[0068] The purity of the CBD drug substance achieved is greater than 98%. The other cannabinoids which may occur in the extract are: CBDA, CBDV, CBD-C4 and THC.

[0069] Distinct chemotypes of Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. One type of plant produces predominantly CBD. Only the (−)-trans isomer occurs naturally, furthermore during purification the stereochemistry of CBD is not affected.

Production of the Intermediate

[0070] An overview of the steps to produce a botanical extract, the intermediate, are as follows:

1. Growing

2. Decarboxylation

[0071] 3. Extraction No. 1—using liquid CO.sub.2
4. Extraction No. 2—‘winterization’ using ethanol

5. Filtration

6. Evaporation

[0072] High CBD chemovars were grown, harvested and dried and stored in a dry room until required. The botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer for up to 3 months prior to extraction.

[0073] Decarboxylation of CBDA to CBD was carried out using a large Heraeus tray oven. The decarboxylation batch size in the Heraeus is approximately 15 Kg. Trays were placed in the oven and heated to 105° C.; the BRM took 96.25 minutes to reach 105° C. Held at 105° C. for 15 Minutes. Oven then set to 150° C.; the BRM took 75.7 minutes to reach 150° C.; BRM held at 150° C. for 130 Minutes. Total time in the oven was 380 Minutes, including 45 minutes cooling and 15 Minutes venting.

[0074] Extraction No 1 was performed using liquid CO.sub.2 at 60 bar/10° C. to produce botanical drug substance (BDS) which was used for crystallisation to produce the test material.

[0075] The crude CBD BDS was winterised in Extraction No 2 under standard conditions (2 volumes of ethanol at minus 20° C. for around 50 hours). The precipitated waxes were removed by filtration and the solvent evaporated using the rotary evaporator (water bath up to 60° C.) to yield the BDS.

Production of the Drug Substance

[0076] The manufacturing steps to produce the drug substance from the intermediate botanical extract are as follows:

1. Crystallization using C5-C12 straight chain or branched alkane

2. Filtration

[0077] 3. Optional recrystallization from C5-C12 straight chain or branched alkane
4. Vacuum drying

[0078] Intermediate botanical extract (12 kg) produced using the methodology above was dispersed in C5-C12 straight chain or branched alkane (9000 ml, 0.75 vols) in a 30 litre stainless steel vessel.

[0079] The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.

[0080] The crystals were isolated by vacuum filtration, washed with aliquots of cold C5-C12 straight chain or branched alkane (total 12000 ml), and dried under a vacuum of <10 mb at a temperature of 60° C. until dry before submitting the drug substance for analysis.

[0081] The dried product was stored in a freezer at minus 20° C. in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.

Production of the Drug Product

[0082] 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.

[0083] The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at higher doses.

[0084] The drug product formulation is as described in Table 6 below:

TABLE-US-00006 TABLE 6 Drug Product specification Reference Qualitative to Quality Component Composition Function Standard Cannabidiol (CBD) 25 mg/ml or 100 mg/ml Active In-house 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.

[0085] The drug substance, CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.

[0086] A sweetener and fruit flavouring are required to improve palatability of the sesame oil solution.

[0087] Ethanol was required to solubilize the sweetener and the flavouring.

[0088] The composition can be substantially equivalent, by which is meant the functional ingredients can vary from the qualitative composition specified in Table 6 by an amount of up to 10%.

[0089] Example 1 below describes the use of a highly purified cannabis extract comprising cannabidiol (CBD) in an expanded access treatment program in children with TRE.

Example 1: Efficacy of Cannabidiol Reducing Seizure Frequency in Children and Young Adults with Aicardi Syndrome

Materials and Methods

[0090] Of 137 children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE), 14 suffered from Aicardi syndrome. These subjects were tested with a highly purified extract of cannabidiol (CBD) obtained from a cannabis plant. The participants in the study were part of an expanded access compassionate use program for CBD.

[0091] All of these patients diagnosed with Aicardi Syndrome presented with multiple seizure types which included

[0092] focal seizures with impairment; infantile spasm; clonic seizures; tonic seizures; tonic-clonic seizures; atonic seizures; myoclonic seizures; absence seizures; and focal seizures evolving to secondary generalised seizures.

[0093] All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable motor seizure types.

[0094] The patients then received a highly purified CBD extract (greater than 98% CBD w/w) in sesame oil, of known and constant composition, at a dose of 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED) regimen.

[0095] The daily dose was gradually increased by 2 to 5 mg/kg increments until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved.

[0096] Patients were 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 CBD therapy.

[0097] All patients were taking at least two concomitant anti-epileptic drugs. These included clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; zonisamide. The average number of concomitant antiepileptic drugs being taken was 2.7.

Results

[0098] There were 14 children and young adult patients who received at least 3 months of treatment all of whom suffered from treatment-resistant epilepsy which is characterised by Aicardi Syndrome.

[0099] The change from baseline in the number of different seizures and total number of seizures after 12 weeks treatment are summarized in Table 7 below.

TABLE-US-00007 TABLE 7 Changes in Seizure Frequency with CBD Therapy Total Convulsive Focal seizures Infantile seizures seizures with impairment spasm Average change −69% −77% −62% −55.5% in baseline (%)

[0100] Table 7 shows that after 3 months of therapy, there was an average decrease in total seizures of 69% in the Aicardi syndrome patients. There was also a dramatic reduction of 77% of all convulsive seizures, a 62% reduction in the number of focal seizures with impairment and a 55.5% reduction in infantile spasm.

[0101] Previous data collected at an earlier stage of the expanded access compassionate use program for CBD described two patients. One patient experienced a reduction in focal onset seizures evolving to secondary generalisation (from 47 seizures at baseline to 17 per month at week 12) and the other patient experienced a decrease in tonic seizures (from 67 seizures at baseline to 6 per month at week 12) and tonic-clonic seizures (from 7 seizures at baseline to 5 per month at week 12).

CONCLUSIONS

[0102] These data indicate that CBD significantly reduces the number of seizures in Aicardi Syndrome patients that do not respond well to existing AED. Importantly a number of seizure types that are associated with Aicardi Syndrome namely: convulsive seizures; focal seizures with impairment and infantile spasm were significantly reduced. In particular the fact that these patients were considered treatment resistant the reduction in the number of seizures is very surprising.

REFERENCES

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