NZ789786A - Sleep Disorder Compositions and Treatments Thereof - Google Patents

Abstract

The invention relates to 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 cannabinoid fraction comprising Δ9 Tetrahydrocannabinol (THC), Cannabidiol (CBD), and Cannabinol (CBN) and a terpene fraction in an amount of at least 3% by weight of the extract. The invention also relates to methods of treating sleep disorders using this pharmaceutical composition. THC), Cannabidiol (CBD), and Cannabinol (CBN) and a terpene fraction in an amount of at least 3% by weight of the extract. The invention also relates to methods of treating sleep disorders using this pharmaceutical composition.

Description

Sleep Disorder itions and Treatments Thereof This ation is a divisional application of New Zealand patent application No. 759963, the contents of which are hereby incorporated in its entirety by this cross-reference. New Zealand patent application No. 759963 is derived from , filed on 19 June 2018, the entire ts of which are also incorporated herein by this reference.

Field 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.

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) ors, and the relaxation of laws regulating Cannabis use - in some ictions decriminalisation - there now exists the opportunity to explore the potential of Cannabis as a source of new therapeutics.

There is also a growing nt of ts suffering from chronic diseases, such as sleep disorders, to seek natural remedies as alternative or complementary therapy.

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

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

The Cannabis extract comprises a cannabinoid fraction and a terpene fraction. The cannabinoid fraction typically ses as the primary cannabinoid Δ9-Tetrahydrocannabinol (THC). The cannabinoid fraction may also comprise one or more further cannabinoids including Cannabidiol (CBD) and Cannabinol (CBN). The terpene fraction typically comprises betamyrcene , linalool and nerolidol. ably the Cannabis extract does not contain (or contains 28_1 (GHMatters) P106152.NZ.1 22/06/22 very low , such as not more than about 0.001wt%) Δ9-Tetrahydrocannabivarin (THCV), alpha-pinene or beta-pinene, terpinolene, caryophyllene, ne and limonene.

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

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, nts, excipients or any combination thereof.

Description of Embodiment(s) The present invention provides a pharmaceutical composition comprising a Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, nts, excipients or any combination thereof.

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 ary metabolites varies depending on several s, including Cannabis variety, part of the Cannabis plant extracted, method of extraction, processing of the extract, and season.

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

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 t is formed from the flowers and shake of a Cannabis plant.

Suitable tants e, for example, alcohols (e.g., methanol, ethanol, propanol, butanol, propylene glycol, etc.), water, hydrocarbons (e.g., butane, hexane, etc.), oils (e.g., olive oil, 18747428_1 (GHMatters) 2.NZ.1 22/06/22 ble oil, essential oil, etc.), a solvent (e.g., ethyl acetate, polyethylene glycol, etc.) or a supercritical fluid (e.g., liquid CO2).

The extractant may be tely or lly removed prior to incorporation of the Cannabis extract into the pharmaceutical ition, or it may be included in the pharmaceutical composition as a carrier. The extractant may be removed by heating the extract optionally under d pressure. In some embodiments, the pharmaceutical composition comprises a residual amount of an extractant (such as l). In some embodiments, the residual amount of extractant may be up to about 10mg/g or about 5mg/g. 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.

The Cannabis extract comprises a cannabinoid fraction comprising rahydrocannabinol (THC), Cannabidiol (CBD), and Cannabinol (CBN). Of these cannabinoids, THC and CBD do not occur in significant concentrations in Cannabis plant material and are formed during the extraction process through decarboxylation of corresponding carboxylic acid derivatives of these cannabinoids (or cannabinoid acids), which are biosynthesised by the Cannabis plant. The precise concentration of neutral THC or CBD in a is plant is difficult to quantify due to the potential for decarboxylation of the corresponding cannabinoid acids during analysis. Accordingly, when the ceutical itions of the invention comprise THC or CBD derived from a Natural source, the composition comprises decarboxylated THC or CBD.

The extraction process typically comprises a decarboxylation step. Decarboxylation refers to the loss of a carboxyl group during conversion of a carboxylic acid tive of a cannabinoid into the inoid itself. rahydrocannabinolic acid (THC-A) and idiolic acid (CBD-A) are not thermally stable and may be decarboxylated by exposure to light or heat. Some studies have also shown that THC-A and CBD-A can be decarboxylated upon exposure to cofactors or certain solvents. Typically, decarboxylation is carried out by heating the extract in the presence of extractant to a temperature of at least 60C (e.g. at least 80C). This heating step may be maintained for 30 minutes or longer. In some embodiments, the decarboxylation occurs during extractant removal.

In addition, THC has been shown to oxidise to cannabinol (CBN) when exposed to oxygen and light, including during decarboxylation. Accordingly, in some embodiments, the extraction comprises exposing the extract to light under an oxygen atmosphere. In other 18747428_1 (GHMatters) 2.NZ.1 22/06/22 ments, the extraction is carried out in the absence of oxygen, for example under an atmosphere of nitrogen.

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 m). The Cannabis composition may comprise up to about 5% by weight (e.g., up to about 2% by weight) visible particles.

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.

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, sunflower 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.

The term binoid" as used herein relates to any molecule that has been isolated from a Cannabis plant or synthetically created to have activity involving the endocannabinoid system.

The term “cannabinoid fraction” is used to be the combination of cannabinoid compounds present in the is extract.

The terms "terpenes" and "terpenoids" as used herein refer to a class of hydrocarbon molecules, which often provide a unique smell. Terpenes are derived from units of isoprene, which has the molecular formula C5H8. The basic lar formula of terpenes are multiples of the isoprene unit, i.e. (C5H8)n, where n is the number of linked isoprene units.

Terpenoids are terpene compounds that have been further lised in the plant, typically through an oxidative process, and ore usually contain at least one oxygen atom.

The term “terpene fraction” is used to be the combination of terpene and oid compounds present in the Cannabis extract.

The inventors have observed that the efficacy of a pharmaceutical composition is enhanced when the e fraction has a certain profile, i.e. a n tion of particular terpenes/terpenoids are present in the extract. It is believed that the increase in efficacy may 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 be synergistic (i.e. non-additive). It is also believed that the presence of specific ents in the terpene on may enhance the patient’s tolerance to cannabinoid therapy.

In some ments, the Cannabis extract contains high amounts (e.g., greater than 50% by weight) of a main cannabinoid, typically THC. In some ments, 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 %, about 90% to about %, 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 ses about 0.001% to about 50% by weight of non-cannabinoids, for e, about 0.001% to about 20% by weight or about 0.001% to about 10% by weight non-cannabinoids.

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. In some embodiments, the pharmaceutical formulation consists of the Cannabis extract.

In some embodiments, one or more additional compounds (e.g., cannabinoid, e or terpenoid compounds) may be added to the Cannabis extract. The addition of the one or more additional compounds may 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 ed compounds obtained from other is extracts, or they may be added by blending two or more ts.

To date, over 100 cannabinoids have been identified in Cannabis extracts. A comprehensive list of these cannabinoids may be found in Mahmoud A. El Sohly and Waseem Gul, ituents of Cannabis Sativa.” In Handbook of Cannabis Roger Pertwee (Ed.) Oxford University Press (2014) (ISBN: 9780199662685). Cannabinoids that have been identified in Cannabis extracts 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 AM-C5 A and Cannabigerovarinic acid A (E)-CBGVAC3A); (±)-Cannabichromene , (±)- 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-Cl, Cannabidiolic acid CBDA-C5, Cannabidivarinic acid CBDVA- 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 C3); Cannabinodiol CBNDC5, Cannabinodivarin CBND-C3); Δ9-Tetrahydrocannabinol Δ9-THCC5 , Δ9-Tetrahydrocannabinol-C4 Δ9-THCC4, rahydrocannabivarin Δ9-THCV-C3, rahydrocannabiorcol, Δ9-THCO-Cl, Δ9-Tetrahydrocannabinolic acid A Δ9-THCA-C5 A, Δ9-Tetrahydrocannabinolic acid B, Δ9-THCA-C5 B, Δ9-Tetrahydrocannabinolic acid-C4 A and/or B Δ9-THCA-C4 A and/or B, Δ9-Tetrahydro-cannabivarinic acid A Δ9-THCVA-C3 A, Δ9-Tetrahydrocannabiorcolic acid A and/or B Δ9-THCOA-Cl A and/or B), (-)-Δ8-trans- (6aR,10aR)-Δ8-Tetrahydrocannabinol Δ8-THC-C5, (-)-Δ8-trans-(6aR,10aR)- Tetrahydrocannabinolic acid A Δ8-THCA-C5 A, (-)-(6aS,10aR)-Δ9-Tetrahydrocannabinol (-)-cis- Δ9-THC-C5); Cannabinol CBN-C5, Cannabinol-C4 CBN-C4, Cannabivarin CBN-C3, Cannabinol C2 CBN-C2, Cannabiorcol CBN-Cl, Cannabinolic acid A CBNA-C5 A, Cannabinol methyl ether CBNM-C5, (-)-(9R,10R)-trans-Cannabitriol (-)-trans-CBT-C5, S,10S)-Cannabitriol (+)- trans-CBT-C5, (±)-(9R,10S/9S,10R)—); itriol (±)-cis-CBT-C5, (-)-(9R,10R)-transOEthyl-cannabitriol (-)-trans-CBT-OEt-C5, (±)-(9R,10R/9S,10S)-Cannabitriol-C3 (±)-trans-CBTC3 , 8,9-Dihydroxy-Δ6a(10a)-tetrahydrocannabinol 8,9-Di-OH-CBT-C5, idiolic acid A cannabitriol ester CBDA-C5 BT-C5 ester, (-)-(6aR,9S,10S,10aR)-9,10- Dihydroxyhexahydrocannabinol, Cannabiripsol, Cannabiripsol-C5, (-)-6a,7,10a-Trihydroxy-Δ9-tetrahydrocannabinol (-)-Cannabitetrol, -Oxo-Δ6a(10a)tetrahydrocannabinol OTHC); (5aS,6S,9R,9aR)-Cannabielsoin , (5aS,6S,9R,9aR)-C3-Cannabielsoin CBE-C3, (5aS,6S,9R,9aR)-Cannabielsoic acid A 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), (-)-Δ7-trans-(1R,3R,6R)-Isotetrahydrocannabinol, (±)-Δ7-1,2-cis-(1R,3R,6S/1S,3S,6R)-Isotetrahydrocannabivarin, (-)-Δ7-trans-(1R,3R,6R)- Isotetrahydrocannabivarin; (±)-(laS,3aR,8bR,8cR)-Cannabicyclol CBL-C5, (±)-(1aS,3aR,8bR,8cR)-Cannabicyclolic acid A CBLA-C5 A, (±)-(laS,3aR,8bR,8cR)-Cannabicyclovarin CBLV-C3; Cannabicitran CBTC5; Cannabichromanone CBCN-C5, ichromanoneC3 CBCN-C3, and Cannabicoumaronone CBCON-C5.

The Cannabis extract may comprise 99% by weight of a main cannabinoid based on the total weight of the extract, for example, from 0.005-90%, 0.005-65%, 0.005-40%, 0.005-10%, 0.005-2%, 0.005-0.1%, 0.005-0.05%, 0.01-0.05%, 0.01-99%, 0.01-90%, 0.01-10%, %, 0.01-0.1%, 0.01-0.05%, 0.015-0.03% 5-90%, 10-90%, 20-90%, 25-85%, 50-99%, 40- 90%, 50-90% or 55-85% by weight based on the total weight of the extract. The main cannabinoid may be Δ9-tetrahydrocannabinol (THC). In some embodiments, the Cannabis 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 extract comprises the main cannabinoid in an amount of 5-90%, 10-90%, 20-90%, 25-85%, 50- 99%, 55-95%, , 75-95% or 80-90% by weight of the cannabinoid on. lly, the Cannabis extract r comprises one or more secondary cannabinoids. Cannabidiol (CBD) and/or cannabinol (CBN) may also be present in the Cannabis extract as secondary cannabinoids. Typically, each secondary cannabinoid is present in an amount from about 0.001% to about 30% by weight of the cannabinoid fraction, for example, from 0.001-10%, 1-10%, 2-10%, 3-5% or 8-10% by weight based on the total weight of the cannabinoid fraction.

Other cannabinoids may also be present, but typically these do not form part of the active ingredients.

The pharmaceutical composition may comprise THC in a concentration of about 1mg/ml to about 100mg/ml, for example, from about 5mg/ml to about 50mg/ml, about 5mg/ml to about 30mg/ml, about 10mg/ml to about l or about 18mg/ml to about 22mg/ml.

In some embodiments, the Cannabis extract comprises 20% by weight of cannabidiol (CBD) as a secondary cannabinoid, for example, from 0.0001-20%, 0.001-10%, 1- % or 1-10% by weight of the extract or cannabinoid on. The pharmaceutical composition may comprise CBD in a concentration of about 0.5mg/ml to about 10mg/ml, for example, from about 0.5mg/ml to about 5mg/ml, about 0.5mg/ml to about 2.5mg/ml or about 0.9mg/ml to about 1.1mg/ml.

The ratio by weight of THC to CBD may be from 10:1 to 50:1, for example from 10:1 to 30:1, 15:1 to 25:1 or about 20:1.

In some embodiments, the Cannabis extract comprises 0.0001-20% by weight of cannabiniol (CBN), for example, from 0.001-20%, 0.001-10%, 1-20% or 1-10% by weight of the extract or inoid fraction. The pharmaceutical composition may comprise CBN in a concentration of about 0.5mg/ml to about l, for example, from about 0.5mg/ml to about 5mg/ml, about 1mg/ml to about 5mg/ml or about 1.8mg/ml to about 2.2mg/ml.

The ratio by weight of THC to CBN may be from 5:1 to 20:1, for example from 5:1 to :1 or about 10:1.

The ratio by weight of CBN:CBD may be from about 1:1 to about 10:1, for example from about 1:1 to about 5:1, about 1.5:1 to about 3:1 or about 2:1. lly, the Cannabis extracts also comprise other inoids in addition to THC, CBN and CBD. These cannabinoids include Δ9-Tetrahydrocannabinolic acid (THCA), (-)- 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 Cannabidivarin (CBDV) and Cannabigerol (CBG). Each of these cannabinoids may be present in an amount from 0.001% to 30% by weight of the extract or cannabinoid fraction.

In some embodiments, n cannabinoids may be absent, or present in ectable s (e.g., less than 0.001% by weight of the e). In some embodiments, the Cannabis extract may exclude (or comprise in an amount of less than or equal to 0.5% by weight of the cannabinoid fraction) one or more of the following cannabinoids: Δ9-Tetrahydrocannabivarin , Cannabidiolic acid (CBDA), Cannabigerolic acid (CBGA) and (-)-Cannabidivarin .

The Cannabis extract comprises a non-cannabinoid fraction, which typically includes a e fraction. The e fraction comprises terpenes and terpenoids. The Cannabis extract comprises a terpene fraction in an amount of at least about 3% by weight of the extract, for example, at least about 3.5%, 4%, or 4.5% by weight. 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%, or 4% by weight of the extract. In some embodiments, the Cannabis extract comprises about 3% to about 50% by weight of terpene and terpenoid compounds, for example, about 3% to about 20% by weight, about 3% to about 10% by weight, about 3% to about 6% by weight or about 3 to about 5% by weight of the extract or composition.

The ratio by weight of the cannabinoid fraction to the terpene fraction may be from about 8:1 to about 33:1, for example, from about 10:1 to about 30:1, about 10:1 to about 25:1 or about 15:1 to about 25:1. In some embodiments, the ratio by weight of the main cannabinoid to the terpene fraction may be from about 5:1 to about 30:1, for example, about 10:1 to about 25:1 or about 15:1 to about 20:1.

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 se about 20% by weight cannabinoids and about 3% by weight terpenes, corresponding to a ratio of inoid fraction:terpene fraction of about 20:3 (about 7:1). Following extraction and concentration (i.e., removal of the tant), the amount of cannabinoids may increase to about 50-90% by weight and the terpene fraction may amount to about 0.1-6% by weight of the Cannabis extract, corresponding to a significant increase in the ratio of cannabinoid fraction:terpene on. This l scenario shows that while the cannabinoids are 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 trated when the extractant is removed, the relative amount of the terpene fraction is d, likely due to the volatility of many of the terpenes/terpenoids present in the terpene fraction. Therefore, the profile of the terpene on t in the Cannabis extract is significantly different from the profile of the terpene fraction that exists in Nature.

A variety of terpenes and terpenoids have been identified in Cannabis extracts, including monoterpenes, monoterpenoids, sesquiterpenes and sesquiterpenoids. For e, the following terpenes and terpenoids have been identified in Cannabis extracts: Alloaromadendrene, allyl hexanoate, benzaldehyde, (Z)-a-cis-bergamotene, (Z)-a-transbergamotene , ß-bisabolol, epi-a-bisabolol, ß-bisabolene, borneol (camphol), cis-y-bisabolene, bomeol acetate (bomyl acetate), -cadinene, camphene, camphor, rveol, caryophyllene (ß-caryophyllene), lene (-caryophyllene), γ-cadinene, Δcarene, hyllene oxide, 1,8-cineole, citral A, citral B, cinnameldehyde, -copaene (aglaiene), γ-curcumene, ß-cymene, ene, γ-elemene, ethyl decdienoate, ethyl maltol, ethyl propionate, ethylvanillin, eucalyptol, -eudesmol, ß-eudesmol, γ-eudesmol, eugenol, cis-ß-famesene ((Z)-ß-farnesene), trans--farnesene, ß-famesene, trans-γ-bisabolene, fenchone, fenchol (norbomanol, ß-fenchol), geraniol, -guaiene, guaiol, methyl anthranilate, methyl salicylate, 2-methyl heptanone, 3-methylheptanone, hexyl acetate, ipsdienol, isoamyl acetate, lemenol, limonene, d-limonene ene), ol (linalyl alcohol, ß-linolool), -longipinene, menthol, γ-muurolene, myrcene (ß-myrcene), nerolidol, trans-nerolidol, nerol, ß-ocimene (cis-ocimene), octyl acetate, -phellandrene, phytol, -pinene (2-pinene), ß-pinene, pulegone, sabinene, cis-sabinene hydrate (cis-thujanol), ß-selinene, -selinene, γ-terpinene, terpinolene (isoterpine), terpineol (-terpineol), terpineolol, -terpinene (terpilene), -thujene (origanene), vanillin, viridiflorene e), and -ylange.

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.

The terpene fraction lly comprises beta-myrcene. It is believed that betamyrcene enhances the ilability of the cannabinoids present in the t and/or assists 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 0-50% by weight of the terpene fraction, for example, from about 0.001% to about 45%, about 0.001% to about 25%, 5.1% to 29%, about 5.5% to about %, about 20% to about 50%, about 20% to about 45% or about 30% to about 45% by weight of the terpene fraction. In some embodiments, the pharmaceutical composition comprises beta- 18747428_1 ters) P106152.NZ.1 22/06/22 myrcene in a concentration of up to about 10mg/ml, for example, up to about 5mg/ml, about 1mg/ml or about 0.5mg/ml.

In some embodiments, the ratio by weight of THC to beta-myrcene may be from :1 to about 55:1, for example, from about 30:1 to about 50:1 or from about 35:1 to about 45:1.

The terpene fraction may further comprise one or more of linalool and nerolidol.

Linalool is a terpenoid that is found in many flower and spice plants having the molecular formula C10H18O. It is believed that when linalool is present in a is extract, it provides 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 t in an amount of 0-50% by weight of the terpene fraction. In other embodiments, ol is present in amount of from about 0.05% to 50% by weight of the terpene fraction, for example, from about 0.1% to about 20%, about 0.05 to about 25%, about 0.001% to about 45%, about 0.001% to about 25%, about 20% to about 50%, about 20% to about 45% or about 30% to about 45% by weight of the terpene on. In some embodiments, the pharmaceutical composition comprises linalool in a concentration of up to about 10mg/ml, for example, up to about 5mg/ml, about 1mg/ml or about 0.5mg/ml.

In some embodiments, the ratio by weight of THC to linalool may be from 20:1 to about 55:1, for example, from about 30:1 to about 50:1 or from about 35:1 to about 45:1.

Nerolidol is a sesquiterpenoid having the molecular formula of C15H26O. 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 se nerolidol (i.e., both nerolidol 1 and nerolidol 2) in an amount of at least 0.001% by weight of the terpene on, for example, from about 0.01% to about 30% or 0.01% to 20% by weight of the terpene fraction. lly, 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 ments, 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 t 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 e 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 % or 0.001 to 15% by weight of the terpene fraction. In some embodiments, the 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 pharmaceutical composition comprises nerolidol in a tration of up to about , for example, up to about , about 1mg/ml or about 0.25mg/ml.

In some embodiments, the ratio by weight of THC to nerolidol may be from 50:1 to about 100:1, for example, from about 60:1 to about 95:1 or from about 70:1 to about 90:1.

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. In some embodiments, the pharmaceutical composition comprises beta-caryophyllene in a concentration of up to about 1mg/ml, for example, up to about 0.5mg/ml or about 0.25mg/ml.

In some embodiments, the extract further comprises humulene. It is believed that that humulene enhances the sedative properties of the extract. Humulene is also sometimes called alpha-caryophyllene. In some embodiments, the pharmaceutical composition comprises humulene in a concentration of up to about 1mg/ml, for example, up to about 0.5mg/ml or about 0.25mg/ml.

In some embodiments, the Cannabis extract further comprises 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. In some ments, the pharmaceutical composition comprises ocimene in a tration of up to about 1mg/ml, for example, up to about 0.5mg/ml or about 0.25mg/ml.

In some embodiments, the terpene on comprises beta-myrcene, linalool and nerolidol 1. The ratio by weight of beta-myrcene to linalool may be about 1:1 (e.g. from 1:2 to 2:1). The ratio by weight of beta-myrcene to dol may be about 2:1 (e.g., from 1:1 to 3:1).

The ratio by weight of linalool to nerolidol may be about 2:1 (e.g., from 1:1 to 3:1). In some embodiments, the ratio by weight of beta-myrcene:linalool:nerolidol is about 2:2:1.

In some embodiments, the terpene fraction may be present in the ition in an amount from 3% to 6% by weight of the extract and may se:  beta-myrcene in an amount of from 0% to 50% by weight of the terpene fraction;  linalool in an amount of from 0% to 50% by weight of the terpene fraction;  nerolidol 1 in an amount of from 0% to 20% by weight of the terpene on; and  nerolidol 2 in an amount of from 0% to 20% by weight of the terpene fraction. 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 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 e or less than or equal to 0.5mg/ml of the pharmaceutical composition). In some embodiments, one or more of the following terpenes or terpenoids are absent, or present in non-detectable amounts: alphapinene , beta-pinene, limonene, p-cymene, camphene, terpinene, gamma-terpinene, delta-s-carene, olene, isopulegol, ol, and guaiol.

The s of cannabinoids can be determined by high-performance liquid chromatography , including ultra performance liquid chromatography (UPLC) and amounts of terpenes can be determined by HPLC and/or gas chromatography (GC). It will be appreciated that, as for all plant extracts, the amount of each component in the Cannabis extract may vary in some cases by +/- 10%, +/- 25% or +/- 50%. In some embodiments, the amount of a inoid and/or a terpene may be determined by UPLC using a Waters Acquity UPLC system equipped with a Waters iode array detector (PDA) or detection by mass spectrometry. Using UPLC the limit of quantitation (LoQ) of THC, CBD and/or CBN or related substances may be less than 1g/ml, for example, the LoQ of CBD may be ≤ 0.086g/ml, CBN may be ≤ 0.038g/ml and/or THC may be ≤ 0.089g/ml may be detected in an analyte.

Accordingly, in some embodiments, the pharmaceutical compositions comprise CBD in an amount greater than 0.086g/ml, CBN in an amount greater than 0.038g/ml and/or THC in an amount greater than 0.089g/ml.

The Cannabis extract is preferably free of toxins associated with plant extracts. For example, preferably the Cannabis extract is free of aflatoxins (such as xin B1, B2, G1 and G2), mycotoxins (such as ochratoxin A), heavy metals (such as arsenic, cadmium, lead and mercury) and pesticides. In some embodiments, the pharmaceutical composition comprises less than 4g/ml total aflatoxins and/or less than 2g/ml aflatoxin A. In some embodiments, the pharmaceutical composition may comprise less than 20g/ml oxin. In some ments, the ceutical composition comprises ≤0.3ppm arsenic, ≤0.5ppm cadmium, ≤5ppm lead and/or ≤0.5ppm mercury.

In some embodiments, the pharmaceutical composition may comprise not more than 20% by weight total ash.

The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof. 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 The term “pharmaceutical ition” relates to a composition comprising at least one active ingredient that is in a pharmaceutically acceptable form. The term “pharmaceutical composition” may encompass compositions intended to be sold as nutraceutical products (e.g. supplements that provide a health benefit). In some embodiments, the pharmaceutical composition is a nutraceutical composition.

The pharmaceutical ition may comprise the Cannabis extract in a maximum amount of up to 99wt% of the pharmaceutical composition, for example, up to 95wt%, 90wt%, 85wt%, 80wt%, 75wt%, 70wt%, 65wt%, 60wt%, 55wt%, 50wt%, 45wt%, 40wt%, 35wt%, 30wt%, 25wt%, 20wt%, 15wt%, 10wt%, 5wt%, 4wt%, 3wt%, 2wt%, 1wt% or lower. The minimum amount of Cannabis t in the pharmaceutical compositions may be at least 0.001wt%, 0.005wt%, 0.01wt%, 0.05wt%, 0.1wt%, 0.5wt%, 1wt%, 5wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt% or higher. The ceutical compositions may comprise the Cannabis extract in amount between any of these minimum and maximum s, such as 0.001wt% to 99wt%, 0.1wt% to 65wt% or 1wt% to 50wt%. In some embodiments, the one or more ceutically acceptable carriers, diluents, adjuvants, excipients or any combination thereof provides the balance of weight of the pharmaceutical composition.

The r, diluent, nt 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. The pharmaceutical compositions may be formulated, for example, by employing 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 e, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins). The ceutically acceptable carrier may be any carrier included in the United States copeia/National Formulary (USP/NF), the British Pharmacopoeia (BP), the European Pharmacopoeia (EP), or the Japanese Pharmacopoeia (JP). In some embodiments, the r, diluent, adjuvant and/or excipient may be tural (e.g., synthetically produced).

The pharmaceutical composition includes those suitable for oral, sublingual, buccal, rectal, nasal, topical, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for stration by inhalation or insufflation. 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 The Cannabis extract, together with a conventional adjuvant, carrier, excipient or t, may thus be placed into the form of pharmaceutical compositions and unit dosages f, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as ons, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal stration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

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 n any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

For preparing ceutical compositions from the Cannabis extract bed herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include s, 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.

Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, , dextrin, , gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is ed 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, s and lozenges are ed. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

Liquid form preparations include solutions, dispersions, suspensions, and emulsions, for example, a pharmaceutically able oil, water or water-propylene glycol solutions. For example, a sublingual preparation can be prepared in a carrier comprising a pharmaceutically acceptable oil, and eral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 e liquid form compositions include sterile ons, 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.

Other liquid form preparations include those prepared by ing the Cannabis extract with one or more oils (e.g., an essential oil) or waxes. An “essential oil” is an oil extracted from a material, such as a plant material (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 oils and waxes include Sesame oil, Olive oil, Sunflower oil, Arnica essential oil, Lavender essential oil, Lavender Spike essential oil, Frankincense essential oil, Lemongrass essential oil, Cinnamon Leaf ial oil, Rosemary Cineole essential oil, Rosemary essential oil, Bergamot essential oil, Myrrh essential oil, Sage essential oil, Coconut oil, Bees wax and Hemp oil.

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 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 n formulation agents such as ding, stabilising and/or dispersing . Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of e solid or by lyophilisation from solution, for tution with a suitable vehicle, e.g., sterile, n-free water, before use.

Pharmaceutical forms suitable for injectable use include sterile able solutions or dispersions, and sterile powders for the extemporaneous preparation of e 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.

The t or dispersion medium for the injectable solution or sion 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. 28_1 (GHMatters) P106152.NZ.1 22/06/22 Pharmaceutical forms suitable for injectable use may be red by any appropriate route including intravenous, uscular, intracerebral, intrathecal, epidural injection or infusion.

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 s sterilised active ingredients into a e 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 e injectable solutions, red methods of preparation are vacuum drying or freeze-drying of a previously sterile suspension of the active ingredient plus any additional desired ingredients.

The active ingredients may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be ed 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, , and the like.

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

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 , alginic acid and the like; a lubricant such as ium stearate; and a sweetening agent such a e, 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.

In some ments, the pharmaceutical ition is formulated for sublingual administration. Sublingual administration relates to administration of a formulation under the tongue of a subject. In some instances, sublingual administration may be considered to be a form of oral administration or topical administration. Sublingual administration may be considered a form of oral administration as the formulation is taken “by mouth” and in some 28_1 (GHMatters) P106152.NZ.1 22/06/22 instances, after application under the tongue, the subject may swallow the formulation which may allow for at least a portion of the active ingredients to be absorbed through the digestive tract. Subligual administration may be considered a form of topical administration as it may include administration of the active ingredient(s) in the formulation through the mucus membrane under the tongue. Formulations suitable for sublingual administration include tablets (e.g. dissolvable, dispersible, effervescent and multi-purpose tablets), strips, drops, sprays, lozenges and combinations thereof.

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 ning 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 ntially 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.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and ning , as desired. s suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous al, such as natural or synthetic gums, , methylcellulose, sodium carboxymethylcellulose, or other well-known suspending Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal , isotonic and tion delaying agents and the like.

Also included are solid form preparations that are intended to be ted, shortly before use, to liquid form preparations for oral stration. Such liquid forms e solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and l sweeteners, dispersants, thickeners, solubilising agents, and the like.

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 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 example, be formulated with an aqueous or oily base with the on 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, ising , dispersing agents, suspending agents, thickening agents, or colouring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually e 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.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The ations may be ed 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 sion.

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 ing to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.

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 le propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, orofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.

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

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 e in capsules or cartridges of, e.g. gelatin, or r packs from which the powder may be administered by means of an inhaler. 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for e 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.

When desired, formulations d to give ned release of the active ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses ning appropriate quantities of the active component. The unit dosage form can be a ed preparation, the package containing discrete quantities of preparation, such as packaged 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.

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 d; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in ation with the required ceutical carrier. The ication 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 sleep er.

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

In some embodiments, the pharmaceutical composition further comprises an active agent other than the is 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 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. 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 The pharmaceutical compositions may be used to treat a sleep disorder. Sleep disorders are described in the ational Classification of Sleep Disorders (ICDS). ICDS-3 was published in 2014 and characterises sleep disorders as belonging to one of the ing classes: (1) Insomnias; (2) Sleep Related Breathing Disorders; (3) Central Disorders of Hypersomnolence; (3) Circadian Rhythm 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) mnias; (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, alking, sleep terrors, sleep talking, nightmares, sleep paralysis, REM sleep behaviour disorder, g, sleeping sickness, a sleep disorder associated with another disease or condition, or any other sleep disorder.

By tive 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 peutically effective amount”. By peutically 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.

In some ments, the methods comprise administration of THC in an amount from 1mg/day to 50mg/day, for example, from 5mg/day to 40mg/day, 5mg/day to 30mg/day, 5mg/day to 25mg/day or 10mg/day to ay. In some ments, the methods may comprise administering THC in an amount of 10mg/day or 20mg/day. The methods may comprise administering CBD in an amount from 0.001mg/day to 10mg/day, for example, from 0.01mg/day to 10mg.day or 0.1mg/day to 5mg/day. In some embodiments, the methods may comprise administering CBD in an amount of 1mg/day. The methods may comprise administering CBN in an amount from 0.001mg/day to 10mg/day, for example, from 0.01mg/day to 10mg.day or day to 5mg/day. In some embodiments, the methods comprise administering CBN in an amount of 1mg/day or 2mg/day. The s may comprise administering THC, CBD and/or CBN in any combination of these daily dosage s. The pharmaceutical compositions preferably comprise amounts of THC, CBD and CBN suitable for administration of any of these daily dosage amounts. 18747428_1 ters) P106152.NZ.1 22/06/22 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 lactic 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 e. A reference to “treating” a sleep disorder therefore encompasses: (a) assisting the t to fall asleep; (b) assisting the patient remain asleep once sleep has been ed; (c) relieving or ameliorating the effects of the sleep er, e.g. enhancing wakefulness during non-sleep periods; or (d) preventing the sleep er from occurring in a subject predisposed to, or at risk of, the sleep disorder, so that the sleep er does not develop or occur in the subject, or develops in a less severe form.

In some embodiments, the sleep disorder is insomnia. Symptoms and severity of insomnia may be ed by the Insomnia Severity Index (ISI) questionnaire. Typically the ISI is administered by a clinician, nurse or researcher or may be self-administered by the patient.

The ISI assesses both night-time and e components of insomnia and is available in several languages. The ISI asks seven questions each to be scored on a scale of 0-4 relating to (1) the difficulty in falling asleep, (2) difficulty staying asleep, (3) problems waking too early, (4) satisfaction relating to current sleep patterns, (5) perception as to how noticeable the sleep problem may be to others, (6) degree of concern regarding the sleep problem, and (7) the extent to which the sleep problem interferes with daily oning. The methods may e an improvement in one or more of these seven aspects of insomnia. In some ments of the methods of treatment, the t to be treated may have an initial ISI score of 7 or more, in some cases, the initial ISI score may be 10 or more. In some embodiments, a method of treating insomnia may provide a reduction of the ISI score of the patient relative to an initial ISI score. This reduction in ISI score may be by 1, 2, 3, 4, 5, 6 or more units on the ISI scale, and preferably results in the patient having an ISI score of 7 or less after treatment.

The ISI may be used alone to assess the severity of the patient’s ia or it may be used together with one or more other onnaires, such as quality of life enjoyment and satisfaction questionnaire (Q-les-Q), work and social adjustment scale (WSAS), depression anxiety stress scale (DASS) questionnaire, dysfunctional beliefs about sleep (DBAS) questionnaire, multidimensional fatigue inventory questionnaire, and any other recognised questionnaire known in the field.

Typically the patient is assessed by one or more questionnaires prior to receiving treatment and then at regular als (e.g. an interval of 1, 2, 3, 4, 5, 6, 7 or 8 weeks) during 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 the course of treatment. The assessment during treatment may begin 2 weeks after cement of treatment.

In some embodiments, the treatment may be maintained for up to 14 days, for example, the treatment may be maintained for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days.

In some embodiments, the treatment is maintained for longer than 14 days, for example, for 3 weeks, 1, 2, 3, 4, 5, 6, 12, 18, 24, 36 months or longer.

Typically, the pharmaceutical composition is stered once daily preferably a short time before the patient attempts to sleep. In some embodiments, the pharmaceutical composition is stered within about 2 hours of the patient attempting to sleep, for example, within about 1.5 hours, within about 1 hour or within about 30 minutes prior to sleep.

In some embodiments, the stration is sublingual administration. In such embodiments, the pharmaceutical ition may be presented as sublingual drops.

In some embodiments, the insomnia may be assessed by measuring one or more objective measures of sleep. Objective measures of sleep may be measured by polysomnography (PSG) and/or actigraphy. The objective measures of sleep may include measuring: Sleep Onset Latency (SO); Wake After Sleep Onset (WASO); Total Sleep Time (TST); Sleep ency (SE); REM versus NREM sleep patterns including slow-wave sleep patterns and percentage of time in all sleep stages; sleep apnea; periodic limb movements; and combinations f. In some embodiments, a method of treating insomnia may provide an improvement in one or more objective measures of sleep, for example, 2, 3, 4, 5, 6 or more of the objective measures of sleep.

The patient in need of therapy for insomnia may be any t suffering from insomnia, for example, as assessed by ISI. However, in some embodiments, not all patients may be suitable. For example, in some embodiments, a t who satisfies one or more of the following factors may be excluded: a. Untreated cardiovascular disease, arrhythmias (other than well controlled atrial fibrillation), hypertension or severe heart failure: or b. History of ies particularly to plant-based products containing terpenes. ie rs and aromatic natural oils for example citrus, mango, lavender, thyme, cedarwood and pine products: or c. Known hypersensitivity to cannabinoids: or 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 d. Currently regularly using (on 3 or more nights/days per week) psychotropic or CNS- active drugs, such as Cannabis, opioids, benzodiazepines: or e. lnability to refrain from use of psychotropic or CNS-active drugs (including Cannabis. s, benzodiazepines) for at least one week prior to treatment: or f. ity to refrain from use of Cytochrome P450 inhibitors for at least one week prior to treatment. Examples include macrolide antibiotics (erythromycin, clarithromycin), azole antifungals (itraconazole, ketoconazole, posaconazole, voriconazole), protease tors (ritonavir, telaprevir, boceprevir), calcium channel blockers (amlopdipine), high cholesterol medication (gemfibrozil), cyclosporine, danazol, tachycardia medication (amiodarone), hypertension medication (verapamil diltiazem), niacin (vitamin B3 >1g/day), and/or grapefruit juice; or g. ted lic disorders such as diabetes; or h. Presence of severe depression, severe anxiety or other severe psychopathologic conditions based on self-report or depression scores on the DASS of 11 or greater or anxiety scores on the DASS of 8 or greater; or i. History of suicide attempt; or j. History of seizures or epilepsy; or k. y of drug or alcohol abuse; or l. Insomnia ated with sleep (AHl of 15 of greater events/hour) or movement ers such as restless legs, periodic limb movement (PLM) (30 or greater events/hour or 5 or greater /hour with associated PLM arousals); or m. Current practice of behavioural therapies to facilitate sleep; or n. Current Cannabis use n 2 months prior to cement of treatment); or o. Pregnancy or lactation; or p. Inability to refrain from 2 or more standard drinks/day of alcohol consumption; or q. Inability to refrain from 400mg/day or more of caffeine consumption; or r. Shift workers or other s and athletes who require testing and screening for Cannabis products as part of their ment; or s. Any person required to drive within 10 hours of dose, or those with a self-reported history of falling asleep while driving; or t. Current delayed sleep phase syndrome where wake up time is regularly later than 8.00am.

The method may also comprise administering an active agent other than the Cannabis extract. This active agent may be administered simultaneously or utively with the Cannabis extract. By consecutively it is meant that each of the Cannabis extract and the 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 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 t and the other active agent may be the same or different.

In r aspect, also provided is the use of the Cannabis extract in the preparation of a medicament for the treatment of the sleep disorder.

Also provided is a kit comprising in separate parts: (a) an effective amount of the Cannabis t; and (b) a pharmaceutically acceptable carrier, t, adjuvant, excipient or a ation thereof.

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

In another aspect, there is provided the pharmaceutical composition for treating the sleep er. The pharmaceutical composition may be any of the ceutical 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.

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. e 1 – is extracts The following Cannabis indica ‘bedita’ extract formulation was produced:  THC - 20mg/ml, e.g. 18-22 mg/ml  CBN - 2mg/ml, e.g. 1-3 mg/ml  CBD - 1mg/ml, e.g. 0.5-1.5 mg/ml  Linalool - 0.5mg/ml (or less) 18747428_1 (GHMatters) P106152.NZ.1 22/06/22  Myrcene - 0.5mg/ml (or less)  Nerolidol - 0.25mg/ml (or less)  Remaining plant material made up of other cannabinoids or other es (less than % of Total or less than 15% of Total) wherein each other cannabinoid or terpene is present at low concentrations (e.g. <0.5%) No alpha pinene and beta pinene was detected ( <0.5%); Limonene levels were low e.g. < 0.2%.

THCV was at low levels (< 0.5%).

The formulation was completed using sunflower oil as the carrier oil.

Example 2 - A Study to Evaluate the Efficacy of Sublingual Cannabinoid Based Medicine Extract Compared with Placebo for the Treatment of Sleep Disorders Due to Insomnia.

This study is a randomised double-blind placebo controlled cross-over study evaluating the efficacy of a medicinal Cannabis extract containing THC for improving sleep in people with insomnia. Efficacy is evaluated using tive sleep quality measures using the standard Insomnia Severity Index, objective measures of sleep determined using PSG and actigraphy, and tive measures of sleep outcome and y of life using daily sleep diary and standard questionnaires for quality of life, mood, stress, anxiety, fatigue including Depression Anxiety Stress Scales (DASS). Dysfunctional Belief About Sleep (DBAS), Multidimensional e Inventory (MFI).

The primary aim of this study is to evaluate the efficacy of a sublingual cannabinoid extract (composition 1 of the present invention) containing deltatetrahydrocannibinol (THC) for improving sleep in people with insomnia.

The secondary aim is to evaluate sleep quality and quality of life improvements in people with insomnia when using composition 1 of the t invention as compared with a o. A r secondary aim is to determine patient safety of composition 1 as measured by incidence of adverse events during course of the study.

Composition 1 ses deltatetrahydrocannibinol (THC) 20 mg/ml, inol (CBN) 2 mg/ml and cannabidiol (CBD) 1 mg/ml as an extract of Cannabis plant with excipient 18747428_1 ters) P106152.NZ.1 22/06/22 sunflower oil. The sunflower oil is used as the excipient to stabilise the formulation including the cannabinoids and as a diluent of the plant extract.

Each dose is delivered sublingually with 0.5 ml cannabinoid extract (THC 10 mg, CBN 1 mg and CBD 0.5 mg).

Participants (between ages 25 and 70 years of age) male or female with chronic insomnia will be screened on Day 1 of the study.

Each qualifying subject admitted into the study meets all of the inclusion and none of the ion criteria. 24 ipants are enrolled in the study. This study is conducted over 9- 12 months. The study requires participants to spend 3 overnight stays in clinic at The sity of Western Australia, Centre for Sleep Science. Participants will be required to take the igational Product for 2 weeks and placebo for 2 weeks at home.

This study conforms to the National Statement on Ethical Conduct in Human Research and meets the relevant requirements of the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH-135/95) and the TGA.

Unless the context requires otherwise, all percentages referred to herein are tages by weight of the pharmaceutical composition. Similarly, unless the context requires ise, all ratios referred to herein are ratios by .

Various es of the invention are described and/or claimed with reference to a certain value, or range of values. These values are intended to relate to the results of the various appropriate measurement techniques, and therefore should be interpreted as including a margin of error inherent in any particular measurement technique. Some of the values referred to herein are denoted by the term “about” to at least in part account for this ility. The term “about”, when used to describe a value, preferably means an amount within ±25%, ±10%, ±5%, ±1% or ±0.1% of that value.

Various values are described in terms of their percentage ve to the total weight of (i) the pharmaceutical ition, (ii) Cannabis extract or (iii) fraction of the extract (e.g. the cannabinoid fraction or the terpene fraction). The tages of components included in the Cannabis extract or a fraction thereof (e.g. the cannabinoid fraction or terpene fraction) are intended to denote the percentage by weight of the specified compound relative to the 18747428_1 (GHMatters) P106152.NZ.1 22/06/22 percentage by weight of the other compounds present in the extract or specified fraction, for e, absent the carriers, diluents, adjuvants and excipients or any combination thereof. For example, a pharmaceutical ition comprising a Cannabis extract comprising a e fraction in an amount of at least 3% by weight of the extract is intended to denote a pharmaceutical composition wherein the tive weight of terpenes and terpenoids is 3% by weight or more when compared to the cumulative weight of compounds t in the extract including cannabinoids, terpenes, terpenoids and extractant/residual extractant. Further, a Cannabis extract comprising THC in an amount of about 85% by weight of the cannabinoid fraction is intended to denote an extract comprising THC in an amount of 85% by weight relative to the cumulative weight of all cannabinoids present in the extract.

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.

It is to be understood that, if any prior art publication is referred to herein, such nce 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.

In the claims which follow and in the preceding description of the ion, except where the context requires ise 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 ce or addition of further features in various ments of the invention. 18747428_1 (GHMatters) P106152.NZ.1 22/06/22

Claims (12)

Claims

1. A pharmaceutical composition comprising a Cannabis extract and optionally one or more pharmaceutically acceptable carriers, diluents, adjuvants, ents or any combination thereof, the Cannabis extract comprising a inoid fraction comprising Δ9-Tetrahydrocannabinol (THC), Cannabidiol (CBD), and Cannabinol (CBN) and a terpene fraction in an amount of at least 3% by weight of the extract.

2. The pharmaceutical composition of claim 1, comprising THC in an amount from 5% to 90% by weight of the extract.

3. The pharmaceutical composition of claim 1 or 2, comprising CBD in an amount from 1% to 20% by weight of the extract.

4. The ceutical composition of any one of claims 1 to 3, comprising CBN in an amount from 1% to 20% by weight of the extract.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the terpene fraction comprises one or more of linalool, myrcene, and nerolidol.

6. The pharmaceutical composition of any one of claims 1 to 5, n the e fraction comprises beta-myrcene in an amount from 1% to 50% by weight of the terpene fraction.

7. The pharmaceutical composition of any one of claims 1 to 6, n the THC is a main cannabinoid.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the ratio of THC:CBN is from 5:1 to 20:1.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the ratio of THC:CBD is from 10:1 to 50:1.

10. The pharmaceutical ition of any one of claims 1 to 9, wherein the Cannabis extract is a Cannabis oil.

11. The pharmaceutical composition of any one of claims 1 to 10, the Cannabis extract comprises the terpene fraction in an amount of less than 50% by weight of the extract.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the ratio of the inoid fraction:terpene fraction is about 8:1 to about 33:1. 28_1 (GHMatters) P106152.NZ.1