Use of cannabinoids in the treatment of epilepsy

Abstract

The present disclosure relates to the use of cannabidiol (CBD) for the treatment of atonic seizures. In particular the CBD appears particularly effective in reducing atonic seizures in patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome; CDKL5 and Dup15q in comparison to other seizure types. The disclosure further relates to the use of CBD in combination with one or more anti-epileptic drugs (AEDs).

Claims

1. A method of treating seizures in a patient having Lennox-Gastaut Syndrome, Dravet Syndrome, Tuberous Sclerosis Complex, or Doose Syndrome, comprising orally administering to the patient a pharmaceutical formulation comprising a cannabidiol (CBD) drug substance, wherein the CBD is present in the pharmaceutical formulation at a concentration of about 100 mg/mL, wherein the drug substance comprises CBD and at least one of (i) cannabidivarin (CBDV) at not more than 1.0% w/w based on the weight of the drug substance, (ii) delta-9 tetrahydrocannabinol (Δ.sup.9THC) at not more than 0.15% w/w based on the weight of the drug substance, or (iii) cannabidiol-C4 (CBD-C4) at not more than 0.5% w/w based on the weight of the drug substance, and wherein the patient is administered a starting dose of CBD of about 5 mg/kg/day, and after administering the starting dose of CBD, the starting dose is gradually increased by about 5 mg/kg increments up to a maximum of about 25 mg/kg/day.

2. The method of claim 1, wherein the drug substance comprises at least two of (i) CBDV at not more than 1.0% w/w based on the weight of the drug substance, (ii) Δ.sup.9THC at not more than 0.15% w/w based on the weight of the drug substance, or (iii) CBD-C4 at not more than 0.5% w/w based on the weight of the drug substance.

3. The method of claim 1, wherein the drug substance comprises (i) CBDV at not more than 1.0% w/w based on the weight of the drug substance, (ii) Δ.sup.9THC at not more than 0.15% w/w based on the weight of the drug substance, and (iii) CBD-C4 at not more than 0.5% w/w based on the weight of the drug substance.

4. The method of claim 3, wherein the drug substance comprises not more than 0.15% w/w cannabidiolic acid (CBDA) based on the weight of the drug substance.

5. The method of claim 4, wherein the starting dose of CBD is increased to a dose ranging from about 10 mg/kg/day to about 25 mg/kg/day.

6. The method of claim 1, wherein the administering reduces the number of seizures by at least 50% compared to the number of seizures experienced during a baseline period before CBD was administered.

7. The method of claim 4, wherein the administering reduces the number of seizures by at least 50% compared to the number of seizures experienced during a baseline period before CBD was administered.

8. The method of claim 5, wherein the administering reduces the number of seizures by at least 50% compared to the number of seizures experienced during a baseline period before CBD was administered.

9. The method of claim 6, wherein the seizures are atonic seizures, tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, or myoclonic seizures.

10. The method of claim 7, wherein the seizures are atonic seizures, tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, or myoclonic seizures.

11. The method of claim 8, wherein the seizures are atonic seizures, tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, or myoclonic seizures.

12. The method of claim 4, wherein the patient has Lennox-Gastaut syndrome.

13. The method of claim 12, wherein the starting dose of CBD is increased to a dose ranging from about 10 mg/kg/day to about 20 mg/kg/day.

14. The method of claim 13, wherein the administering reduces the number of seizures by at least 50% compared to the number of seizures experienced during a baseline period before CBD was administered.

15. The method of claim 14, wherein the seizures are atonic seizures, tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, or myoclonic seizures.

16. The method of claim 4, wherein the patient has Dravet syndrome.

17. The method of claim 16, wherein the starting dose of CBD is increased to a dose ranging from about 10 mg/kg/day to about 20 mg/kg/day.

18. The method of claim 17, wherein the administering reduces the number of seizures by at least 50% compared to the number of seizures experienced during a baseline period before CBD was administered.

19. The method of claim 18, wherein the seizures are atonic seizures, tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, or myoclonic seizures.

20. The method of claim 4, wherein the patient has Tuberous Sclerosis Complex.

21. The method of claim 20, wherein the starting dose of CBD is increased to about 25 mg/kg/day.

22. The method of claim 21, wherein the administering reduces the number of seizures by at least 50% compared to the number of seizures experienced during a baseline period before CBD was administered.

23. The method of claim 22, wherein the seizures are atonic seizures, tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, or myoclonic seizures.

24. The method of claim 4, wherein the patient has Doose Syndrome.

25. The method of claim 24, wherein the starting dose of CBD is increased to a dose ranging from about 10 mg/kg/day to about 25 mg/kg/day.

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

27. The method of claim 26, wherein the administering reduces the number of seizures by at least 50% compared to the number of seizures experienced during a baseline period before CBD was administered.

28. The method of claim 27, wherein the seizures are atonic seizures, tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, or myoclonic seizures.

29. An oral pharmaceutical formulation comprising (a) a cannabidiol (CBD) drug substance, (b) sesame oil, (c) ethanol, and (d) favoring, sweetener, or a combination thereof, wherein the CBD is present in the pharmaceutical formulation at a concentration ranging from about 90 mg/mL to about 110 mg/mL, and wherein the drug substance comprises CBD and at least one of (i) cannabidivarin (CBDV) at not more than 1.0% w/w based on the weight of the drug substance, (ii) delta-9 tetrahydrocannabinol (Δ.sup.9THC) at not more than 0.15% w/w based on the weight of the drug substance, or (iii) cannabidiol-C4 (CBD-C4) at not more than 0.5% w/w based on the weight of the drug substance.

30. The oral pharmaceutical formulation of claim 29, comprising flavoring and sweetener.

31. The oral pharmaceutical formulation of claim 29, wherein: the ethanol is present at a concentration of about 71.1 mg/ml to about 86.9 mg/mL.

32. The oral pharmaceutical formulation of claim 30, wherein the sweetener is present at a concentration of about 0.45 mg/ml to about 0.55 mg/ml, and the flavoring is present at a concentration of about 0.18 mg/ml to about 0.22 mg/ml.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the ILEA 2010 proposal for revised terminology for organization of seizures and epilepsies.

DEFINITIONS

(2) Definitions of some of the terms used to describe the invention are detailed below:

(3) The cannabinoids described in the present application are listed below along with their standard abbreviations.

(4) TABLE-US-00004 TABLE 4 Cannabinoids and their abbreviations CBD Cannabidiol CBDA Cannabidiolic acid CBDV Cannabidivarin CBDVA Cannabidivarinic acid THC Tetrahydrocannabinol

(5) 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).

(6) “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.

(7) “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.

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

(9) 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.

(10) “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.

(11) “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: 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.

(12) “Atonic Seizures” are defined as a convulsive type of epileptic seizure which causes the muscles to relax and the patient to flop or fall.

(13) “Mixed seizures” are defined as the existence of both generalised and focal seizures in the same patient.

(14) 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 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

(15) 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.

(16) 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.

(17) 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).

(18) 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.

(19) Both the botanical starting material and the botanical extract are controlled by specifications. The drug substance specification is described in Table 5 below.

(20) 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

(21) 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.

(22) 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

(23) 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

(24) 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.

(25) 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.

(26) 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.

(27) 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

(28) 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

(29) 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.

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

(31) 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. 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

(32) 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.

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

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

(35) 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.

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

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

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

(39) 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%.

(40) 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 ATONIC SEIZURES IN CHILDREN AND YOUNG ADULTS WITH INTRACTABLE EPILEPSY

Materials and Methods

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

(42) The epileptic syndromes that these patients suffered from were as follows: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome, CDKL5 and Dup15q.

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

(44) 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.

(45) 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.

(46) 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 4 weeks of CBD therapy.

(47) 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. The majority took either clobazam and/or valproic acid.

Results

(48) There were 27 children and young adult patients all of whom suffered from atonic seizures received treatment with CBD for at least 12 weeks.

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

(50) TABLE-US-00007 TABLE 7 Summary of 50% responders after 12 weeks of treatment for atonic seizures Atonic seizures Total seizures (n = 27) (n = 137) >50% reduction in 63% (n = 17) 46% (n = 63) seizures <50% reduction in 37% (n = 10) 54% (n = 74) seizures

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

Conclusions

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

(53) 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 atonic seizures that they suffered from was remarkable.

(54) Furthermore when these data are compared to the other sub-types of generalised seizure, it can clearly be seen that CBD was able to selectively reduce the occurrence of atonic seizures. Table 8 below details these findings.

(55) TABLE-US-00008 TABLE 8 Summary of 50% responders after 12 weeks of treatment for all seizure sub-types Tonic- Atonic Tonic clonic Clonic Myoclonic Absence seizures seizures seizures seizures seizures seizures (n = 27) (n = 45) (n = 65) (n = 8) (n = 30) (n = 28) >50% 63% 49% 43% 50% 43% 64% reduction (n = 17) (n = 22) (n = 28) (n = 4) (n = 13) (n = 18) in seizures <50% 37% 51% 37% 50% 57% 36% reduction (n = 10) (n = 23) (n = 37) (n = 4) (n = 17) (n = 10) in seizures

(56) From Table 8 it can be seen that when the number of atonic seizures recorded is compared with other generalised seizure types such as tonic seizures (49% of patients experienced a greater than 50% reduction in seizure), tonic-clonic seizures (43% of patients experienced a greater than 50% reduction in seizure), and myoclonic seizures (43% of patients experienced a greater than 50% reduction in seizure) the fact that nearly two thirds (63%) of patients experiencing atonic seizures had a greater than 50% reduction in the number of seizures that occurred is very surprising.

REFERENCES:

(57) Ames F R and Cridland S (1986). “Anticonvulsant effects of cannabidiol.” S Afr Med J 69:14.

(58) 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

(59) 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

(60) 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

(61) Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011 Apr.;52 Suppl 2:3-9.

(62) Eadie, M J (December 2012). “Shortcomings in the current treatment of epilepsy.” Expert Review of Neurotherapeutics 12 (12): 1419-27.

(63) Geffrey A, Pollack S, Paolini J, Bruno P, Thiele E (2014) “Cannabidiol (CBD) treatment for refractory epilepsy in Tuberous Sclerosis Complex (TSC).” American Epilepsy Society Annual Meeting. 5-9 Dec. 2014.

(64) 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.

(65) Maa E and Figi P (2014). “The case for medical marijuana in epilepsy”, Epilepsia 55(6):783-786

(66) Mechoulam R and Carlini E A (1978). “Toward drugs derived from cannabis.” Die naturwissenschaften 65:174-9.

(67) Pelliccia A, Grassi G, Romano A, Crocchialo P (2005). “Treatment with CBD in oily solution of drug resistant paediatric epilepsies”. Congress of Cannabis and the Cannabinoids, Leiden, The Netherlands. International Association for Cannabis as a Medicine. p14.

(68) 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

(69) 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;

(70) Tomson, T; Wiebe, S; ILAE Commission on, Epidemiology (September 2011). “Standards for epidemiologic studies and surveillance of epilepsy.” Epilepsia. 52 Suppl 7: 2-26