Use of cannabinoids in the treatment of epilepsy

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of focal seizures. In one embodiment the patients suffering from focal seizures are children and young adults. CBD appears particularly effective in reducing focal seizures in patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; CDKL5; Neuronal ceroid lipofuscinoses (NCL); febrile infection related epilepsy syndrome (FIRES); Aicardi syndrome and brain abnormalities in comparison to other seizure types. Significantly CBD additionally is very effective in the reduction of a sub-type of focal seizures, focal seizures with impairment.

Claims

1. A method of treating focal seizures in Dravet Syndrome, comprising administering to a subject in need thereof a drug product comprising a cannabidiol (CBD) drug substance, wherein the CBD drug substance has a purity of at least 98% (w/w), wherein the CBD is administered at a dose ranging from about 5 mg/kg/day to about 25 mg/kg/day.

2. The method of claim 1, wherein the focal seizures are focal seizures with impairment.

3. The method of claim 1, wherein the Dravet Syndrome is treatment-resistant.

4. The method of claim 1, wherein the CBD is administered in combination with one or more concomitant anti-epileptic drugs (AED).

5. The method of claim 1, wherein the CBD is a highly purified extract of cannabis.

6. The method of claim 5, wherein the highly purified extract further comprises less than 0.15% tetrahydrocannabinol (THC).

7. The method of claim 5, wherein the highly purified extract further comprises up to 1% (w/w) cannabidivarin (CBDV).

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

9. The method of claim 4, wherein the one or more AED is selected from the group consisting of: carbamezapine, clobazam, clonazepam, clonidine, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, oxycarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.

10. The method of claim 1, wherein the dose of the CBD is increased to about 10 mg/kg/day.

11. The method of claim 1, wherein the dose of the CBD is increased to about 12 mg/kg/day.

12. The method of claim 1, wherein the dose of the CBD is increased to about 14 mg/kg/day.

13. The method of claim 1, wherein the dose of the CBD is increased to about 15 mg/kg/day.

14. The method of claim 1, wherein the dose of the CBD is increased to about 18 mg/kg/day.

15. The method of claim 1, wherein the dose of the CBD is increased to about 20 mg/kg/day.

16. A method of treating focal seizures in Dravet Syndrome, comprising administering to a subject in need thereof a drug product comprising a cannabidiol (CBD) drug substance, wherein the CBD drug substance has a purity of at least 98% (w/w), and the CBD is administered at a dose of 5 mg/kg/day, and then the dose is increased by 2 to 5 mg/kg increments, up to 25 mg/kg/day.

17. The method of claim 16, wherein the focal seizures are focal seizures with impairment.

18. The method of claim 16, wherein the Dravet Syndrome is treatment-resistant.

19. The method of claim 16, wherein the CBD comprises Δ9-tetrahydrocannabinol (THC).

20. The method of claim 19, wherein the CBD comprises not more than 0.15% (w/w) Δ9-tetrahydrocannabinol (THC).

21. The method of claim 16, wherein the dose of the CBD is increased to about 10 mg/kg/day.

22. The method of claim 16, wherein the dose of the CBD is increased to about 12 mg/kg/day.

23. The method of claim 16, wherein the dose of the CBD is increased to about 14 mg/kg/day.

24. The method of claim 16, wherein the dose of the CBD is increased to about 15 mg/kg/day.

25. The method of claim 16, wherein the dose of the CBD is increased to about 18 mg/kg/day.

26. The method of claim 16, wherein the dose of the CBD is increased to about 20 mg/kg/day.

27. The method of claim 16, wherein the CBD is administered in combination with one or more concomitant anti-epileptic drugs (AED).

28. The method of claim 27, wherein the one or more AED is selected from the group consisting of: carbamezapine, clobazam, clonazepam, clonidine, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, oxycarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.

Description

DETAILED DESCRIPTION

(1) Preparation of Highly Purified CBD Extract

(2) 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 the Examples below.

(3) 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 98% CBD.

(4) 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).

(5) 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.

(6) Both the botanical starting material and the botanical extract are controlled by specifications. The drug substance specification is described in Table 1 below.

(7) 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 Point 65-67° C. Identification E Specific Conforms with certified Optical CBD Reference Standard; Rotation −110° to −140° (in 95% ethanol) Total Purity Calculation ≥98.0% Chromatographic HPLC-UV ≥98.0% Purity 1 Chromatographic GC-FID/MS ≥98.0 % Purity 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

(8) 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.

(9) 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.

(10) Production of the Intermediate

(11) An overview of the steps to produce a botanical extract, the intermediate, are as follows: 1. Growing 2. Decarboxylation 3. Extraction No. 1—using liquid CO.sub.2 4. Extraction No. 2—‘winterization’ using ethanol 5. Filtration 6. Evaporation

(12) 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.

(13) 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 G. 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.

(14) Extraction No 1 was performed using liquid CO.sub.2 at 60 bar/10° C. to produce botanical drug substance (BDS).

(15) 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, which was then used for crystallisation to produce the test material.

(16) Production of the Drug Substance

(17) 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 3. Optional recrystallization from C5-C12 straight chain or branched alkane 4. Vacuum drying

(18) 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.

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

(20) 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 until dry before submitting the drug substance for analysis.

(21) 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.

(22) Production of the Drug Product

(23) 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.

(24) The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at higher doses.

(25) The drug product formulation is as described in Table 6 below:

(26) TABLE-US-00006 TABLE 6 Drug Product specification 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.

(27) The drug substance, CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.

(28) A sweetener and fruit flavouring are required to improve palatability of the sesame oil solution.

(29) Ethanol was required to solubilize the sweetener and the flavouring.

(30) 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%.

(31) 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 GBD has anticonvulsant efficacy in multiple species and models.

(32) Example 1 describes data produced in an expanded access treatment program in children with TRE.

EXAMPLE 1

Efficacy of Cannabidiol Reducing Focal Seizures in Children and Young Adults With Intractable Epilepsy

(33) Materials and Methods

(34) Of 137 children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE), fifty-one suffered from epilepsy that was characterised by focal seizures. These subjects were tested with a highly purified extract of cannabidiol (CBD) obtained from a cannabis plant. All subjects presented with focal type seizures, often in addition to generalised seizures. The participants in the study were part of an expanded access compassionate use program for CBD.

(35) The epileptic syndromes that these patients suffered from were as follows: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; CDKL5; Neuronal ceroid lipofuscinoses (NCL); febrile infection related epilepsy syndrome (FIRES); Aicardi syndrome and brain abnormalities.

(36) Other seizure types experienced by these patients included: tonic, clonic, tonic-clonic, myoclonic, atonic, absence, myoclonic-absence, focal seizures without impairment, focal seizures with impairment and focal seizures evolving to bilateral convulsive seizures.

(37) All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable seizure types.

(38) 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.

(39) 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.

(40) 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 every 4 weeks of CBD therapy.

(41) The patients on the study were all taking at least one concomitant AED. These included: carbamezapine, clobazam, clonazepam, clonidine, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, oxycarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.

(42) Results

(43) The 51 children and young adult patients ail of whom suffered from focal seizures received treatment with CBD who received treatment for at least 12 weeks.

(44) A summary of the 50% responders, based on 12 weeks of treatment are summarized in Table 7 below.

(45) TABLE-US-00007 TABLE 7 Summary of 50% responders after 12 weeks of treatment for focal seizures Focal seizures Total seizures (n = 51) (n = 137) >50% reduction in 63% (n = 32) 46% (n = 63) seizures <50% reduction in 37% (n = 19) 54% (n = 74) seizures

(46) Table 7 shows that after 3 months of therapy, a remarkable 63% of patients had an equal to or greater than >50% reduction in focal seizures, these data infer that the CBD is very effective at reducing this type of seizure.

(47) Conclusions

(48) These data indicate that CBD significantly reduces the number of local seizures in a high proportion of patients that do not respond well to existing AED.

(49) It was surprising that in this group of patients which are treatment-resistant such a high number were able to gain an effect. The fact that nearly two thirds of the patients (63%) benefitted from at least a fifty percent reduction in the number of focal seizures that they suffered from was remarkable.

EXAMPLE 2

Efficacy of Cannabidiol Reducing Focal Seizures with Impairment in Children and Young Adults with Intractable Epilepsy

(50) Materials and Methods

(51) Of 137 children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE), thirty-seven suffered from epilepsy that was characterised by focal seizures with impairment. These subjects were tested with a highly purified extract of cannabidiol (CBD) obtained from a cannabis plant. All subjects presented with focal seizures with impairment, often in addition to other generalised and/or focal seizures. The participants in the study were part of an expanded access compassionate use program for CBD.

(52) The epileptic syndromes that these patients suffered from were as follows: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; CDKL5; febrile infection related epilepsy syndrome (FIRES); Aicardi syndrome and brain abnormalities.

(53) All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable seizure types.

(54) 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.

(55) 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.

(56) 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 every 4 weeks of CBD therapy.

(57) The patients on the study were all taking at least one concomitant AED. These included: carbamezapine, clobazam, clonazepam, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam. N-desmethylclobazam, nordiazepam, oxycarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, topiramate, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.

(58) Results

(59) The 37 children and young adult patients all of whom suffered from focal seizures with impairment received treatment with CBD who received treatment for at least 12 weeks.

(60) A summary of the 50% responders, based on 12 weeks of treatment are summarized in Table 8 below.

(61) TABLE-US-00008 TABLE 8 Summary of 50% responders after 12 weeks of treatment for focal seizures with impairment Focal Seizures with Total seizures Impairment (n = 37) (n = 137) >50% reduction in 65% (n = 24) 46% (n = 63) seizures <50% reduction in 35% (n = 13) 54% (n = 74) seizures

(62) Table 8 shows that after 3 months of therapy, a remarkable 65% of patients had an equal to or greater than >50% reduction in focal seizures with impairment, these data infer that the CBD is very effective at reducing this type of seizure.

(63) Furthermore when these data are compared to the other sub-types of focal seizure, namely focal seizure without impairment and focal seizures leading to secondary generalisation it can clearly be seen that CBD was able to selectively reduce the occurrence of focal seizures with impairment. Table 9 below details these findings.

(64) TABLE-US-00009 TABLE 9 Summary of 50% responders after 12 weeks of treatment for all focal seizure types Focal Focal Focal Seizures Seizures Seizures Leading to with without Secondary Total Focal Impairment Impairment Generalised seizures (n = 37) (n = 6) (n = 15) (n = 51) >50% reduction 65% (n = 24) 50% (n = 3) 47% (n = 7) 63% (n = 32) in seizures <50% reduction 35% (n = 13) 50% (n = 3) 53% (n = 8) 37% (n = 19) in seizures
Conclusions

(65) These data indicate that CBD significantly reduces the number of focal seizures with impairment in a selective manner.

(66) It was surprising that in this group of patients which are treatment-resistant such a high number were able to gain an effect. The fact that over two thirds of the patients (65%) benefitted from at least a fifty percent reduction in the number of focal seizures with impairment that they suffered from was remarkable.

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