Field

[0001 ] The invention relates to a method for treating a sleep disorder. The invention also relates to a pharmaceutical composition comprising an extract from a Cannabis plant, and its use in the treatment of the sleep disorder.

Background

[0002] The biological activity of Cannabis is well known, and has led it to become a "recreational" drug. However, with the discovery of a class of cannabinoid (CB) receptors, and the relaxation of laws regulating Cannabis use - in some jurisdictions decriminalisation - there now exists the opportunity to explore the potential of Cannabis as a source of new therapeutics.

[0003] There is also a growing movement of patients suffering from chronic diseases, such as sleep disorders, to seek natural remedies as alternative or complementary therapy.

[0004] Accordingly, there is a continuing need to develop new treatments for sleep disorders, which is derived, at least in part, from a natural source.

Summary

[0005] The invention provides a method of treating a sleep disorder comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a Cannabis extract. Accordingly, also provided is a pharmaceutical composition comprising the Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0006] The Cannabis extract comprises a cannabinoid fraction and a terpene fraction. The cannabinoid fraction typically comprises as the primary cannabinoid A ⁹ -Tetrahydrocannabinol (THC) or Cannabidiol (CDB). The cannabinoid fraction may also comprise one or more further cannabinoids selected from Cannabinodiol (CBN) and A ⁹ -Tetrahydrocannabivarin (THCV). The terpene fraction typically comprises beta-myrcene. The terpene fraction may further comprise one or more of linalool, nerolidol and limonene. When present, the limonene may be present in an amount of at least about 5.4% by weight of the terpene fraction. [0007] In one aspect, there is provided a pharmaceutical composition comprising a Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof, the Cannabis extract comprising a terpene fraction comprising limonene in an amount of at least about 5.4% by weight of the terpene fraction.

[0008] Preferably, the Cannabis extract comprises A ⁹ -Tetrahydrocannabinol (THC), Cannabidiol (CDB), Cannabinodiol (CBN) and beta-myrcene.

[0009] In one embodiment of the present invention the THC in the pharmaceutical composition is in an amount from 0% to 90% by weight of the extract.

[0010] In some embodiments of the present invention the pharmaceutical composition further comprises one or more of beta-caryophyllene, linalool, nerolidol 1 , ocimene, alpha- pinene, and beta-pinene.

[001 1 ] In one embodiment of the present invention the THC in the pharmaceutical composition is in an amount from 0% to 90% by weight of the extract.

[0012] In some embodiments of the present invention the pharmaceutical composition further comprises one or more of beta-caryophyllene, linalool, nerolidol 1 , ocimene, alpha- pinene, and beta-pinene.

[0013] In a further aspect, there is provided use of the Cannabis extract in the preparation of a medicament for treating a sleep disorder.

[0014] In yet another aspect, there is provided a pharmaceutical composition for treating a sleep disorder, wherein the pharmaceutical composition comprises a Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0015] In one embodiment, the present invention provides a pharmaceutical composition comprising a Cannabis extract comprising a terpene fraction, wherein said composition comprises:

(i) A ⁹ -Tetrahydrocannabinol (THC) in an amount from 0% to 90% by weight of the Cannabis extract;

(ii) Cannabidiol (CBD) in an amount from 0% to 20% by weight of the Cannabis extract;

(iii) Cannabinodiol (CBN) in an amount from 0% to 20% by weight of the Cannabis extract;

(iv) beta-myrcene in an amount from 0% to 20% by weight of the Cannabis extract; and

(v) limonene in an amount of at least about 5.4% by weight of the terpene fraction; wherein the pharmaceutical composition optionally comprises one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0016] In one embodiment, the present invention provides a pharmaceutical composition for treatment of a sleep disorder comprising a Cannabis extract comprising a terpene fraction, wherein said composition comprises:

(i) A ⁹ -Tetrahydrocannabinol (THC) in an amount from 0% to 90% by weight of the Cannabis extract;

(ii) Cannabidiol (CBD) in an amount from 0% to 20% by weight of the Cannabis extract;

(iii) Cannabinodiol (CBN) in an amount from 0% to 20% by weight of the Cannabis extract; and

(iv) beta-myrcene in an amount from 0% to 20% by weight of the Cannabis extract; and

(v) limonene in an amount of at least about 5.4% by weight of the terpene fraction; wherein the pharmaceutical composition optionally comprises one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0017] In a further aspect, there is provided use of the Cannabis extract in the preparation of a medicament for treating a sleep disorder.

[0018] In yet another aspect, there is provided a pharmaceutical composition for treating a sleep disorder, wherein the pharmaceutical composition comprises a Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0019] In a further aspect the present invention provides An oral pharmaceutical solution comprising a Cannabis extract comprising a terpene fraction, wherein said composition comprises:

(i) A ⁹ -Tetrahydrocannabinol (THC) in an amount from 0% to 90% by weight of the Cannabis extract; (ii) Cannabidiol (CBD) in an amount from 0% to 20% by weight of the Cannabis extract;

(iii) Cannabinodiol (CBN) in an amount from 0% to 20% by weight of the Cannabis extract;

(iv) beta-myrcene in an amount from 0% to 20% by weight of the Cannabis extract; and

(v) limonene in an amount of at least about 5.4% by weight of the terpene fraction; wherein the pharmaceutical composition optionally comprises one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0020] Preferably, the oral pharmaceutical solution is in sublingual spray form. Description of Embodiment(s)

[0021 ] The present invention provides a pharmaceutical composition comprising a Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0022] Cannabis plants produce a diverse array of secondary metabolites, including cannabinoids, terpenes and terpenoids, sterols, triglycerides, alkanes, squalenes, tocopherols, carotenoids and alkaloids. The mix of these secondary metabolites varies depending on several factors, including Cannabis variety, part of the Cannabis plant extracted, method of extraction, processing of the extract, and season.

[0023] There are several varieties of Cannabis plant, which have been described under two distinct naming conventions. One of these conventions identifies three distinct species of Cannabis plant, namely Cannabis sativa Linnaeus, Cannabis indica LAM., and Cannabis ruderalis. Another convention identifies all Cannabis plants as belonging to the Cannabis sativa L. species, with the various varieties divided amongst several subspecies, including: Cannabis sativa ssp. sativa and ssp. indica. As used herein, the term "Cannabis" refers to any and all of these plant varieties.

[0024] Extracts of Cannabis may be prepared by any means known in the art. The extracts may be formed from any part of the Cannabis plant containing cannabinoid, terpene and terpenoid compounds. Extracts may be formed by contacting an extractant with a leaf, seed, trichome, flower, keif, shake, bud, stem or a combination thereof. In some embodiments, the extract is formed from the flowers and shake of a Cannabis plant. Any suitable extractant known in the art may be used, including, for example, alcohols (e.g. methanol, ethanol, propanol, butanol, propylene glycol etc.), water, hydrocarbons (e.g. butane, hexane, etc.), oils (e.g. olive oil, vegetable oil, essential oil, etc.), a solvent (e.g. ethyl acetate, polyethylene glycol, etc.) or a supercritical fluid (e.g. liquid C0 ₂ ). The extractant may be completely or partially removed prior to incorporation of the Cannabis extract into the pharmaceutical composition, or it may be included in the pharmaceutical composition as a carrier. The extractant may be removed by heating the extract optionally under reduced pressure. It will be appreciated that some of the more volatile plant metabolites (such as terpenes) may also be removed with the extractant. Accordingly, in some embodiments, removing the extractant may enrich the cannabinoid fraction of the extract. In some embodiments, the extract is filtered to remove particulate material, for example, by passing the extract through filter paper or a fine sieve (e.g. a sieve with pore sizes of 5 μηι).

[0025] In some embodiments, the Cannabis extract is formed by applying heat and pressure to the plant material. Typically, in these embodiments, no extractant is required.

[0026] In some embodiments, the Cannabis extract is a Cannabis oil. As used herein, a "Cannabis oil" is an extract formed by contacting at least a part of a Cannabis plant with an oil. The extracting oil may optionally be removed. Extracting oils may be selected from olive oil, hemp oil, sesame oil, coconut oil, vegetable oil, canola oil, grape seed oil, almond oil, medium- chain triglyceride (MCT) oil, and any other edible oil, or a combination thereof.

[0027] The term "cannabinoid" as used herein relates to any cannabinoid that have been isolated from a Cannabis plant or synthetically created to have activity involving the

endocannabinoid system.

[0028] The term "cannabinoid fraction" is used to describe the combination of cannabinoid compounds present in the Cannabis extract.

[0029] The term "terpenes" or "terpenoids" as used herein refers to a class of hydrocarbon molecules, which often provide a unique smell. Terpenes are derived from units of isoprene, which has the molecular formula C ₅ H ₈ . The basic molecular formula of terpenes are multiples of the isoprene unit, i.e. (C ₅ H ₈ ) _n where n is the number of linked isoprene units. Terpenoids are terpene compounds that have been further metabolised in the plant, typically through an oxidative process, and therefore usually contain at least one oxygen atom.

[0030] The term "terpene fraction" is used to describe the combination of terpene and terpenoid compounds present in the Cannabis extract. [0031 ] The inventors have observed that the efficacy of a pharmaceutical composition is enhanced when the terpene fraction has a certain profile, i.e. a certain proportion of particular terpenes/terpenoids are present in the extract. It is believed that the increase in efficacy may be synergistic (i.e. non-additive). It is also believed that the presence of specific components in the terpene fraction may enhance the patient's tolerance to cannabinoid therapy.

[0032] In some embodiments, the Cannabis extract contains high amounts (e.g. greater than 50% by weight) of a main cannabinoid, typically THC. In some embodiments, the

Cannabis extract may comprise the cannabinoid fraction in an amount of about 50% to about 99.999% by weight, for example, about 55% to about 99.999%, about 60% to about 99.999%, about 70% to about 99.999%, about 80% to about 99.999%, about 90% to about 99.999%, about 90% to about 99.99%, about 90% to about 99.9%, or about 90% to about 99.5% by weight of the Cannabis extract. In some embodiments, the Cannabis extract comprises about 0.001 % to about 50% by weight of non-cannabinoids, for example, about 0.001 % to about 20% by weight or about 0.001 % to about 10% by weight non-cannabinoids.

[0033] In some embodiments, the cannabinoid fraction is present from about 0.001 to about 60% by weight of the pharmaceutical composition, for example, about 5% to about 55% or about 10% to about 50% by weight of the pharmaceutical composition.

[0034] In some embodiments, one or more additional compounds (e.g. cannabinoid, terpene or terpenoid compounds) may be added to the Cannabis extract. The addition of compounds may be to compensate for natural variations in the relative amounts of certain compounds being expressed in the Cannabis plant. The added compounds may be synthetic versions of the desired compounds, they may be purified compounds obtained from other Cannabis extracts, or they may be added by blending two or more extracts.

[0035] To date, over 100 cannabinoids have been identified in Cannabis plants. A comprehensive list of these cannabinoids may be found in Mahmoud A. El Sohly and Waseem Gul, "Constituents of Cannabis Sativa." In Handbook of Cannabis Roger Pertwee (Ed.) Oxford University Press (2014) (ISBN: 9780199662685). Cannabinoids that have been identified in Cannabis plants include: Cannabigerol (E)-CBG-C5, Cannabigerol monomethyl ether (E)- CBGM-C5 A, Cannabigerolic acid A (Z)-CBGA-C5 A, Cannabigerovarin (E)-CBGV-C3, Cannabigerolic acid A (E)-CBGA-C5 A, Cannabigerolic acid A monomethyl ether (E)CBGAM-C5 A and Cannabigerovarinic acid A (E)-CBGVAC3A); (±)-Cannabichromene CBC-C5, (±)- Cannabichromenic acid A CBCA-C5 A, (±)-Cannabivarichromene, (±)-Cannabichromevarin CBCV-C3, (±)-Cannabichromevarinic acid A CBCVA-C3 A); (-)-Cannabidiol CBD-C5, Cannabidiol momomethyl ether CBDMC5, Cannabidiol-C4 CBD-C4, (-)-Cannabidivarin CBDVC3, Cannabidiorcol CBD-CI, Cannabidiolic acid CBDA-C5, Cannabidivarinic acid CBDVA- C3); Cannabinodiol CBNDC5, Cannabinodivarin CBND-C3); A ⁹ -Tetrahydrocannabinol A ⁹ -THC- C5, A ⁹ -Tetrahydrocannabinol-C4 A ⁹ -THCC4, A ⁹ -Tetrahydrocannabivarin A ⁹ -THCV-C3, A ⁹ -Tetrahydrocannabiorcol, A ⁹ -THCO-CI, A ⁹ -Tetrahydrocannabinolic acid A A ⁹ -THCA-C5 A, A ⁹ -Tetrahydrocannabinolic acid B, A ⁹ -THCA-C5 B, A ⁹ -Tetrahydrocannabinolic acid-C4 A and/or B A ⁹ -THCA-C4 A and/or B, A ⁹ -Tetrahydro-cannabivarinic acid A A ⁹ -THCVA-C3 A,

A ⁹ -Tetrahydrocannabiorcolic acid A and/or B A ⁹ -THCOA-CI A and/or B), (-)-A ⁸ -trans-(

6aR,10aR)-A ⁸ -Tetrahydrocannabinol A ⁸ -THC-C5, (-)-A ⁸ -trans-(6aR,10aR)- Tetrahydrocannabinolic acid A A ⁸ -THCA-C5 A, (-)-(6aS,10aR)-A ⁹ -Tetrahydrocannabinol (-)-cis- A ⁹ -THC-C5); Cannabinol CBN-C5, Cannabinol-C4 CBN-C4, Cannabivarin CBN-C3, Cannabinol C2 CBN-C2, Cannabiorcol CBN-CI, Cannabinolic acid A CBNA-C5 A, Cannabinol methyl ether CBNM-C5, (-)-(9R,10R)-trans-Cannabitriol (-)-trans-CBT-C5, (+)-(9S,10S)-Cannabitriol (+)- trans-CBT-C5, (±)-(9R,10S/9S,10R)— ); Cannabitriol (±)-cis-CBT-C5, (-)-(9R,10R)-trans-10-O- Ethyl-cannabitriol (-)-trans-CBT-OEt-C5, (±)-(9R,10R/9S,10S)-Cannabitriol-C3 (±)-trans-CBT- C3, 8,9-Dihydroxy-A6a(10a)-tetrahydrocannabinol 8,9-Di-OH-CBT-C5, Cannabidiolic acid A cannabitriol ester CBDA-C5 9-OH-CBT-C5 ester, (-)-(6aR,9S,10S,10aR)-9,10- Dihydroxyhexahydrocannabinol, Cannabiripsol, Cannabiripsol-C5,

(-)-6a,7,10a-Trihydroxy-A ⁹ -tetrahydrocannabinol (-)-Cannabitetrol,

10-Oxo-A6a(1 (^tetrahydrocannabinol OTHC); (5aS,6S,9R,9aR)-Cannabielsoin CBE-C5, (5aS,6S,9R,9aR)-C3-Cannabielsoin CBE-C3, (5aS,6S,9R,9aR)-Cannabielsoic acid A

CBEA-C5 A, (5aS,6S,9R,9aR)-Cannabielsoic acid B CBEA-C5 B;

(5aS,6S,9R,9aR)-C3-Cannabielsoic acid B CBEA-C3 B, Cannabiglendol-C3 OH-iso-HHCV-C3, Dehydrocannabifuran DCBF-C5, Cannabifuran CBF-C5),

(-)-A ⁷ -trans-(1 R,3R,6R)-lsotetrahydrocannabinol,

(±)-Δ ⁷ -1 ,2-cis-(1 R,3R,6S/1 S,3S,6R)-lsotetrahydrocannabivarin, (-)-A ⁷ -trans-(1 R,3R,6R)- Isotetrahydrocannabivarin; (±)-(laS,3aR,8bR,8cR)-Cannabicyclol CBL-C5,

(±)-(1 aS,3aR,8bR,8cR)-Cannabicyclolic acid A CBLA-C5 A,

(±)-(laS,3aR,8bR,8cR)-Cannabicyclovarin CBLV-C3; Cannabicitran CBTC5;

Cannabichromanone CBCN-C5, CannabichromanoneC3 CBCN-C3, and Cannabicoumaronone CBCON-C5.

[0036] The Cannabis extract may comprise 50-99% by weight of a main cannabinoid. The main cannabinoid may be A ⁹ -tetrahydrocannabinol (THC) or cannabidiol (CBD). In some embodiments, the Cannabis extract comprises the main cannabinoid in an amount of 55-95% by weight of the cannabinoid fraction. Tyically, the Cannabis extract further comprises one or more secondary cannabinoids. THC or CBD may also be present in the Cannabis extract as a secondary cannabinoid. Typically, each secondary cannabinoid is present in an amount from 0.001 % to about 30% by weight of the cannabinoid fraction.

[0037] The extract may comprise THC in an amount from 0% to 90% by weight of the extract, for example, from 0.001 -90% or 2-85% by weight of the extract. When THC is present as the main cannabinoid, the extract may comprise THC in an amount of 40-90%, 50-90% or 55-85% by weight of the extract. When THC is present as a secondary cannabinoid, the extract may comprise THC in an amount of 0.001 -20% by weight of THC as a secondary cannabinoid, for example, from 0.001 -15% or 0.005-10% by weight of the extract.

[0038] Accordingly, in some embodiments, the Cannabis extract comprises 0-20% by weight of cannabidiol (CBD) as a secondary cannabinoid, for example, from 0.001 -20% or 0- 10% by weight of the extract.

[0039] In some embodiments, the Cannabis extract comprises 0-20% by weight of cannabinodiol (CBN), for example, from 0.001 -20% or 0-10% by weight of the extract.

[0040] In some embodiments, the Cannabis extract comprises 0-50% by weight

A ⁹ -Tetrahydrocannabivarin (THCV), for example, from 0.001 -20% or 0-10% by weight of the extract.

[0041 ] Typically, the Cannabis extracts also comprise other cannabinoids in addition to THC and/or CBD. These cannabinoids include A ⁹ -Tetrahydrocannabinolic acid (THCA), A ⁹ -Tetrahydrocannabivarin (THCV), (-)-Cannabidivarin (CBDV) and Cannabigerol (CBG). Each of these cannabinoids may be present in an amount from 0.001 % to 30% by weight of the composition.

[0042] In some embodiments, certain cannabinoids may be absent, or present in non- detectable amounts (e.g. less than 0.001 % by weight of the analyte). In some embodiments, the Cannabis extract may exclude one or more of the following cannabinoids: Cannabidiol (CBD), A ⁹ -Tetrahydrocannabivarin (THCV), Cannabidiolic acid (CBDA), Cannabigerolic acid (CBGA), Cannabinodiol (CBN) and (-)-Cannabidivarin (CBDV).

[0043] The Cannabis extract comprises non-cannabinoid compounds, which typically includes a terpene fraction, i.e. terpenes and terpenoids. In some embodiments, the Cannabis extract comprises a terpene fraction in an amount of less than 50% by weight, for example, less than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1 % by weight of the extract. ln some embodiments, the Cannabis extract may comprise terpene and terpenoid compounds in an amount of more than 0.001 % by weight of the extract, for example, more than 0.001 %, 0.005%, 0.01 %, 0.05%, 0.1 %, 0.5%, or 1 % of the total weight of the extract. In some embodiments, the Cannabis extract comprises about 0.001 % to about 50% by weight of terpene and terpenoid compounds, for example, about 0.001 % to about 20% by weight, about 0.001 % to about 10% by weight, about 0.001 % to about 6% by weight or about 0.001 to about 5% by weight of the composition.

[0044] Typically, the terpene fraction in the plant material used to form the extract may have a different terpene/terpenoid profile than the terpene profile of the final extract, both in terms of the amounts of specific compounds in the terpene fraction and the weight of the terpene fraction relative to the other components. For example, a Cannabis flower may comprise about 20% by weight cannabinoids and about 3% by weight terpenes. Following extraction and concentration (i.e. removal of the extractant), the amount of cannabinoids may increase to an amount of about 50-90% by weight and the terpene fraction may amount to about 0.1 -6% by weight of the Cannabis extract. This typical scenario shows that while the cannabinoids are concentrated when the extractant is removed, the relative amount of the terpene fraction is reduced, likely due to the volatility of many of the terpenes/terpenoids present in the terpene fraction. Therefore, the profile of the terpene fraction present in the Cannabis extract is significantly different from the profile of the terpene fraction that exists in Nature.

[0045] A variety of terpenes and terpenoids have also been identified in Cannabis extracts, including monoterpenes, monoterpenoids, sesquiterpenes and sesquiterpenoids. For example, the following terpenes and terpenoids have been identified in Cannabis extracts:

Alloaromadendrene, allyl hexanoate, benzaldehyde, (Z)-a-cis-bergamotene, (Z)-a-trans- bergamotene, β-bisabolol, epi-a-bisabolol, β-bisabolene, borneol (camphol), cis-y-bisabolene, bomeol acetate (bomyl acetate), a-cadinene, camphene, camphor, cis-carveol, caryophyllene (β-caryophyllene), a-humulene (a-caryophyllene), γ-cadinene, Δ-3-carene, caryophyllene oxide, 1 ,8-cineole, citral A, citral B, cinnameldehyde, a-copaene (aglaiene), γ-curcumene, β-cymene, β-elemene, γ-elemene, ethyl decdienoate, ethyl maltol, ethyl propionate, ethylvanillin, eucalyptol, a-eudesmol, β-eudesmol, γ-eudesmol, eugenol, cis-B-famesene ((Z)-B-farnesene), trans-a-farnesene, trans-B-famesene, trans-Y-bisabolene, fenchone, fenchol (norbomanol, β-fenchol), geraniol, a-guaiene, guaiol, methyl anthranilate, methyl salicylate, 2-methyl-4- heptanone, 3-methyl-4-heptanone, hexyl acetate, ipsdienol, isoamyl acetate, lemenol, limonene, d-limonene (limonene), linolool (linalyl alcohol, β-linolool), α-longipinene, menthol, γ-muurolene, myrcene (β-myrcene), nerolidol, trans-nerolidol, nerol, β-ocimene (cis-ocimene), octyl acetate, α-phellandrene, phytol, α-pinene (2-pinene), β-pinene, pulegone, sabinene, cis-sabinene hydrate (cis-thujanol), β-selinene, a-selinene, γ-terpinene, terpinolene (isoterpine), terpineol (a-terpineol), terpineol-4-ol, a-terpinene (terpilene), a-thujene (origanene), vanillin, viridiflorene (ledene), and a-ylange.

[0046] It is believed that the presence of the particular terpenes/terpenoids in the terpene fraction is associated with beneficial effects of the pharmaceutical composition in use.

[0047] The terpene fraction typically comprises beta-myrcene. It is believed that beta- myrcene may enhance the bioavailability of the cannabinoids present in the extract and/or may assist in allowing the cannabinoids to pass the blood-brain-barrier. Beta-myrcene may be present in an amount of from 0% to about 40% by weight of the extract. In some embodiments, beta-myrcene is present in an amount of about 0-40% by weight of the terpene fraction, for example, from 0.001 % to about 25%, 5.1 % to 29% or about 5.5% to about 25% of the terpene fraction.

[0048] The terpene fraction may further comprise one or more of linalool, nerolidol and limonene.

[0049] When present, the limonene may be present in an amount of at least about 5.4% by weight by weight of the terpene fraction, for example, from about 5.5% to about 50% or about 5.5% to about 20% by weight of the terpene fraction. Limonene is a cyclic monoterpene having the molecular formula C ₁₀ H ₁₆ . There are a number of different naturally occurring isomers; however, the most common form is the dextrorotatory isomer, namely D-limonene.

[0050] Linalool is a terpenoid that is found in many flower and spice plants having the molecular formula C ₁₀ H ₁₈ O. It is believed that when linalool is present in a Cannabis extract, that is may provide a sedative effect. In some embodiments, linalool may be present in an amount of at least 0.05% by weight of the terpene fraction. In some preferred embodiments, linalool is present in an amount of at least 5% by weight of the terpene fraction. In other embodiments, linalool is present in amount of from 0.05% to 25% by weight of the terpene fraction, for example, from 0.1 % to 20% by weight of the terpene fraction.

[0051 ] Nerolidol is a sesquiterpenoid having the molecular formula of Ci ₅ H ₂ 60. It exists in Nature in two isomeric forms, namely nerolidol 1 and nerolidol 2, which differ in the geometry around a central olefin, i.e. either cis or trans isomers. The extract may comprise nerolidol (i.e. both nerolidol 1 and nerolidol 2) in an amount of at least 0.001 % by weight of the terpene fraction, for example, from 0.01 % to 20% by weight of the terpene fraction. Typically, nerolidol 1 is present in greater amount relative to nerolidol 2. In some embodiments, nerolidol 1 may be absent (or present in an amount below the limit of detection). In some embodiments, nerolidol 2 may be absent (or present in an amount below the limit of detection). In some embodiments, nerolidol 1 and nerolidol 2 are absent (or present in an amount below the limit of detection). Nerolidol 1 may be present in the extract in an amount of at least about 0.001 % by weight of the terpene fraction, for example, from 0.001 % to 20% or 0.001 to 15% by weight of the terpene fraction. Nerolidol 2 may be present in the extract in an amount of at least about 0.001 % by weight of the terpene fraction, for example, from 0.001 % to 20% or 0.001 to 15% by weight of the terpene fraction.

[0052] The Cannabis extract may also comprise a pinene (e.g. alpha-pinene and/or beta- pinene). Pinene is a bicyclic monoterpene having the molecular formula C ₁₀ H ₁₆ . Pinene is found in Nature in two isomeric forms: alpha-pinene and beta-pinene. The extract may comprise pinene (i.e. alpha-pinene and beta-pinene) in an amount of at least 5% by weight of the terpene fraction, for example, at least 6%, 7%, 8%, 9% or 10% by weight of the terpene fraction. Typically, beta-pinene is present in an amount greater than the amount of alpha- pinene. However, in some embodiments, alpha-pinene is present in greater amount relative to beta-pinene. The ratio of beta-pinene to alpha-pinene may be about 1 :1 , about 2:1 , about 3:1 , about 4:1 or about 5:1 . Alpha-pinene may be present in the extract in an amount of at least about 0.001 % by weight of the terpene fraction, for example, from 0.001 % to 30% or from 0.001 to 20% by weight of the terpene fraction. Beta-pinene may be present in the extract in an amount of at least about 0.001 % by weight of the terpene fraction, for example, 0.001 % to 80%, 10% to 80%, 20% to 75% or 40% to 75% by weight of the terpene fraction.

[0053] The terpene fraction may also comprise beta-caryophyllene. Beta-caryophyllene may be present in an amount of at least 0.001 % by weight of the terpene fraction, for example, from 0.001 % to 20% or 0.001 % to 15% of the terpene fraction.

[0054] In some embodiments, the extract further comprises humulene. It is believed that that humulene may enhance the sedative properties of the extract. Humulene is also sometimes called alpha-caryophyllene.

[0055] The Cannabis extract may also include ocimene. Ocimene may be present in an amount of at least 0.001 % by weight of the terpene fraction, for example, from 0.001 % to 20% or 0.001 % to 5% by weight of the terpene fraction. [0056] In some embodiments, the terpene fraction comprises beta-myrcene, D-limonene, beta-caryophyllene, linalool, nerolidol 1 , ocimene, alpha-pinene, and beta-pinene.

[0057] In some embodiments, the terpene fraction may be present in the composition in an amount from 0.001 % to 6% by weight of the extract and may comprise:

• beta-myrcene in an amount of from 0% to 40% by weight of the terpene fraction;

• beta-caryophyllene in an amount of from 0% to 20% by weight of the terpene fraction;

• D-limonene in an amount of from about 5.5% to about 50% by weight of the terpene fraction;

• linalool in an amount of from 0% to 20% by weight of the terpene fraction;

• beta-pinene in an amount of from 0% to 80% by weight of the terpene fraction;

• alpha-pinene in an amount of from 0% to 20% by weight of the terpene fraction;

• nerolidol 1 in an amount of from 0% to 20% by weight of the terpene fraction;

• nerolidol 2 in an amount of from 0% to 20% by weight of the terpene fraction; and

• ocimene in an amount of from 0% to 20% by weight of the terpene fraction.

[0058] In some embodiments, specific terpenes or terpenoids may be absent, or present in non-detectable amounts (e.g. less than 0.001 % by weight of the analyte). In some

embodiments, one or more of the following terpenes or terpenoids are absent, or present in non-detectable amounts: alpha-bisabolol, caryophyllene oxide, p-cymene, camphene, alpha- terpinene, gamma-terpinene, delta-s-carene, terpinolene, isopulegol, geraniol, and guaiol.

[0059] The cannabinoid fraction and the terpene fraction for two exemplary pharmaceutical compositions are set out in the following Tables 1 and 2. Amounts of cannabinoids are reported as determined by high-performance liquid chromatography (HPLC) and amounts of terpenes are reported as determined by gas chromatography (GC). It will be appreciated that, as the Cannabis extract is derived from Nature, the amount of each component may vary in some cases by +/- 10%, +/- 25% or +/- 50%. The ranges of amounts corresponding to each of these limits to account for the potential variation in the composition are also shown in Table 1 and 2.

Table 1 - THC-rich pharmaceutical composition

Table 2 - CBD-rich pharmaceutical composition

[0060] The pharmaceutical composition may further comprise one or more

pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof.

[0061 ] The carrier, diluent, adjuvant and/or excipient are "pharmaceutically acceptable" meaning that they are compatible with the other ingredients of the composition and are not deleterious to a subject upon or following administration. [0062] The pharmaceutical compositions may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilisers, flavours, etc.) according to techniques such as those well known in the art of pharmaceutical formulation (See, for example, Remington: The Science and Practice of Pharmacy, 21 st Ed., 2005, Lippincott Williams & Wilkins). The pharmaceutically acceptable carrier may be any carrier included in the United States Pharmacopeia/National Formulary (USP/NF), the British Pharmacopoeia (BP), the European Pharmacopoeia (EP), or the

Japanese Pharmacopoeia (JP). In some embodiments, the carrier, diluent, adjuvant and/or excipient may be non-natural (e.g. synthetically produced).

[0063] The pharmaceutical composition includes those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.

[0064] The Cannabis extract, together with a conventional adjuvant, carrier, excipient or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

[0065] Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

[0066] For preparing pharmaceutical compositions from the Cannabis extract described herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form

preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. [0067] Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium

carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0068] Liquid form preparations include solutions, dispersions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

[0069] Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The Cannabis extract can be suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.

[0070] Other liquid form preparations include those prepared by combining the Cannabis extract with one or more naturally derived oils (e.g. an essential oil) or waxes. An "essential oil" is an oil derived by extraction (e.g. steam extraction, or contacting the plant material with an extractant) or pressing, which contains primarily hydrophobic, and generally fragrant, components of the plant material. Suitable naturally derived oils and waxes include Sesame oil, Olive oil, Arnica essential oil, Lavender essential oil, Lavender Spike essential oil, Frankincense essential oil, Lemongrass essential oil, Cinnamon Leaf essential oil, Rosemary Cineole essential oil, Rosemary essential oil, Bergamot essential oil, Myrrh essential oil, Sage essential oil, Coconut oil, Bees wax and Hemp oil.

[0071 ] The pharmaceutical compositions may be formulated for parenteral administration (e. g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers optionally with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. [0072] Pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against oxidation and the contaminating action of microorganisms such as bacteria or fungi.

[0073] The solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

[0074] Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.

[0075] Sterile injectable solutions are prepared by incorporating the Cannabis extract in the required amount in the appropriate carrier with various other ingredients such as those enumerated above, as required, followed by sterilisation. Generally, dispersions are prepared by incorporating the various sterilised active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile suspension of the active ingredient plus any additional desired ingredients.

[0076] When the active ingredients are suitably protected they may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be

incorporated directly with the food of the diet. For oral therapeutic administration, the active may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0077] The amount of active ingredient in therapeutically useful compositions should be sufficient that a suitable dosage will be obtained.

[0078] The tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

[0079] Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound(s) may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the gut.

[0080] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0081 ] Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.

[0082] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.

[0083] For topical administration to the epidermis the active ingredients may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. [0084] Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0085] Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.

[0086] In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.

[0087] Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.

[0088] The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

[0089] Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier may form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g. gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[0090] In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.

[0091 ] When desired, formulations adapted to give sustained release of the active ingredient may be employed. [0092] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0093] It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of a HCV viral infection in living subjects having a diseased condition in which bodily health is impaired.

[0094] Also described herein are compositions absent a carrier where the compositions are in unit dosage form. Accordingly, also provided is a medicament comprising the Cannabis extract.

[0095] In some embodiments, the pharmaceutical composition further comprises an active agent other than the Cannabis extract. Any suitable active agent may be used provided that the activity of the active agent and/or the Cannabis extract is not diminished when combined.

Methods of treatment

[0096] In another aspect, also provided is a method for treating a sleep disorder. The method comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition described herein.

[0097] The pharmaceutical compositions may be used to treat a sleep disorder. Sleep disorders are described in the International Classification of Sleep Disorders (ICDS). ICDS-3 was published in 2014 and characterises sleep disorders as belonging to one of the following classes: (1 ) Insomnias; (2) Sleep Related Breathing Disorders; (3) Central Disorders of Hypersomnolence; (3) Circadian Rhythm Sleep-Wake Disorders; (4) Parasomnias; (5) Sleep Related Movement Disorders. Accordingly, the sleep disorders to be treated by the

pharmaceutical composition may include any sleep disorders from the classes (1) Insomnias; (2) Sleep Related Breathing Disorders; (3) Central Disorders of Hypersomnolence; (3) Circadian Rhythm Sleep-Wake Disorders; (4) Parasomnias; (5) Sleep Related Movement Disorders. In particular, the pharmaceutical compositions may be effective in the treatment of a sleep disorder selected from: insomnia, narcolepsy, hypersomnia, sleep apnoea, periodic limb movement disorder, restless legs syndrome, nocturnal eating (drinking) syndrome, jet lag, shift work sleep disorder, irregular sleep-wake pattern, confusional arousals, sleepwalking, sleep terrors, sleep talking, nightmares, sleep paralysis, REM sleep behaviour disorder, snoring, sleeping sickness, a sleep disorder associated with another disease or condition, or any other sleep disorder.

[0098] By "effective amount" it is meant an amount sufficient that when administered to the patient an amount of the drug is provided to achieve an effect. In the case of a therapeutic method, this effect may be the treatment of the sleep disorder. Therefore, the "effective amount" may be a "therapeutically effective amount". By "therapeutically effective amount" it is meant an amount sufficient that when administered to the patient an amount of drug is provided to treat the disease or a symptom of the disease.

[0099] As used herein, the terms "treating", "treatment", "treat" and the like mean affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing, or reducing the severity of, a disease or associated symptom, and/or may be therapeutic in terms of a partial or complete cure of a disease. A reference to "treating" a sleep disorder therefore encompasses: (a) assisting the patient to fall asleep; (b) assisting the patient remain asleep once sleep has been achieved; (c) relieving or ameliorating the effects of the sleep disorder, e.g. enhancing wakefulness during non-sleep periods; or (d) preventing the sleep disorder from occurring in a subject predisposed to, or at risk of, the sleep disorder, so that the sleep disorder does not develop or occur in the subject, or develops in a less severe form.

[0100] The method may also comprise administering an active agent other than the Cannabis extract. This active agent may be administered simultaneously or consecutively with the Cannabis extract. By consecutively it is meant that each of the Cannabis extract and the other active agent are administered separately and may be at different times. Typically, when the Cannabis extract and the other active agent are administered consecutively they are administered within 24 hours, or within 12, 8, 6, 5, 4, 3, 2, or 1 hour(s) of each other. The Cannabis extract may be administered before or after the other active agent. Further, the route of administration for the Cannabis extract and the other active agent may be the same or different. [0101 ] In another aspect, also provided is the use of the Cannabis extract in the preparation of a medicament for the treatment of the sleep disorder.

[0102] Also provided is a kit comprising in separate parts:

(a) an effective amount of the Cannabis extract; and

(b) a pharmaceutically acceptable carrier, diluent, adjuvant, excipient or a combination thereof.

[0103] In some embodiments, the kit further comprises a part comprising (c) an effective amount of an active agent other than the Cannabis extract.

[0104] In another aspect, there is provided the pharmaceutical composition for treating the sleep disorder. The pharmaceutical composition may be any of the pharmaceutical compositions described above, comprising any above-described combination of components, provided that it comprises the Cannabis extract with the specified terpene fraction. The sleep disorder may also be any of those described above.

Examples

[0105] The invention will be further described by way of non-limiting examples. It will be understood to persons skilled in the art of the invention that many modifications may be made without departing from the spirit and scope of the invention.

Example 1 - Cannabis extracts

[0106] The following Cannabis extracts are described:

AZ7 - infusion of the Ogre Shock plant.

AZ8 - infusion of the ACDC plant.

Terpenes ²

alpha-bisabolol 0.000 0.000

camphene BDL BDL

delta-s-carene BDL BDL

beta-caryophyllene 0.003 0.002

caryophyllene oxide BDL BDL

p-cymene BDL BDL

geraniol 0.000 0.000

guaiol 0.000 BDL

alpha-humulene BDL BDL

isopulegol BDL BDL

D-limonene 0.005 0.005

linalool 0.002 0.001

beta-myrcene 0.002 0.005

nerolidol 1 0.001 0.000

nerolidol 2 BDL 0.000

ocimene 0.001 0.001

alpha-pinene 0.004 0.013

beta-pinene 0.020 0.047

alpha-terpinene BDL 0.000

gamma-terpinene 0.000 BDL

terpinolene 0.000 BDL

tot.il terpenes 0.038 0.073

total 3.711 2.213

Notes: (1) Cannabinoids were detected using HPLC analysis, an amount reported as 0 wt% indicates that the compound was either not detected, or present in an amount below the detection limit of the HPLC; (2) Terpenes were detected using GC analysis, an amount reported as 0 wt% indicates that the compound was either not detected, or present in an amount below the detection limit of the GC; (3) In order to allow for Natural variation, amount within +/- 10%, +/- 25% or +/- 50% of the reported values.

[0107] Unless the context requires otherwise, all percentages referred to herein are percentages by weight of the pharmaceutical composition.

[0108] The term "about", when used to describe a value, preferably means an amount within ±10% of that value.

[0109] The terms "a", "an", "and" and/or "the" and similar referents in the context of describing the invention and the claims which follow are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. [01 10] It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

[01 1 1 ] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.