• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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  • 优先权
    • 专利摘要:
    The invention relates to a pharmaceutical composition comprising a Cannabis extract and, optionally, one or more carriers, diluents, adjuvants, pharmaceutically acceptable excipients or any combination thereof, Cannabis extract comprising a cannabinoid fraction composed of ¿9 Tetrahydrocannabinol ( THC), Cannabidiol (CBD) and Cannabinol (CBN) and a fraction of terpene in an amount of at least 3% by weight of the extract. The invention also relates to methods for treating sleep disorders using this pharmaceutical composition.
    公开号:BR112019026877A2
    申请号:R112019026877-4
    申请日:2018-06-19
    公开日:2020-06-30
    发明作者:Mara GORDON；Stewart Smith；Stewart WASHER；Patrizia Washer；Harry KARELIS
    申请人:Zelda Therapeutics Operations Pty Ltd；
    IPC主号:
    专利说明:

    [001] [001] The invention relates to a method for treating a sleep disorder. The invention also relates to a pharmaceutical composition comprising extract from a Cannabis plant and its use in the treatment of sleep disorders. BACKGROUND
    [002] [002] The biological activity of Cannabis is well known and has become a "recreational" drug. However, with the discovery of a class of cannabinoid receptors (CB) and the relaxation of laws that regulate the use of Cannabis - decriminalization, in some jurisdictions - there is now an opportunity to explore the potential of Cannabis as a source of new therapies.
    [003] [003] There is also a growing movement of patients suffering from chronic diseases, such as sleep disorders, in the search for medicines as alternative or complementary therapy.
    [004] [004] It is therefore necessary to develop new treatments for sleep disorders, which are derived, at least in part, from a natural source. SUMMARY
    [005] [005] The invention provides a method for treating a sleep disorder comprising a patient in need of administering an effective amount of a pharmaceutical composition comprising a Cannabis extract. Accordingly, a pharmaceutical composition comprising Cannabis extract and optionally one or more carriers, diluents, adjuvants, pharmaceutically acceptable excipients or any combination thereof is also provided.
    [006] [006] Cannabis extract comprises a fraction of cannabinoid and a fraction of terpene. The cannabinoid fraction generally comprises the primary cannabinoid Δ9-Tetrahydrocannabinol (THC). The cannabinoid fraction can also comprise one or more additional cannabinoids, including Cannabidiol (CBD) and Cannabinol (CBN). The terpene fraction normally comprises beta-myrcene, linalool and nerolidol. Preferably, Cannabis extract does not contain (or contains very low levels, such as no more than about 0.001% by weight) of Δ9-Tetrahydrocannabivarin (THCV), alpha-pinene or beta-pinene, terpinolene, karyophyllene, humulene and limonene.
    [007] [007] In an additional aspect, the use of Cannabis extract is provided in the preparation of a medication to treat a sleep disorder.
    [008] [008] In yet another aspect, a pharmaceutical composition is provided to treat 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 of themselves. DESCRIPTION OF THE MODE (S)
    [009] [009] The present invention provides a pharmaceutical composition comprising a cannabis extract and, optionally, one or more carriers, diluents, adjuvants, pharmaceutically acceptable excipients or any combination thereof.
    [0010] [0010] Cannabis plants produce a diverse variety 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 the Cannabis variety, part of the extracted Cannabis plant, extraction method, extract processing and season.
    [0011] [0011] There are several varieties of Cannabis plants that have been described in two separate naming conventions. One of these conventions identifies three distinct species of Cannabis plants, namely Cannabis sativa Linnaeus, Cannabis indica LAM., And Cannabis ruderalis. Another convention identifies all Cannabis plants as belonging to the species of Cannabis sativa L., with the various species distributed among several subspecies, including: Cannabis sativa ssp. sativa and ssp. indicates. As used in the present invention, the term "Cannabis" refers to any and all varieties of these plants.
    [0012] [0012] Extracts can be formed from any part of the Cannabis plant containing cannabinoids, terpenes and terpenoid compounds. The extracts can be made by contacting an extractor with a leaf, seed, trichome, flower, keif, bran (shake), bud, stem or a combination of them. In some modalities, the extract is formed from the flowers and bran of a Cannabis plant. Suitable extraction agents include, for example, alcohols (for example, methanol, ethanol, propanol, butanol, propylene glycol, etc.), water, hydrocarbons (for example, butanes, hexanes, etc.), oils (for example, olive oil olive, vegetable oil, essential oil, etc.), a solvent (for example, ethyl acetate, polyethylene glycol, etc.) or a supercritical fluid (for example, liquid CO2).
    [0013] [0013] The extracting agent can be completely or partially removed before the incorporation of Cannabis extract in the pharmaceutical composition, or it can be included in the pharmaceutical composition as a carrier. The extracting agent can be removed by heating the extract, optionally under reduced pressure. In some embodiments, the pharmaceutical composition comprises a residual amount of an extraction agent (such as ethanol). In some embodiments, the residual amount of extracting agent can be up to about 10 mg / g or about 5 mg / g. It would be appreciated that some of the more volatile plant metabolites (such as terpenes) can also be removed with the extraction agent. Therefore, in some embodiments, removal of the extracting agent can enrich the cannabinoid fraction of the extract.
    [0014] [0014] Cannabis extract comprises a cannabinoid fraction comprising Δ9-Tetrahydrocannabinol (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 the decarboxylation of carboxylic acid derivatives corresponding to these cannabinoids (or cannabinoid acids), which are biosynthesized by the Cannabis plant. It is difficult to quantify the precise concentration of neutral THC or CBD in a Cannabis plant due to the potential for decarboxylation of the corresponding cannabinoid acids during the analysis. Correspondingly, when the pharmaceutical compositions of the invention comprise THC or CBD derived from a Natural source, the composition comprises THC or decarboxylated CBD.
    [0015] [0015] The extraction process normally comprises a decarboxylation step. Decarboxylation refers to the loss of a carboxyl group during the conversion of a cannabinoid carboxylic acid derivative to the cannabinoid itself. Δ9-Tetrahydrocannabinolic acid (THC-A) and cannabidiolic acid (CBD-A) are not thermally stable and can be decarboxylated by exposure to light or heat. Some studies have shown that THC-A and CBD can be decarboxylated upon exposure to cofactors or certain solvents. Normally, decarboxylation is performed by heating the extract in the presence of an extraction agent to a temperature of at least 60 ° C (for example, at least 80 ° C). This warm-up step can be maintained for 30 minutes or more. In some embodiments, decarboxylation occurs during removal of the extraction agent.
    [0016] [0016] In addition, THC has been shown to oxidize to cannabinol (CBN) when exposed to oxygen and light, including during decarboxylation. Therefore, in some embodiments, extraction comprises exposing the extract to light under an oxygen atmosphere. In other modalities, extraction is carried out in the absence of oxygen, for example, under a nitrogen atmosphere.
    [0017] [0017] In some embodiments, the extract is filtered to remove particulate material, for example, when passing the extract through filter paper or a fine sieve (for example, a sieve with pores of 5 µm). The Cannabis composition can comprise up to about 5% by weight (for example, up to about 2% by weight) of visible particles.
    [0018] [0018] In some modalities, Cannabis extract is formed by applying heat and pressure to plant material. Usually, in these modalities, no extraction agent is needed.
    [0019] [0019] In some modalities, Cannabis extract is a Cannabis oil. As used in the present invention, a "Cannabis oil" is an extract formed by contacting at least part of a Cannabis plant with an oil. The extraction oil can be optionally removed. Extraction oils can be selected from olive oil, sunflower oil, hemp oil, sesame oil, coconut oil, vegetable oil, canola oil, grape seed oil, almond oil, triglyceride oil medium-chain (MCT) and any other edible oil, or a combination thereof.
    [0020] [0020] The term "cannabinoid" as used in the present invention refers to any molecule that has been isolated from a Cannabis plant or created synthetically to have activity involving the endocannabinoid system.
    [0021] [0021] The term "cannabinoid fraction" is used to describe the combination of cannabinoid compounds present in Cannabis extract.
    [0022] [0022] The terms "terpenes" and "terpenoids" are used in the present invention to refer to a class of hydrocarbon molecules, which generally provide a unique smell. Terpenes are derived from isoprene units, which have the molecular formula C5H8. The basic molecular formula of terpenes are multiples of the isoprene unit, that is, (C5H8) n, where n is the number of linked isoprene units. Terpenoids are terpene compounds that have been metabolized in the plant, typically through an oxidative process and therefore generally contain at least one oxygen atom.
    [0023] [0023] The term "terpene fraction" is used to describe the combination of terpene and terpenoid compounds present in Cannabis extract.
    [0024] [0024] The inventors observed that the effectiveness of a pharmaceutical composition is improved when the terpene fraction has a certain profile, that is, a certain proportion of particular terpenes / terpenoids are present in the extract. Increased efficacy is believed to be synergistic (ie, non-additive). Thus, it is believed that the presence of specific components in the terpene fraction may increase the patient's tolerance to cannabinoid therapy.
    [0025] [0025] In some embodiments, Cannabis extract contains large amounts (for example, greater than 50% by weight) of a major cannabinoid, typically THC. In some embodiments, 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 Cannabis extract. In some embodiments, 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-cannabinoid weight.
    [0026] [0026] In some embodiments, the cannabinoid fraction present is 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 Cannabis extract.
    [0027] [0027] In some embodiments, one or more additional compounds (for example, cannabinoid compounds, terpenes or terpenoids) can be added to the Cannabis extract. The addition of one or more additional compounds can compensate for natural variations in the relative amounts of certain compounds that are expressed in the Cannabis plant. The added compounds can be synthetic versions of the desired compounds, they can be purified compounds obtained from other Cannabis extracts, or they can be added by mixing two or more extracts.
    [0028] [0028] To date, more than 100 cannabinoids have been identified in Cannabis extracts. A comprehensive list of these cannabinoids can 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). The 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 monomethyl ether A (E) CBGAM-C5 A and cannabigerovarinic acid A (E) -CBGVAC3A); (±) -CBC-C5 -ababichromene, acid (±) - cannabichromenic CBCA-C5 A, (±) -canabivichromene, (±) -canabicromevarin CBCV-C3, (±) -canabichromevarinic A CBCVA-C3 A); (-) - cannabidiol CBD-C5, CBDMC5 cannabidiol ether , cannabidiol-C4 CBD-C4, (-) - cannabidivarin CBDVC3, cannabidiorcol CBD-Cl, cannabidiolic acid CBDA-C5, cannabidivarinic acid CBDVA-C3); cannabinodiol CBNDC5, cannabinodivarin CBND-C3); Δ9-T3; etrahydrocannabinol Δ9-THC-C5, Δ9-Tetrahydrocannabinol-C4 Δ9-THCC4, Δ9-Tetrahydrocannabivarin Δ9-THCV-C3, Δ9-Tetrahydrocannabiorcol, Δ9-THCO-C, Δ9-Tetrahydrochloric acid Tetrahydrocannabinolic B, Δ9-THCA-C5 B, C4 A Δ9-Tetrahydrocannabinolic and / or B Δ9-THCA-C4 A and / or B, Δ9-Tetrahydrocannabivarinic acid A Δ9-THCVA-C3 A, Δ9-Tetrahidranic acid or B Δ9-THCOA-Cl A and / or B), (-) - Δ8-trans- (6aR, 10aR) -Δ8-Tetrahydrocannabinol Δ8-THC-C5, acid (-) - Δ8-trans- (6aR, 10aR ) - Tetrahydrocannabinolic A Δ8-THCA-C5 A, (-) - (6aS, 10aR) -Δ9-Tetrahydrocannabinol (-) -cis-Δ9-THC-C5); Cannabinol CBN-C5, Cannabinol-C4 CBN-C4, Cannabinoline 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, (+) - (9S, 10S) -canabitriol (+) - 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) -Cababitriol-C3 (±) -trans-CBT-C3, 8,9-Dihydroxy-Δ6a (10a) - tetrahydrocannabinol 8,9-Di-OH-CBT-C5, CBDA-C5 ester 9-OH -CBT-C5 of cannabidiol ester of cannabidiolic acid A, (-) - (6aR, 9S, 10S, 10aR) -9,10- Dihydroxyhexahidrocanabinol, Canabiripsol, Cannabiripsol-C5, (-) - 6a, 7,10a-Trihydroxy- Δ9-tetrahydrocannabinol (-) - Cannabitetrol, 10-Oxo-Δ6a (10a) tetrahydrocannabinol OTHC); (5aS, 6S, 9R, 9aR) -Canabielsoin CBE-C5, (5aS, 6S, 9R, 9aR) -C3-Cannabielsoin CBE-C3, acid (5aS, 6S, 9R, 9aR) -
    [0029] [0029] Cannabis extract can comprise 0.005-99% by weight of a cannabinoid based on the total weight of the extract, for example, 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 , 01-2%, 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 can be Δ9- Tetrahydrocannabinol (THC). In some modalities, Cannabis extract comprises the main cannabinoid in the amount of 5-90%, 10-90%, 20-90%, 25-85%, 50-99%, 55-95%, 70-95%, 75-95% or 80-90% by weight of the cannabinoid fraction. Typically, Cannabis extract additionally comprises one or more secondary cannabinoids. Cannabidiol (CBD) and / or cannabinol (CBN) may also be present in Cannabis extract as secondary cannabinoids. Typically, each secondary cannabinoid is present in an amount of about 0.001% to about 30% by weight of the cannabinoid fraction, for example, 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 most of them are not part of the active ingredients.
    [0030] [0030] The pharmaceutical composition can 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 30mg / ml or about 18mg / ml to about 22mg / ml.
    [0031] [0031] In some embodiments, Cannabis extract comprises 0.001-20% by weight of cannabidiol (CBD) as a secondary cannabinoid, for example, 0.0001-20%, 0.001-10%, 1-20% or 1- 10% by weight of the extract or fraction of cannabinoid. The pharmaceutical composition can 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.
    [0032] [0032] The weight ratio of THC to CBD can be from 10: 1 to 50: 1, for example, from 10: 1 to 30: 1, 15: 1 to 25: 1 or about 20: 1.
    [0033] [0033] In some embodiments, Cannabis extract comprises 0.0001-20% by weight of cannabinol (CBN), for example, 0.001-20%, 0.001-10%, 1-20% or 1-10% in weight of cannabinoid extract or fraction. The pharmaceutical composition can comprise CBN in a concentration of about 0.5mg / ml to about 10mg / ml, 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.
    [0034] [0034] The weight ratio of THC to CBN can be from 5: 1 to 20: 1, for example, from 5: 1 to 15: 1 or about 10: 1.
    [0035] [0035] The weight ratio of CBN: CBD can 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.
    [0036] [0036] Cannabis extracts usually also comprise other cannabinoids, in addition to THC, CBN and CBD. These cannabinoids include Δ9-Tetrahydrocannabinolic acid (THCA), (-) - Cannabidivarin (CBDV) and Cannabigerol (CBG). Each of these cannabinoids can be present in an amount of 0.001% to 30% by weight of the cannabinoid extract or fraction.
    [0037] [0037] In some embodiments, certain cannabinoids may be absent, or present in undetectable amounts (for example, less than 0.001% by weight of the analyte). In some embodiments, Cannabis extract may exclude (or comprise an amount less than or equal to 0.5% by weight of the cannabinoid fraction) one or more of the following cannabinoids: Δ9-Tetrahydrocannabivarin (THCV), Cannabidiolic acid (CBDA) , Cannabigerolic acid (CBGA) and (-) - Cannabidivarin (CBDV).
    [0038] [0038] Cannabis extract comprises a non-cannabinoid fraction, which normally includes a terpene fraction. The terpene fraction comprises terpenes and terpenoids. The Cannabis extract comprises a fraction of terpene 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, Cannabis extract comprises a fraction of terpene 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, 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.
    [0039] [0039] The weight ratio of the cannabinoid fraction to the terpene fraction can 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
    [0040] [0040] Normally, 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 amount of specific compounds in the terpene fraction and the weight of the terpene fraction relative to the other components. For example, a Cannabis flower can contain about 20% by weight of cannabinoids and about 3% by weight of terpenes, corresponding to a proportion of the cannabinoid fraction: terpene fraction of about 20: 3 (about 7: 1). After extraction and concentration (ie removal of the extraction agent), the amount of cannabinoids can increase to around 50-90% by weight and the terpene fraction can reach about 0.1-6% by weight of Cannabis extract, corresponding to a significant increase in the ratio of the cannabinoid fraction: terpene fraction. This typical scenario shows that, although cannabinoids are concentrated when the extraction agent is removed, the relative amount of the terpene fraction is reduced, probably 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 existing in nature.
    [0041] [0041] A variety of terpenes and terpenoids have been identified in Cannabis extracts, including monoterpenes, monoterpenoids, sesquiterpenes and sesquiterpenoids. For example, the following terpenes and terpenoids have been identified in Cannabis extracts: Aloaromadendrene, allyl hexanoate, benzaldehyde, (Z) -a-cis-bergamotene, (Z) -α-trans-bergamotene, β-bisabolol, epi-a -bisabolol, β-bisabolene, borneol (canfol), cis-y-
    [0042] [0042] It is believed that the presence of particular terpenes / terpenoids in the terpene fraction is associated with beneficial effects of the pharmaceutical composition in use.
    [0043] [0043] The terpene fraction normally comprises beta-mycrene. Beta-myrcene is believed to improve the bioavailability of cannabinoids present in the extract and / or help to allow cannabinoids to pass through the blood-brain barrier. Beta-myrcene can be present in an amount of about 0% to about 40% by weight of the extract. In some embodiments, beta-mircene is present in an amount of about 0-50% by weight of the terpene fraction, for example, from about 0.001% to about
    [0044] [0044] In some embodiments, the weight ratio of THC to beta-myrcene can 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.
    [0045] [0045] The terpene fraction can additionally comprise one or more of linalool and nerolidol.
    [0046] [0046] Linalool is a terpenoid found in many flowers and spice plants with the molecular formula C10H18O. It is believed that when linalool is present in a Cannabis extract, it offers 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 0-50% by weight of the terpene fraction. In other embodiments, linalool is present in an amount of about 0.05% to 50% by weight of the terpene fraction, for example, from about 0.1% to about 20%, about 0.05% 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% at about 45% by weight of the terpene fraction. In some embodiments, the pharmaceutical composition comprises linalool at a concentration of up to about 10mg / ml, for example, up to about 5mg / ml, about 1mg / ml or about 0.5mg / ml.
    [0047] [0047] In some embodiments, the weight ratio of THC to linalool can be from 20: 1 to about 55: 1, for example, from about 30: 1 to about 50: 1 or about 35: 1 at about 45: 1.
    [0048] [0048] Nerolidol is a sesquiterpenoid with the molecular formula of C15H26O. It exists in nature in two isomeric forms, namely, nerolidol 1 and nerolidol 2, which differ in geometry around a central olefin, that is, cis or trans isomers. The extract can comprise nerolidol (i.e. nerolidol 1 and nerolidol 2) in an amount of at least 0.001% by weight of the terpene fraction, for example, from about 0.01% to about 30% or 0.01% to 20% by weight of the terpene fraction. Normally, nerolidol 1 is present in greater quantity than nerolidol 2. In some embodiments, nerolidol 1 may be absent (or present in an amount below the detection limit). In some embodiments, nerolidol 2 may be absent (or present in an amount below the detection limit). In some embodiments, nerolidol 1 and nerolidol 2 are absent (or present in an amount below the detection limit). Nerolidol 1 can be present in the extract in an amount of at least about 0.001% by weight of the terpene fraction, for example, from about 0.001% to about 20% or 0.001% to 15% by weight of the terpene fraction . Nerolidol 2 can be present in the extract in an amount of at least about 0.001% by weight of the terpene fraction, for example, from about 0.001% to about 20% or 0.001% to 15% by weight of the terpene fraction . In some embodiments, the pharmaceutical composition comprises nerolidol in a concentration of up to about 5mg / ml, for example, up to about 3mg / ml, about 1mg / ml or about 0.25mg / ml.
    [0049] [0049] In some embodiments, the weight ratio of THC to nerolidol can be from 50: 1 to about 100: 1, for example, from about 60: 1 to about 95: 1 or about 70: 1 about 90: 1.
    [0050] [0050] The terpene fraction can also include beta-karyophylene. Beta-karyophylene can be present in an amount of at least 0.001% by weight of the terpene fraction, for example, from 0.001% to about 20% or 0.001% to 15% of the terpene fraction. In some embodiments, the pharmaceutical composition comprises beta-karyophylene at a concentration of up to about 1mg / ml, for example, up to about 0.5mg / ml or about 0.25mg / ml.
    [0051] [0051] In some embodiments, the extract additionally comprises humulene. Humulene is believed to enhance the extract's sedative properties. Humulene is also sometimes referred to as alpha-karyophylene. 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.
    [0052] [0052] In some modalities, Cannabis extract additionally comprises ocimene. Ocimene can be present in an amount of at least 0.001% by weight of the terpene fraction, for example, from 0.001% to about 20% or 0.001% to 5% by weight of the terpene fraction. In some embodiments, the pharmaceutical composition comprises ocimene in a concentration of up to about 1mg / ml, for example, up to about 0.5mg / ml or about 0.25mg / ml.
    [0053] [0053] In some embodiments, the terpene fraction comprises beta-myrcene, linalool and nerolidol 1. The weight ratio of beta-myrcene to linalool can be about 1: 1 (for example, from 1: 2 to 2: 1). The weight ratio of beta-myrcene to nerolidol can be about 2: 1 (for example, from 1: 1 to 3: 1). The weight ratio of linalool to nerolidol can be about 2: 1 (for example, from 1: 1 to 3: 1). In some embodiments, the weight fraction of beta-myrcene: linalool is about 2: 2: 1.
    [0054] [0054] In some embodiments, the fraction of terpene may be present in the composition in an amount of 3% to 6% by weight of the extract and may comprise:
    [0055] [0055] In some embodiments, specific terpenes or terpenoids may be absent, or present in undetectable amounts (for example, less than 0.001% by weight of the analyte or less than or equal to 0.5 mg / ml of the pharmaceutical composition). In some embodiments, one or more of the following terpenes or terpenoids are absent, or present in undetectable amounts: alpha-pinene, beta-pinene, limonene, p-cymene, camphene, alpha-terpinene, gamma-terpinene, delta-s -carene, terpinolene, isopulegol, geraniol and guaiol.
    [0056] [0056] The amounts of cannabinoids can be determined by high performance liquid chromatography (HPLC), including ultra efficient liquid chromatography (UPLC) and quantities 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 can vary in some cases by +/- 10%, +/- 25% or +/- 50%. In some embodiments, the amount of a cannabinoid and / or a terpene can be determined by UPLC using a Waters UPLC Acquity system equipped with a Waters photodiode array (PDA) detector or mass spectrometry detection. Using UPLC, the limit of quantification (LoQ) of THC, CBD and / or CBN or related substances can be less than 1g / ml, for example, the CBD LoQ can be ≤ 0.086g / ml, CBN can be ≤ 0.038g / ml and / or THC can be ≤ 0.089g / ml can be detected in an analyte.
    [0057] [0057] Cannabis extract is preferably free of toxins associated with plant extracts. For example, Cannabis extract is preferably free of aflatoxins (like aflatoxin B1, B2, G1 and G2), mycotoxins (like ochratoxin A), heavy metals (like arsenic, cadmium, lead and mercury) and pesticides. In some embodiments, the pharmaceutical composition comprises less than 4 µg / ml total aflatoxins and / or less than 2 µg / ml aflatoxin A. In some embodiments, the pharmaceutical composition may comprise less than 20 µg / ml ochratoxin . In some embodiments, the pharmaceutical composition comprises ≤ 0.3 ppm of arsenic, ≤ 0.5 ppm of cadmium, ≤ 5 ppm of lead and / or 0.5 ppm of mercury.
    [0058] [0058] In some embodiments, the pharmaceutical composition may comprise no more than 20% by weight of total ash.
    [0059] [0059] The pharmaceutical composition may additionally comprise one or more carriers, diluents, adjuvants, pharmaceutically acceptable excipients or any combination thereof.
    [0060] [0060] The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient that is in a pharmaceutically acceptable form. The term "pharmaceutical composition" can include compositions intended to be sold as nutraceutical products (for example, supplements that provide a health benefit). In some embodiments, the pharmaceutical composition is a nutraceutical composition.
    [0061] [0061] The pharmaceutical composition can comprise the extract of
    [0062] [0062] The carrier, diluent, adjuvant and / or excipient are "pharmaceutically acceptable", which means that they are compatible with the other ingredients of the composition and are not harmful to an individual upon or after administration. The pharmaceutical compositions can be formulated, for example, using solid or liquid carriers or diluents, as well as pharmaceutical additives of a type suitable for the desired mode of administration (for example, excipients, binders, preservatives, stabilizers, flavorings, etc.) according to with techniques such as those well known in the pharmaceutical formulation technique (See, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott
    [0063] [0063] The pharmaceutical composition includes those suitable for oral, sublingual, buccal, rectal, nasal, topical, vaginal or parenteral administration (including intramuscular, subcutaneous and intravenous administration) or in a form suitable for administration by inhalation or insufflation.
    [0064] [0064] Cannabis extract, together with a conventional adjuvant, carrier, excipient or diluent, can thus be placed in the form of pharmaceutical compositions and unit dosages thereof, and in that form can be used as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs or capsules filled with it, 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] [0065] Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional compounds or active ingredients, and such unit dosage forms may contain any suitable effective amount of the active principle proportional to the range. intended daily dosage to be used.
    [0066] [0066] To prepare pharmaceutical compositions from the Cannabis extract described in the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, wafers, suppositories and dispensable granules. A solid carrier can be one or more substances that can act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.
    [0067] [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, such as a carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is, therefore, in association with this. Likewise, cachets and lozenges are included. Tablets, powders, capsules, pills, wafers and lozenges can be used as solid forms suitable for oral administration.
    [0068] [0068] Preparations in liquid form include solutions, dispersions, suspensions and emulsions, for example, a pharmaceutically acceptable oil, water or water-propylene glycol solutions. For example, a sublingual preparation can be prepared in a carrier comprising a pharmaceutically acceptable oil, and liquid parenteral injection preparations can be formulated as solutions in an aqueous solution of polyethylene glycol.
    [0069] [0069] Sterile liquid compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. Cannabis extract can be suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
    [0070] [0070] Other preparations in liquid form include those prepared by combining Cannabis extract with one or more oils (for example, an essential oil) or waxes. An "essential oil" is an oil extracted from a material, such as a plant material (for example, steam extraction or contact of the plant material with an extraction agent) or pressing, which contains mainly hydrophobic and generally perfumed components of the plant material. Suitable oils and waxes include sesame oil, olive oil, sunflower oil, Arnica essential oil, lavender essential oil, wild lavender essential oil, incense essential oil, lemongrass essential oil, essential oil of cinnamon leaf, Rosemary Cineole essential oil, Rosemary essential oil, bergamot essential oil, myrrh essential oil, sage essential oil, coconut oil, beeswax and hemp oil.
    [0071] [0071] The pharmaceutical compositions can be formulated for parenteral administration (for example, by injection, for example bolus injection or continuous infusion) and can be presented as a unit dose in the form of ampoules, pre-filled syringes, small infusion volume or in multiple dose containers optionally with an added preservative. The compositions can take forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution, for constitution with a suitable vehicle, for example, sterile water, free of pyrogen, before use.
    [0072] [0072] The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions. They must be stable in the conditions of manufacture and storage and must be preserved against oxidation and the contaminating action of microorganisms, such as bacteria or fungi.
    [0073] [0073] The solvent or dispersion medium for the solution or dispersion for injection 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] [0074] The pharmaceutical forms suitable for injectable use can be delivered by any appropriate route, including intravenous, intramuscular, intracerebral, intrathecal, injection or epidural infusion.
    [0075] [0075] Sterile injectable solutions are prepared by incorporating Cannabis extract in the required amount into the appropriate carrier with various other ingredients, such as those listed above, as needed, followed by sterilization. Generally, dispersions are prepared by incorporating the various sterile active ingredients in a sterile vehicle that contains the basic dispersion medium and the other ingredients required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying or lyophilization of a previously sterile suspension of the active principle, in addition to any additional desired ingredients.
    [0076] [0076] The active ingredients can be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or can be wrapped in a hard or soft gelatin capsule, or can be compressed into tablets or can be incorporated directly with the diet food. For oral therapeutic administration, the active can be incorporated with excipients and used in the form of ingestible tablets,
    [0077] [0077] The amount of active ingredient in therapeutically useful compositions must be sufficient for an adequate dosage to be obtained.
    [0078] [0078] The tablets, lozenges, capsules and the like can also contain the components as listed below: 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 as sucrose, lactose or saccharin can be added or a flavoring agent, such as mint, wintergreen oil, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier.
    [0079] [0079] In some embodiments, the pharmaceutical composition is formulated for sublingual administration. Sublingual administration refers to the administration of a formulation under an individual's language. In some cases, sublingual administration can be considered as a form of oral administration or topical administration. Sublingual administration can be considered a form of oral administration, since the formulation is taken "by mouth" and, in some cases, after application under the tongue, the individual can swallow the formulation which can allow at least a portion of the active ingredients is absorbed by the digestive tract. Sublingual administration can be considered a form of topical administration, as it can include the administration of the active ingredient (s) in the formulation through the mucous membrane under the tongue. The formulation suitable for sublingual administration includes tablets (for example, dissolvable, dispersible, effervescent and multipurpose tablets), strips, drops,
    [0080] [0080] Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules can 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 flavoring, such as cherry or orange flavoring. Of course, any material used in the preparation of any dosage unit form must be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound (s) can be incorporated into sustained release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the intestine.
    [0081] [0081] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable dyes, flavors, stabilizing 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, methyl cellulose, sodium carboxymethyl cellulose or other well-known suspending agents.
    [0082] [0082] Pharmaceutically acceptable carriers and / or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and retarding agents and the like.
    [0083] [0083] 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,
    [0084] [0084] For topical administration to the epidermis, the active ingredients can be formulated as ointments, creams or lotions or as a transdermal patch. Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and, in general, also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents.
    [0085] [0085] Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; the tablets comprising the active principle in an inert base, such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
    [0086] [0086] Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations can be supplied in a single or multidose form. In the latter case of a dropper or pipette, this can be achieved by the patient by administering an adequate and predetermined volume of solution or suspension.
    [0087] [0087] In the case of a sprayer, this can be achieved, for example, by means of a spray pump with metering atomization. To improve nasal delivery and retention of the compounds according to the invention, it can be encapsulated with cyclodextrins, or formulated with other agents expected to improve delivery and retention in the nasal mucosa.
    [0088] [0088] The administration of the respiratory tract can also be achieved through an aerosol formulation in which the active ingredient is supplied in a pressurized air package with a suitable propellant, such as a chlorofluorocarbon (CFC), for example, dichlorofluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
    [0089] [0089] The aerosol can conveniently also contain a surfactant, such as lecithin. The dose of the drug can be controlled by providing a metering valve.
    [0090] [0090] Alternatively, the active ingredients can be supplied in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives, such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP) . Conveniently, the powder carrier can form a gel in the nasal cavity. The powder composition can be presented in the form of a unit dose, for example, in capsules or cartridges, for example gelatin, or a tablet pack, from which the powder can be administered by means of an inhaler.
    [0091] [0091] In formulations intended for administration of the respiratory tract, including intranasal formulations, the compound will generally have a small particle size, for example, on the order of 5 to 10 microns or less. Such a particle size can be obtained by means known in the art, for example, by micronization.
    [0092] [0092] When desired, formulations adapted to give sustained release of the active ingredient can be used.
    [0093] [0093] Pharmaceutical preparations are preferably in unit dosage forms. In such a way, the preparation is subdivided into unit doses containing adequate amounts of the active component. The unit dosage form can be a packaged preparation, the package containing discrete amounts of preparation, such as tablets, capsules and powders packaged in bottles or ampoules. Thus, the unit dosage form can be a capsule, tablet, wafers or lozenge itself, or it can be the appropriate number of any of these in packaged form.
    [0094] [0094] It is especially advantageous to formulate parenteral compositions in the form of the dosage unit to facilitate administration and uniformity of dosage. The unit dosage form as used in the present invention refers to physically discrete units suitable as unitary dosages for individuals to be treated; each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for unit dosage forms is dictated 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 technique of composing such active material for the treatment of a sleep disorder.
    [0095] [0095] Compositions that lack a carrier in which the compositions are in a unit dosage form are also described in the present invention. Correspondingly, a drug comprising Cannabis extract is also provided.
    [0096] [0096] In some embodiments, the pharmaceutical composition additionally comprises an active agent other than Cannabis extract. Any suitable active agent can be used as long as the activity of the active agent and / or Cannabis extract is not decreased when combined. TREATMENT METHODS
    [0097] [0097] In another aspect, a method is also provided for the treatment of a sleep disorder. A method of administering an effective amount of the pharmaceutical composition to a patient in need thereof is described in the present invention.
    [0098] [0098] Pharmaceutical compositions can be used to treat a sleep disorder. Sleep disorders are described in the International Classification of Sleep Disorders (ICSD). The ICSD-3 was published in 2014 and characterizes sleep disorders as belonging to one of the following classes: (1) Insomnia; (2) Sleep-Related Breathing Disorders; (3) Central Hypersolence Disorders; (3) Sleep-Wake Circadian Rhythm Disorders; (4) Parasomnias; (5) Sleep-related Movement Disorders. Consequently, sleep disorders to be treated by the pharmaceutical composition can include any disorders from (1) Insomnia; (2) Sleep-Related Breathing Disorders; (3) Central Hypersolence Disorders; (3) Sleep-Wake Circadian Rhythm Disorders; (4) Parasomnias; (5) Sleep-related Movement Disorders. In particular, pharmaceutical compositions can be effective in the treatment of a sleep disorder selected from: insomnia, narcolepsy, hypersomnia, sleep apnea, periodic limb movement syndrome, restless legs syndrome, nighttime eating (drinking) syndrome, jet lag, sleep disturbance due to shift work, irregular sleep-wake pattern, confusional awakening, somnambulism, night terror, sleepwalking, nightmares, sleep paralysis, REM sleep behavior disorder, snoring, sleeping sickness, a disorder of sleep associated with another disease or condition, or any other sleep disorder.
    [0099] [0099] By "effective amount" is meant a sufficient amount of the drug that is provided to the patient to achieve an effect when administered. In the case of a therapeutic method, this effect may be the treatment of the sleep disorder. Therefore, the "effective amount" can be a "therapeutically effective amount". By "therapeutically effective amount" is meant a sufficient amount of the drug that is provided to the patient to treat the disease or a symptom of the disease when administered.
    [00100] [00100] In some modalities, the methods include the administration of THC in an amount of 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 20mg / day. In some modalities, the methods may comprise the administration of THC in an amount of 10mg / day or 20mg / day. The methods may comprise the administration of CBD in an amount of 0.001mg / day to 10mg / day, for example, from 0.01mg / day to 10mg / day or from 0.1mg / day to 5mg / day. In some embodiments, the methods may comprise the administration of CBD in an amount of 1mg / day. The methods may comprise the administration of CBN in an amount from 0.001mg / day to 10mg / day, for example, from 0.01mg / day to 10mg / day or from 0.1mg / day to 5mg / day. In some modalities, the methods may comprise the administration of CBN in an amount of 1mg / day or 2mg / day. The methods can include administering THC, CBD and / or CBN in any combination of these daily dosage amounts. Preferred pharmaceutical compositions comprise amounts of THC, CBD and CBN suitable for administering any of these daily dosage amounts.
    [00101] [00101] As used in the present invention, the terms "treating", "treatment", "treating" and the like mean that they affect an individual, tissue or cell to obtain a desired pharmacological and / or physiological effect. The effect can be prophylactic in terms of total or partial prevention, or reduce the severity of a disease or associated symptom, and / or it can be therapeutic in terms of a partial or complete cure for a disease. A reference to "treating" a sleep disorder, therefore, covers: (a) helping the patient fall asleep; (b) helping the patient to stay asleep once sleep has been achieved; (c) alleviating or improving the effects of the sleep disorder, for example, by improving wakefulness during periods without sleep; or (d) preventing sleep disturbance from occurring in a predisposed individual, or at risk of propensity to sleep disturbance, so that the sleep disturbance does not develop or occur in the individual, or develops less severely.
    [00102] [00102] In some modalities, the sleep disorder is insomnia. Insomnia symptoms and severity can be measured by the Insomnia Severity Index (ISI) questionnaire. Typically, ISI is administered by a doctor, nurse or researcher or can be self-administered by the patient. ISI assesses the nighttime and daytime components of insomnia and is available in several languages. ISI asks seven questions to be scored on a scale of 0-4, related to (1) difficulty falling asleep, (2) difficulty maintaining sleep, (3) problems waking up too early, (4) satisfaction with current sleep patterns, (5) other people's perception of the sleep problem, (6) degree of concern / stress with the sleep problem and (7) the extent to which the sleep problem interferes with daily activities. The methods can provide improvements in one or more of these seven aspects of insomnia. In some modalities of treatment methods, the patient 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 modalities, a method of treating insomnia may provide a reduction in the patient's ISI score compared to an initial ISI score. This reduction in the ISI score can be 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.
    [00103] [00103] ISI can be used alone to assess the severity of the patient's insomnia or it can be used together with one or more other questionnaires, such as the questionnaire of satisfaction and satisfaction with quality of life (Q-les-Q), scale of work and social adjustment (WSAS), questionnaire of anxiety stress scale in depression (DASS), questionnaire of dysfunctional beliefs about sleep (DBAS), multidimensional questionnaire and inventory of fatigue and any other known questionnaire known in the field.
    [00104] [00104] Usually, the patient is evaluated by one or more questionnaires before receiving treatment and then at regular intervals (for example, an interval of 1, 2, 3, 4, 5, 6, 7 or 8 weeks) during the course of treatment. Evaluation during treatment can begin 2 weeks after starting treatment.
    [00105] [00105] In some modalities, the treatment can be maintained for up to 14 days, for example, the treatment can be maintained for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days. In some modalities, the treatment is maintained for more than 14 days, for example, for 3 weeks, 1, 2, 3, 4, 5, 6, 12, 18, 24, 36 months or more.
    [00106] [00106] Usually, the pharmaceutical composition is administered daily, preferably for a short period before the patient falls asleep. In some embodiments, the pharmaceutical composition is administered within about 2 hours after the patient falls asleep, for example, within about 1.5 hours, within about 1 hour or within about 30 minutes before sleep.
    [00107] [00107] In some modalities, the administration is a sublingual administration. In such embodiments, the pharmaceutical composition can be presented as sublingual drops.
    [00108] [00108] In some modalities, insomnia can be assessed by measuring one or more objective measures of sleep. Objective measures of sleep can be measured by polysomnography (PSG) and / or actigraphy. Objective sleep measures may include measuring: Sleep onset (SO) latency; Awakening after the Beginning of Sleep (WASO); Total Sleep Time (TST); Sleep Efficiency (SE); REM versus NREM sleep patterns, including slow wave sleep patterns and time in all stages of sleep; sleep apnea; periodic movements of members; and combinations thereof. In some modalities, 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 among objective measures of sleep.
    [00109] [00109] The patient who needs therapy for insomnia can be any patient who suffers from insomnia, for example, as assessed by ISI. But in some modalities, not all patients may be suitable. For example, in some modalities, a patient who meets one or more of the following factors may be excluded: a. Untreated cardiovascular disease, arrhythmias (except well-controlled atrial fibrillation), hypertension or severe heart failure: or b. History of allergies especially to herbal products containing terpenes, that is, natural aromatic scents and oils, for example, citrus products, mango, lavender, thyme, cedar and pine: or c. Known hypersensitivity to cannabinoids: or d. Current regular use (on 3 or more nights / days per week) of psychotropic or CNS active drugs, such as Cannabis, opioids, benzodiazepines: or e. Inability to refrain from using psychotropic or active drugs in the CNS (including Cannabis, opioids, benzodiazepines) for at least one week before treatment: or f.
    [00110] [00110] The method may also comprise the administration of an active agent other than Cannabis extract. This active agent can be administered simultaneously or consecutively with Cannabis extract. Consecutively, it is understood that each of the Cannabis extracts and the other active agent are administered separately and can be administered at different times. Typically, when 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) from each other. Cannabis extract can be administered before or after the other active agent. In addition, the route of administration of the Cannabis extract and the other active agent may be the same or different.
    [00111] [00111] In an additional aspect, the use of Cannabis extract in the preparation of a medication for the treatment of a sleep disorder is also provided.
    [00112] [00112] A kit composed in separate parts is also provided: (a) an effective amount of Cannabis extract; and (b) a carrier, diluent, adjuvant, pharmaceutically acceptable excipient or a combination thereof.
    [00113] [00113] In some embodiments, the kit additionally comprises a part comprising (c) an effective amount of an active agent other than Cannabis extract.
    [00114] [00114] In another aspect, the pharmaceutical composition for the treatment of sleep disorder is provided. The pharmaceutical composition can be any of the pharmaceutical compositions described above, comprising any combination of the above described components, as long as it comprises Cannabis extract with the specified terpene fraction. Sleep disorders can also be any of those described above. EXAMPLES
    [00115] [00115] Additionally, the invention will be described by non-limiting examples. It will be understood by those skilled in the art of the invention that many modifications can be made without departing from the spirit and scope of the invention. Example 1 - Cannabis extracts
    [00116] [00116] The following formulation of Cannabis extract indicates 'bedite' has been produced: • THC - 20 mg / ml, for example, 18-22 mg / ml • CBN - 2 mg / ml, for example, 1-3 mg / ml ml • CBD - 1 mg / ml, for example, 0.5-1.5 mg / ml • Linalool - 0.5 mg / ml (or less) • Myrcene - 0.5 mg / ml (or less) • Nerolidol - 0.25 mg / ml (or less) • Remaining plant material composed of other cannabinoids or other terpenes (less than 10% of the total or less than 15% of the total), where each other cannabinoid or terpene is present in low concentrations (eg <0.5%)
    [00117] [00117] Alpha-pinene and beta-pinene (<0.5%) were not detected;
    [00118] [00118] Limonene levels were low, for example <0.2%.
    [00119] [00119] THCV was at low levels (<0.5%).
    [00120] [00120] The formulation was completed using sunflower oil as carrier oil. Example 2 - A Study to Assess the Effectiveness of Sublingual Extract from Cannabinoid Drugs in Comparison with Placebo for the Treatment of Sleep Disorders Due to Insomnia.
    [00121] [00121] This study is a crossover, randomized, double-blind, placebo-controlled study that evaluated the effectiveness of a Cannabis extract containing THC to improve sleep in people with insomnia. Efficacy is assessed using subjective measures of sleep quality using the standard Insomnia Severity Index, objective measures of sleep determined using PSG and actigraphy, and subjective measures of sleep and quality of life using daily sleep diaries and questionnaires standardized for quality of life, mood, stress, anxiety, fatigue, including Depression, Anxiety and Stress Scales (DASS). Dysfunctional Beliefs About Sleep (DBAS), Multidimensional Fatigue Inventory (IMF).
    [00122] [00122] The main objective of this study is to evaluate the effectiveness of a sublingual cannabinoid extract (composition 1 of the present invention) containing delta-9-tetrahydrocannibinol (THC) to improve sleep in people with insomnia.
    [00123] [00123] The secondary objective is to assess sleep quality and improvements in quality of life in people with insomnia when using composition 1 of the present invention compared to a placebo. Another secondary objective is to determine patient safety of composition 1, as measured by the incidence of adverse events during the course of the study.
    [00124] [00124] Composition 1 comprises 20 mg / ml delta-9-tetrahydrocannibinol (THC), 2 mg / ml cannabinol (CBN) and 1mg / ml cannabidiol (CBD) as an extract from the Cannabis plant with oil excipient sunflower seeds. Sunflower oil is used as an excipient to stabilize the formulation, including cannabinoids and as a diluent in the plant extract.
    [00125] [00125] Each dose is administered sublingually with 0.5 ml of cannabinoid extract (10mg THC, 1mg CBN and 0.5 mg CBD).
    [00126] [00126] Male or female participants (aged between 25 and 70 years old) with chronic insomnia will be screened on Day 1 of the study.
    [00127] [00127] Each qualified individual admitted to the study meets all the inclusion criteria and none of the exclusion criteria. 24 participants are enrolled in the study. This study is carried out over 9 to 12 months. The study requires participants to spend 3 nights in the clinic at the University of Western Australia, Sleep Sciences Center. At home, participants will be required to take the Investigational Product for 2 weeks and the placebo for 2 weeks.
    [00128] [00128] This study complies with the National Declaration 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.
    [00129] [00129] Otherwise, all percentages referred to in the present invention are percentages by weight of the pharmaceutical composition. Likewise, unless the context requires otherwise, all proportions referred to in the present invention are proportions by weight.
    [00130] [00130] Various features of the invention are described and / or claimed with reference to a certain value, or range of values. These values are intended to relate the results of the various appropriate measurement techniques and, therefore, should be interpreted as including a margin of error inherent in any specific measurement technique. Some of the values referred to in the present invention are denoted by the term "around" at least in part of the account of that variability. The term "around", when used to describe a value, preferably means a value within ± 25%, ± 10%, ± 5%, ± 1% or ± 0.1% of that value.
    [00131] [00131] Various values are described in terms of their percentage in relation to the total weight of (i) pharmaceutical composition, (ii) Cannabis extract or (iii) extract fraction (for example, cannabinoid fraction or terpene fraction ). The percentages of components included in the Cannabis extract or a fraction of it (for example, the cannabinoid fraction or terpene fraction) are intended to denote the percentage by weight of the specified compound in relation to the percentage by weight percentage of the other compounds present the extract or the specified fraction, for example, without carriers, diluents, adjuvants and excipients or any combination thereof. For example, a pharmaceutical composition comprising a Cannabis extract comprising a fraction of terpene in an amount of at least 3% by weight of the extract is intended to denote a pharmaceutical composition in which the cumulative weight of terpenes and terpenoids is 3% by weight or more when compared to the cumulative weight of the compounds present in the extract, including cannabinoids, terpenes, terpenoids and extracting agent / residual extracting agent. In addition, a Cannabis extract comprising THC in an amount of about 85% by weight of the cannabinoid fraction is intended to denote an extract composed of THC in an amount of 85% by weight in relation to the cumulative weight of all cannabinoids present in the extract.
    [00132] [00132] The terms "one", "one", "and" and / or "o" and the like referring in the context of the description of the invention and the claims that follow must be interpreted to cover both the singular and the plural, unless than otherwise indicated in the present invention or clearly contradicted by the context.
    [00133] [00133] It should be understood that, if any publication of the prior art is referred to in the present invention, such reference does not constitute an admission that the publication forms part of the general common knowledge of the technique, whether in Australia or in any other country.
    [00134] [00134] In the claims that follow and in the previous description of the invention, except where the context requires otherwise due to the express language or necessary implication, the word "understand" or variations like "understand" or "understanding" is used in a sense inclusive, that is, to specify the presence of the declared features, but not to prevent the presence or addition of additional features in various embodiments of the invention.
    权利要求:
    Claims (16)
    [1]
    1. Pharmaceutical composition, characterized by the fact that it comprises a Cannabis extract and, optionally, one or more pharmaceutically acceptable carriers, diluents, adjuvants and excipients or any combination thereof, in which the Cannabis extract comprises a cannabinoid fraction comprising Δ9 -Tetrahydrocannabinol (THC), Cannabidiol (CBD) and Cannabinol (CBN) and a fraction of terpene in an amount of at least 3% by weight of the extract.
    [2]
    2. Pharmaceutical composition according to claim 1, characterized by the fact that it comprises THC in an amount of 5% to 90% by weight of the extract.
    [3]
    Pharmaceutical composition according to claim 1 or 2, characterized by the fact that it comprises CBD in an amount of 1% to 20% by weight of the extract.
    [4]
    Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it comprises CBN in an amount of 1% to 20% by weight of the extract.
    [5]
    Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the terpene fraction comprises one or more of linalool, mircene and nerolidol.
    [6]
    Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the terpene fraction comprises beta-mircene in an amount of 1% to 50% by weight of the terpene fraction.
    [7]
    Pharmaceutical composition according to any one of claims 1 to 6, characterized by the fact that THC is the main cannabinoid.
    [8]
    Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the THC: CBN ratio is 5: 1 to 20: 1.
    [9]
    Pharmaceutical composition according to any one of claims 1 to 8, characterized in that the THC: CBD ratio is 10: 1 to 50: 1.
    [10]
    10. Pharmaceutical composition according to any one of claims 1 to 9, characterized by the fact that the Cannabis extract is a Cannabis oil.
    [11]
    Pharmaceutical composition according to any one of claims 1 to 10, characterized in that the cannabis extract comprises the fraction of terpene in an amount of less than 50% by weight of the extract.
    [12]
    Pharmaceutical composition according to any one of claims 1 to 11, characterized in that the ratio of the cannabinoid fraction: terpene fraction is from about 8: 1 to about 33: 1.
    [13]
    Pharmaceutical composition according to any one of claims 1 to 11, characterized in that it is for treating a sleep disorder.
    [14]
    14. Medicament, characterized in that it comprises an effective amount of the pharmaceutical composition defined in any one of claims 1 to 12.
    [15]
    15. Method for treating a sleep disorder, characterized in that it comprises administering to a patient in need thereof an effective amount of the pharmaceutical composition defined in any one of claims 1 to 12.
    [16]
    16. Use of a Cannabis extract, characterized by the fact that it is for the preparation of a medicine to treat a sleep disorder, in which the Cannabis extract comprises a fraction of cannabinoids comprising Δ9-Tetrahydrocannabinol (THC), Cannabidiol (CBD) and Cannabinol (CBN) and a fraction of terpene in an amount of at least 3% by weight of the extract.
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    同族专利:
    公开号 | 公开日
    CL2019003635A1|2020-06-19|
    MX2019015315A|2020-02-17|
    EP3641754A4|2021-03-10|
    AU2018286647A1|2020-01-16|
    SG11201912380XA|2020-01-30|
    CA3065563A1|2018-12-27|
    JP2020524151A|2020-08-13|
    CO2019013887A2|2020-04-01|
    AU2018100837A4|2018-07-26|
    KR20200104278A|2020-09-03|
    EP3641754A1|2020-04-29|
    IL271503D0|2020-02-27|
    AU2018100837B4|2019-02-21|
    WO2018232448A1|2018-12-27|
    CN110944632A|2020-03-31|
    PE20201163A1|2020-10-28|
    US20210145910A1|2021-05-20|
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    法律状态:
    2021-07-20| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI N? 10196/2001, QUE MODIFICOU A LEI N? 9279/96, A CONCESS?O DA PATENTE EST? CONDICIONADA ? ANU?NCIA PR?VIA DA ANVISA. CONSIDERANDO A APROVA??O DOS TERMOS DO PARECER N? 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL N? 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVID?NCIAS CAB?VEIS. |
    2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |
    2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    AU2017902338|2017-06-19|
    AU2017902338A|AU2017902338A0|2017-06-19|Sleep Disorder Composition and Treatment Thereof|
    AU2017904818A|AU2017904818A0|2017-11-29|Sleep Disorder Compositions and Treatments Thereof|
    AU2017904818|2017-11-29|
    PCT/AU2018/050604|WO2018232448A1|2017-06-19|2018-06-19|Sleep disorder compositions and treatments thereof|
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