USE OF CANNABIDIOL IN THE TREATMENT OF EPILEPSY

Abstract

The present disclosure relatesto the use of cannabidiol (CBD) for the treatment of seizures associated with Aicardi Syndrome. In one embodiment the seizures associated with Aicardi Syndrome are convulsive seizures; focal seizures with impairment or infantile spasm. The disclosure further relates to the use of CBD in combination with one or more anti-epileptic drugs (AEDs).

Claims

1. Cannabidiol (CBD) for use in the treatment of seizures associated with Aicardi Syndrome.

2. CBD for use according to claim 1, wherein the seizures associated with Aicardi Syndrome are convulsive seizures.

3. CBD for use according to claim 1, wherein the seizures associated with Aicardi Syndrome are focal seizures with impairment.

4. CBD for use according to claim 1, wherein the seizures associated with Aicardi Syndrome are infantile spasms.

5. CBD for use according to any of the preceding claims, wherein seizures associated with Aicardi Syndrome are treatment resistant.

6. CBD for use according to any of the preceding claims, wherein the CBD is used in combination with two or more concomitant anti-epileptic drugs (AED).

7. CBD for use according to any of the preceding claims, wherein the CBD is present as a highly purified extract of cannabis which comprises at least 95% (w/w) CBD.

8. CBD for use according to claim 7, wherein the extract comprises less than 0.15% THC.

9. CBD for use according to claim 7 or 8, wherein the extract further comprises up to 1% CBDV.

10. CBD for use according to claim 1, wherein the CBD is present as a synthetic compound.

11. CBD for use according to any of the preceding claims, wherein the one or more AED is selected from the group consisting of: clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; zonisamide; perampanel; and fosphenytoin.

12. CBD for use according to any of the preceding claims, wherein the number of different anti-epileptic drugs that are used in combination with the CBD is reduced.

13. CBD for use according to any of the preceding claims, wherein the dose of the one or more anti-epileptic drugs that are used in combination with the CBD is reduced.

14. CBD for use according to any of the preceding claims, wherein the dose of CBD is greater than 5 mg/kg/day.

15. A method of treating seizures associated with Aicardi Syndrome, comprising administering cannabidiol (CBD) to patient subject in need thereof.

16. A composition for use in the treatment of Aicardi Syndrome comprising cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavouring.

17. A composition according to claim 16, wherein the solvent is sesame oil.

18. A composition according to claim 16, wherein the co-solvent is ethanol.

19. A composition according to claim 16, wherein the sweetener is sucralose.

20. A composition according to claim 16, wherein the flavouring is strawberry flavour.

21. A composition according to claim 16, wherein the CBD is present at a concentration of between 25/mg/ml and 100 mg/ml.

22. A composition according to any of claims 16 to 21, which comprises cannabidiol (CBD) at a concentration of between 25 to 100 mg/ml, ethanol at a concentration of 79 mg/ml, sucralose at a concentration of 0.5 mg/ml, strawberry flavouring at a concentration of 0.2 mg/ml and sesame q.s. to 1.0 ml.

Description

DETAILED DESCRIPTION

Preparation of Highly Purified CBD Extract

[0062] 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.

[0063] 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.

[0064] 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).

[0065] 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.

[0066] 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

[0067] 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.

[0068] 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

[0069] An overview of the steps to produce a botanical extract, the intermediate, are as follows: [0070] 1. Growing [0071] 2. Decarboxylation [0072] 3. Extraction No. 1—using liquid CO.sub.2 [0073] 4. Extraction No. 2—‘winterization’ using ethanol [0074] 5. Filtration [0075] 6. Evaporation

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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

[0080] The manufacturing steps to produce the drug substance from the intermediate botanical extract are as follows: [0081] 1. Crystallization using C5-C12 straight chain or branched alkane [0082] 2. Filtration [0083] 3. Optional recrystallization from C5-C12 straight chain or branched alkane [0084] 4. Vacuum drying

[0085] Intermediate botanical extract (12kg) 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.

[0086] The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.

[0087] 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 <10mb at a temperature of 60° C. until dry before submitting the drug substance for analysis.

[0088] 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

[0089] 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.

[0090] The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at higher doses.

[0091] 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.

[0092] The drug substance, CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.

[0093] A sweetener and fruit flavouring are required to improve palatability of the sesame oil solution.

[0094] Ethanol was required to solubilize the sweetener and the flavouring.

[0095] 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%.

[0096] 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 ANC Young Adults with Aicardi Syndrome

Materials and Methods

[0097] 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.

[0098] All of these patients diagnosed with Aicardi Syndrome presented with multiple seizure types which included

[0099] 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.

[0100] All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable motor seizure types.

[0101] 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.

[0102] The daily dose was gradually increased by 2 to 5mg/kg increments until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved.

[0103] 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.

[0104] 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

[0105] 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.

[0106] 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 (%)

[0107] 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.

[0108] 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

[0109] 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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