USE OF CANNABIDIOL IN THE TREATMENT OF NOCTURNAL SNORING

Abstract

The present disclosure relates to the use of cannabidiol (CBD) for the treatment of of nocturnal snoring. In particular the CBD appears particularly effective in treating nocturnal snoring in children and young adults with epilepsy The disclosure further relates to the use of CBD in 5 combination with one or more anti-epileptic drugs (AEDs).

Claims

1-7. (canceled)

8. A method of treating a treatment-resistant epilepsy in a subject in need thereof, wherein the treatment-resistant epilepsy is Doose Syndrome, comprising administering to the subject cannabidiol (CBD) in an amount of from about 5 mg/kg/day to about 25 mg/kg/day, wherein the CBD has a purity of at least 98% (w/w) CBD.

9. The method of claim 8, further comprising treating tonic-clonic seizures in the subject.

10. The method of claim 8, further comprising treating nocturnal snoring in the subject.

11. The method of claim 8, wherein the CBD comprises less than 0.15% THC.

12. The method of claim 8, wherein the CBD further comprises up to 1 CBDV.

13. The method of claim 8, wherein the CBD is used in combination with two or more concomitant anti-epileptic drugs (AED).

14. The method of claim 13, wherein the two or more AED are selected from the group consisting of: clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin.

15. The method of claim 13, wherein the number of different AED that is used in combination with the CBD in treatment is reduced relative to the number of AED prior to treatment with the CBD.

16. The method of claim 13, wherein the dose of the one or more AED that are used in combination with the CBD in treatment is reduced relative to the dose of AED administered prior to treatment with CBD.

17. The method of claim 8, further comprising treating one or more seizures selected from myoclonic, absence, atonic, myoclonic-absence and tonic seizures.

18. The method of claim 8, wherein 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 a maximum dose of 25 mg/kg/day.

19. The method of claim 8, wherein the CBD is administered in a formulation comprising a solvent, co-solvent, sweetener, and flavoring.

20. The method of claim 19, wherein the solvent is sesame oil, the co-solvent is ethanol, the sweetener is sucralose, and the flavoring is strawberry flavor.

21. The method of claim 19, wherein the formulation comprises: (i) cannabidiol (CBD) at a concentration of between about 22.5 mg/ml and about 110 mg/ml, (ii) ethanol at a concentration of about 71.1 mg/ml to about 86.9 mg/ml, (iii) a sweetener at a concentration of about 0.45 mg/ml to about 0.55 mg/ml, (iv) a flavoring at a concentration of about 0.18 mg/ml to about 0.22 mg/ml, and (v) a solvent q.s. to about 1.0 ml.

22. The method of claim 21, wherein the solvent is sesame oil.

23. The method of claim 21, wherein the CBD is at a concentration of about 100 mg/mL ±10%.

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

25. The method of claim 19, wherein the flavoring is strawberry flavoring.

26. The method of claim 8, wherein CBD is administered in a formulation comprising: (i) CBD at a concentration of between about 90 mg/ml and about 110 mg/ml; (ii) ethanol at a concentration of about 71.1 mg/ml to about 86.9 mg/mL; (iii) a sweetener at a concentration of about 0.45 mg/ml to about 0.55 mg/ml; (iv) flavoring at a concentration of about 0.18 mg/ml to about 0.22 mg/ml; and (v) sesame oil, q.s. to about 1.0 ml.

Description

DETAILED DESCRIPTION

Preparation of Highly Purified CBD Extract

[0029] 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.

[0030] 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.

[0031] 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).

[0032] 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.

[0033] Both the botanical starting material and the botanical extract are controlled by specifications. The drug substance specification is described in Table 2 below.

TABLE-US-00002 TABLE 2 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 CBD Optical 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 HPLC-UV Cannabinoids: 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

[0034] 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.

[0035] 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

[0036] An overview of the steps to produce a botanical extract, the intermediate, are as follows: [0037] 1. Growing [0038] 2. Decarboxylation [0039] 3. Extraction No.1—using liquid CO.sub.2 [0040] 4. Extraction No.2—‘winterization’ using ethanol [0041] 5. Filtration [0042] 6. Evaporation

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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

[0047] The manufacturing steps to produce the drug substance from the intermediate botanical extract are as follows: [0048] 1. Crystallization using C5-C12 straight chain or branched alkane [0049] 2. Filtration [0050] 3. Optional recrystallization from C5-C12 straight chain or branched alkane [0051] 4. Vacuum drying

[0052] 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.

[0053] The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.

[0054] 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.

[0055] 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

[0056] 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.

[0057] The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at higher doses.

[0058] The drug product formulation is as described in Table 3 below:

TABLE-US-00003 TABLE 3 Drug Product specification Qualitative Reference to Component Composition Function Quality Standard Cannabidiol 25 mg/ml or 100 mg/ml Active In-house (CBD) Anhydrous 79.0 mg/ml* Excipient Ph. Eur. ethanol 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.

[0059] The drug substance, CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.

[0060] A sweetener and fruit flavouring are required to improve palatability of the sesame oil solution.

[0061] Ethanol was required to solubilize the sweetener and the flavouring.

[0062] 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%.

[0063] 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 Cannabidol Reducing Seizure Frequency in Children and Young Adults with Doose Syndrome

Materials and Methods

[0064] Of 137 children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE), six suffered from Doose 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.

[0065] All of these patients with a diagnosis of Doose Syndrome presented with multiple seizure types which included tonic-clonic seizures; myoclonic seizures; atonic seizures; absence seizures; myoclonic-absence seizures; and tonic seizures. In addition nocturnal snoring was encountered by one of the patients in the study.

[0066] Both patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable motor seizure types.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] All patients were taking at least two concomitant anti-epileptic drugs. These included clobazam; diazepam; lacosamide; lamotrigine; levetiracetam; lorazepam; nordiazepam; n-desmethylclobazam; phenytoin; 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

[0071] There were 6 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 Doose Syndrome.

[0072] The change from baseline in the number of different seizures and total number of seizures after 16 weeks treatment are summarized in Table 4 below.

TABLE-US-00004 TABLE 4 Changes in Total Seizure Frequency with CBD Therapy Subject Change in >50% reduction number baseline (%) in seizures 1 −67.4 Yes 2 −100.0 Yes 3 −68.7 Yes 4 −92.0 Yes 5 −100.0 Yes 6 65.8 No

[0073] Table 4 shows that after 3 months of therapy, there was a decrease in total seizure frequency with five of the Doose syndrome patients.

[0074] Table 5 below describes the data that was collated for the other seizure types including nocturnal snoring.

TABLE-US-00005 TABLE 5 Changes in Total Seizure Frequency with CBD Therapy Atonic seizures Tonic-clonic Absence Nocturnal (n = 2) seizures (n = 5) seizures (n = 3) snoring (n = 1) >50% reduction 50% 80% 100% 100% in seizures <50% reduction 50% 20%  0%  0% in seizures

[0075] As can be seen CBD is a very effective treatment for all of the seizure sub-types associated with Doose Syndrome. In addition the fact that it was able to completely eliminate the occurrence of nocturnal snoring is remarkable.

Conclusions

[0076] These data indicate that CBD significantly reduces the number of seizures in a high proportion of patients that do not respond well to existing AED such as those suffering from Doose Syndrome.

[0077] It was surprising that in this group of patients which are treatment-resistant that CBD was so effective against, in particular, tonic-clonic seizures, absence seizures and nocturnal snoring.

REFERENCES

[0078] Prasad et al. (2013) “Proof of concept trial of dronabinol in obstructive sleep apnea” Front Psychiatry, vol 4, page 1