WO2023023723A1 - Composition comprenant du tétrahydrocannabinol et du cannabidiol et ses utilisations - Google Patents

Composition comprenant du tétrahydrocannabinol et du cannabidiol et ses utilisations Download PDF

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WO2023023723A1
WO2023023723A1 PCT/AU2022/050950 AU2022050950W WO2023023723A1 WO 2023023723 A1 WO2023023723 A1 WO 2023023723A1 AU 2022050950 W AU2022050950 W AU 2022050950W WO 2023023723 A1 WO2023023723 A1 WO 2023023723A1
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thc
pharmaceutical composition
pharmaceutically acceptable
acceptable salt
cbd
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PCT/AU2022/050950
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English (en)
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Joel Ernest George HARDY
Simon Kenneth PETTINGER
John Montgomery
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Cymra Life Sciences Limited
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Priority claimed from AU2021902679A external-priority patent/AU2021902679A0/en
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Publication of WO2023023723A1 publication Critical patent/WO2023023723A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure relates generally to a pharmaceutical composition
  • a pharmaceutical composition comprising cannabidiol (CBD) and A 9 -tetrahydrocannabinol (THC) at a ratio of about 1:2.5 (THC : CBD).
  • CBD cannabidiol
  • compositions comprising THC and other cannabinoids will typically take into consideration the chemical characteristics, stability and degradation products of the cannabinoids, to ensure that therapeutically effective levels of the cannabinoids are administered to the patient, while also minimizing any adverse effects associated with psychotropic cannabinoids.
  • Cannabinoids are extremely hydrophobic and have poor solubility in aqueous solutions, and are, therefore, typically solubilized using oils or other solvents to prepare cannabinoid compositions.
  • a number of studies have highlighted discrepancies between the declared labelled concentrations and the actual content of cannabinoids such compositions (Bonn-Miller etal., 2017, JAMA, 318(17): 1708- 1709).
  • THC and CBD can be converted to A 9 -THC, as well as A 7 -THC, A 8 -THC, A 10 -THC, A 11 - THC and Ao-THC (Kiselak et al. 2020, Forensic Science International, 388: 110173) under storage conditions.
  • CBD and THC may be degraded to cannabinol (CBN), which has been shown to elicit mild psychotropic effects (Kbguel et al., 2018, Adications, 30(2): 140-151).
  • cannabinoid compositions which improve the stability of THC over time, including to control therapeutically effective levels of cannabinoids administered to the patient, and reduce adverse side effects that may otherwise be associated with increased levels of psychotropic cannabinoids.
  • a pharmaceutical composition comprising A 9 -tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt or functional derivative thereof and cannabidiol (CBD) or a pharmaceutically acceptable salt or functional derivative thereof at a ratio of about 1:2.5 (THC : CBD).
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • a method for the treatment of pain comprising administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof.
  • a pharmaceutical composition comprising THC or a pharmaceutically acceptable salt or functional derivative thereof and CBD or a pharmaceutically acceptable salt or functional derivative thereof at a ratio of about 1:2.5 (THC : CBD) in the manufacture of medicament for the treatment of pain.
  • phrases “consisting of” means including, and limited to, whatever follows the phrase “consisting of”. Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other elements may be present.
  • the phrase “consisting essentially of” means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of” indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.
  • a pharmaceutical composition comprising A 9 -tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt or functional derivative thereof and cannabidiol (CBD) or a pharmaceutically acceptable salt or functional derivative thereof at a ratio of about 1:2.5 (THC : CBD).
  • CBD Cannabidiol
  • CBD cannabinoid produced by plants of the genus Cannabis.
  • CBD has antagonist activity on agonists of the CB 1 and CB2 receptors and acts as an inverse agonist of the CB1 and CB2 receptors.
  • CBD is synthesized in cannabis plants as cannabidiolic acid (CBDA), which decarboxylates to CBD (Table 1). While some decarboxylation may occur in the plant, decarboxylation typically occurs post-harvest and is increased by exposing plant material to heat (Sanchez and Verpoote, 2008, Plant Cell Physiology, 49(12): 1767-82). Decarboxylation is usually achieved by drying and/or heating the plant material. Persons skilled in the art would be familiar with methods by which decarboxylation of CBDA can be promoted, illustrative examples of which include air-drying, combustion, vaporization, curing, heating and baking. The decarboxylated CBD will typically bind to and/or stimulate, directly or indirectly, cannabinoid receptors including CB1 and/or CB2.
  • CBDA cannabidiolic acid
  • Total CBD refers to the total amount of CBD and CBDA in the pharmaceutical composition.
  • CBD may be extracted from any suitable plant parts including leaves, flowers or stems and may be produced by any suitable means known to those skilled in the art.
  • CBD extracts may be produced by extraction with supercritical or subcritical CO2, or by volatilization of plant material with a heated gas.
  • Illustrative examples of methods used to extract CBD and other cannabinoids from plant material include the methods described in US Patent No. 10189762 and WO 2004/016277. Such extracts are also referred to herein as plant-derived CBD.
  • the CBD is plant-derived CBD.
  • the CBD is synthetic CBD.
  • Synthesized CBD is particularly useful for pharmaceutical development as it is largely free from contaminants.
  • a number of methods for the synthesis of CBD are known in the art, illustrative examples of which include methods for the synthesis of CBD as described in US Patent No. 10,059,682.
  • CBD is a chiral compound, although only the (-) CBD enantiomer is present in cannabis plants.
  • enantiomer refers to asymmetric molecules that can exist in two different isomeric forms, which have different configurations in space.
  • An enantiomer can rotate plane -polarized light and is, therefore, optically active.
  • Two different enantiomers of the same compound will rotate plane-polarized light in the opposite direction, thus the light can be rotated to the left or counterclockwise for a hypothetical observer (i.e., or it can be rotated to the right or clockwise (i.e., “dextrorotatory” or “+”).
  • the synthesized CBD is a racemic mixture, comprising the (-) CBD enantiomer and the (+) CBD enantiomer.
  • the synthetic CBD consists of the (-) CBD enantiomer.
  • compositions of CBD contemplates the use of pharmaceutically acceptable salts of CBD.
  • Suitable pharmaceutically acceptable salts of CBD would be known to persons skilled in the art, illustrative examples of which include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, which would be known to persons skilled in the art.
  • CBD cannabidiorcol
  • CBD-Ci cannabidiorcol
  • a 9 -tetrahydrocannabinolic acid or “THCA” is synthesized in cannabis plants from the cannabigerolic acid (CBGA) precursor by THCA synthase (Table 2).
  • THCA decarboxylates to the neutral form " A 9 -tetrahydrocannabinol” or “THC”, which is associated with psychoactive effects of cannabis as primarily mediated by its activation of CB1G- protein coupled receptors, which result in a decrease in the concentration of cyclic AMP (cAMP) through the inhibition of adenylate cyclase.
  • THC also exhibits partial agonist activity at the cannabinoid receptors CB1 and CB2.
  • CB1 is mainly associated with the central nervous system, while CB2 is expressed predominantly in the cells of the immune system.
  • THC is also associated with relaxation, fatigue, appetite stimulation, and alteration of the visual, auditory and olfactory senses.
  • THC mediates an anti-cholinesterase action, which may suggest its use for the treatment of Alzheimer's disease and myasthenia gravis (Eubanks et al., 2006, Molecular Pharmaceuticals, 3(6): 773-7).
  • Total A 9 -tetrahydrocannabinol or “total THC” as used herein refers to the total amount of THC and THCA in the composition.
  • THC may be extracted from any suitable plant parts including leaves, flowers or stems and may be produced by any suitable means known to those skilled in the art.
  • THC extracts may be produced by extraction with supercritical or subcritical CO2, or by volatilization of plant material with a heated gas.
  • Illustrative examples of methods used to extract THC and other cannabinoids from plant material include the methods described in US Patent No. 10189762 and WO 2004/016277. Such extracts are also referred to herein as plant-derived THC.
  • the THC is plant-derived THC.
  • the THC is synthetic THC.
  • THC is particularly useful for pharmaceutical development as it can be prepared largely free from contaminants.
  • a number of methods for the synthesis of THC are known in the art, illustrative examples of which include methods for the synthesis of THC (z.e., dronabinol) as described in US Patent Nos. 7323576 and 5227537, and US Patent Application No. 11/840,585.
  • compositions of THC contemplated the use of pharmaceutically acceptable salts of THC.
  • suitable pharmaceutically acceptable salts of THC would be known to persons skilled in the art, illustrative examples of which include salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, which would be known to persons skilled in the art.
  • THC Suitable functional derivatives of THC would be known to persons skilled in the art, illustrative examples of which include THC-TFA and THC-TMS.
  • compositions of the present specification comprise an optimized ratio of THC and CBD (i.e., of about 1:2.5 total THC : total CBD) that surprisingly improves the stability of the THC comprised in pharmaceutical compositions disclosed herein.
  • a ratio of THC and CBD of about 1 :2.5 is intended to encompass a reasonable level of variance, e.g., plus or minus 10%.
  • the ratio of THC and CBD may be 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1.1:2.5, 1.2:2.5: 1.3:2.5, 1.4: 1.5, 1.5:2.5, and so on and so forth.
  • the pharmaceutical composition comprises total THC, wherein the total THC comprises the THC or a pharmaceutically acceptable salt or functional derivative thereof and A 9 -tetrahydrocannabinolic acid (THCA) or a pharmaceutically acceptable salt or functional derivative thereof.
  • THC total THC
  • THCA tetrahydrocannabinolic acid
  • the total THC comprises less than about 1 % (w/w) THCA or a pharmaceutically acceptable salt or functional derivative thereof e.g., less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.09%, less than about 0.08%, less than about 0.06%, less than about 0.05%, less than about 0.04%, less than about 0.03%, less than about 0.02% or less than about 0.01% (w/w) THCA, or a pharmaceutically acceptable salt or functional derivative thereof).
  • the total THC comprises from about 0.1% to about 1% (w/w) THCA, or a pharmaceutically acceptable salt or functional derivative thereof (e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% (w/w) THCA, or a pharmaceutically acceptable salt or functional derivative thereof).
  • a pharmaceutically acceptable salt or functional derivative thereof e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% (w/w) THCA, or a pharmaceutically acceptable salt or functional derivative thereof.
  • the total THC comprises from about 0.1% to about 1% (w/w) THCA, or a pharmaceutically acceptable salt or functional derivative thereof, preferably about 0.1%, preferably about 0.2%, preferably about 0.3%, preferably about 0.4%, preferably about 0.5%, preferably about 0.6%, preferably about 0.7%, preferably about 0.8%, preferably about 0.9%, or more preferably about 1% (w/w) THCA, or a pharmaceutically acceptable salt or functional derivative thereof.
  • the pharmaceutical composition comprises total CBD, wherein the total CBD comprises the CBD or a pharmaceutically acceptable salt or functional derivative thereof and cannabidiolic acid (CBDA) or a pharmaceutically acceptable salt or functional derivative thereof.
  • CBD cannabidiolic acid
  • the total CBD comprises less than about 0.1% (w/w) CBDA or a pharmaceutically acceptable salt or functional derivative thereof (e.g., less than about 0.1%, less than about 0.09%, less than about 0.08%, less than about 0.06%, less than about 0.05%, less than about 0.04%, less than about 0.03%, less than about 0.02% or less than about 0.01% (w/w) CBDA, or a pharmaceutically acceptable salt or functional derivative thereof).
  • a pharmaceutically acceptable salt or functional derivative thereof e.g., less than about 0.1%, less than about 0.09%, less than about 0.08%, less than about 0.06%, less than about 0.05%, less than about 0.04%, less than about 0.03%, less than about 0.02% or less than about 0.01% (w/w) CBDA, or a pharmaceutically acceptable salt or functional derivative thereof.
  • the total CBD comprises from about 0.01% to about 0.1% (w/w) CBDA, or a pharmaceutically acceptable salt or functional derivative thereof (e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1% (w/w) CBDA, or a pharmaceutically acceptable salt or functional derivative thereof).
  • a pharmaceutically acceptable salt or functional derivative thereof e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1% (w/w) CBDA, or a pharmaceutically acceptable salt or functional derivative thereof.
  • the total CBD comprises from about 0.01% to about 0.1% (w/w) CBDA, or a pharmaceutically acceptable salt or functional derivative thereof, preferably about 0.01%, preferably about 0.02%, preferably about 0.03%, preferably about 0.04%, preferably about 0.05%, preferably about 0.06%, preferably about 0.07%, preferably about 0.08%, preferably about 0.09%, or more preferably about 0.1% (w/w) CBDA, or a pharmaceutically acceptable salt or functional derivative thereof.
  • the pharmaceutical composition comprises about 10 mg/mL THC and about 25 mg/mL CBD. In another embodiment, the pharmaceutical composition comprises about 10 mg/mL total THC and about 25 mg/mL total CBD.
  • compositions of the present disclosure comprise an optimized ratio of THC : CBD that unexpectedly improves the stability of THC in pharmaceutical compositions comprising THC and CBD over time after exposure to both ambient and elevated temperature conditions.
  • Ambient conditions refers to storage conditions comprising 25°C ⁇ 2°C, 60% ⁇ 5% relative humidity.
  • Elevated temperature conditions refers to storage conditions comprising 40°C ⁇ 2°C, 75% ⁇ 5% relative humidity.
  • At least about 95% (w/w) of the THC or a pharmaceutically acceptable salt or functional derivative thereof e.g., at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or essentially all of the THC, i.e., 100% (w/w) THC
  • at least three months e.g., three, four, five, six, seven, eight, nine, ten, eleven or twelve months.
  • At least about 95% (w/w) of the THC or a pharmaceutically acceptable salt or functional derivative thereof e.g., at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or essentially all of the THC, i.e., 100% (w/w) THC
  • at least six months e.g., six, seven, eight, nine, ten, eleven or twelve months.
  • At least about 95% (w/w) of the THC or a pharmaceutically acceptable salt or functional derivative thereof e.g., at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or essentially all of the THC, i.e., 100% (w/w) THC
  • at least three months e.g., three, four, five, six, seven, eight, nine, ten, eleven or twelve months.
  • At least about 95% (w/w) of the THC or a pharmaceutically acceptable salt or functional derivative thereof e.g., at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or essentially all of the THC, i.e., 100% (w/w) THC
  • a pharmaceutically acceptable salt or functional derivative thereof e.g., at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or essentially all of the THC, i.e., 100% (w/w) THC
  • the concentration of THC or a pharmaceutically acceptable salt or functional derivative thereof reduces at a rate of from about 0.01% (w/w) to about 2% (w/w) per month (e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% (w/w) per month) under ambient conditions.
  • the concentration of THC or a pharmaceutically acceptable salt or functional derivative thereof reduces at a rate of from about 0.01% (w/w) to about 2% (w/w) per month under ambient conditions, preferably about 0.01%, preferably about 0.02%, preferably about 0.03%, preferably about 0.04%, preferably about 0.05%, preferably about 0.06%, preferably about 0.07%, preferably about 0.08%, preferably about 0.09%, preferably about 0.1%, preferably about 0.2%, preferably about 0.3%, preferably about 0.4%, preferably about 0.5%, preferably about 0.6%, preferably about 0.7%, preferably about 0.8%, preferably about 0.9%, preferably about 1%, preferably about 1.1%, preferably about 1.2%, preferably about 1.3%, preferably about 1.4%, preferably about 1.5%, preferably about 1.6%, preferably about 1.7%, preferably about 1.8%, preferably about 1.9%, or more preferably about 2% (w/w) per month under ambient conditions.
  • the concentration of THC or a pharmaceutically acceptable salt or functional derivative thereof reduces at a rate of from about 0% (w/w) to about 2% (w/w) per month (e.g., about 0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% (w/w) per month) under elevated temperature conditions.
  • the concentration of THC or a pharmaceutically acceptable salt or functional derivative thereof reduces at a rate of from about 0% (w/w) to about 2% (w/w) per month under elevated temperature conditions, preferably about 0%, preferably about 0.01%, preferably about 0.02%, preferably about 0.03%, preferably about 0.04%, preferably about 0.05%, preferably about 0.06%, preferably about 0.07%, preferably about 0.08%, preferably about 0.09%, preferably about 0.1%, preferably about 0.2%, preferably about 0.3%, preferably about 0.4%, preferably about 0.5%, preferably about 0.6%, preferably about 0.7%, preferably about 0.8%, preferably about 0.9%, preferably about 1%, preferably about 1.1%, preferably about 1.2%, preferably about 1.3%, preferably about 1.4%, preferably about 1.5%, preferably about 1.6%, preferably about 1.7%, preferably about 1.8%, preferably about 1.9%, or more preferably about 2% (w/w) per month
  • the THC and CBD are solubilized in an oil.
  • Suitable oils for solubilizing total THC and total CBD would be known to persons skilled in the art, illustrative examples of which include medium chain triglycerides (MCT) oil, coconut oil, olive oil and hemp seed oil.
  • MCT medium chain triglycerides
  • MCT oils are made up of medium-length triglycerides, typically between 6 and 12 carbons long.
  • the MCT oil is selected from the group consisting of C6 MCT oil (z.e., caproic acid, comprising six carbon atoms), C8 MCT oil i.e., caprylic acid, comprising 8 carbon atoms), CIO MCT oil ⁇ i.e., capric acid, comprising 10 carbon atoms) and C12 MCT oil (lauric acid, comprising 12 carbon atoms), or combinations of the foregoing.
  • the oil is coconut oil.
  • Coconut oil comprises a mixture of MCTs, including C12, CIO and C8.
  • Cannabis plants produce a broad range of cannabinoids, terpenes and/or flavonoids, which may be associated with the entourage effect, where different cannabinoids, terpenes and/or flavonoids produced by cannabis plants act in combination to exert different biological/therapeutic effects.
  • the pharmaceutical composition further comprises one or more, or all of the cannabinoids selected from the group consisting of cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), A8-tetrahydrocannabinol (A8-THC), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabigerolic acid (CBGA) and cannabicyclol (CBL).
  • CBD cannabigerol
  • CBN cannabinol
  • CBC cannabichromene
  • A8-tetrahydrocannabinol A8-THC
  • THCV tetrahydrocannabivarin
  • CBDV cannabidivarin
  • CBGA cannabigerolic acid
  • CBL cannabicyclol
  • terpene refers to a class of organic hydrocarbon compounds, which are produced by a variety of plants. Cannabis plants produce and accumulate different terpenes, such as monoterpenes and sesquiterpenes, in the glandular trichomes of the female inflorescence.
  • terpene includes “terpenoids” or “isoprenoids”, which are modified terpenes that contain additional functional groups.
  • Monoterpenes consist of two isoprene units and may be liner or contain ring structures. The primary function of monoterpenes is to protect plants from infection by fungal and bacterial pathogens and insect pests.
  • the pharmaceutical composition further comprises one or more, or all of the monoterpenes selected from the group consisting of -pinene, myrcene, -phellandrene, cA-ocimene, terpinolene and terpineol.
  • Sesquiterpenes differ from other common terpenes as they contain one additional isoprene unit, which creates a 15 carbon structure.
  • the primary function of sesquiterpenes is as a pheromone for the bud and flower.
  • the pharmaceutical composition further comprises one or more, or all or the sesquiterpenes selected from the group consisting of -caryophyllene, bisabolol, humulene, 5-guaiene, y- cadinene, eudesma-3,7(l l)-dene and elemene.
  • the pharmaceutical composition may be administered in dosage unit and in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Formulations include transdermal, aerosol, nasal spray, sublingual spray, liposomal, nanoparticle, microparticle, polymer-based, dispersion, suspension, powder, microspheres, carrier-mediated, and encapsulation.
  • compositions disclosed herein may be prepared according to conventional methods well known in the pharmaceutical and nutraceutical industries, such as those described in Remington’s Pharmaceutical Handbook (Mack Publishing Co., NY, USA).
  • the pharmaceutical composition is formulated for oral administration.
  • compositions suitable for oral administration would be known to persons skilled in the art, illustrative examples of which include liquid, oil, tablets and capsules.
  • oral administration as used herein broadly encompasses formulations for sublingual and buccal administration.
  • compositions for oral administration may contain one or more additional agents selected from the group of sweetening agents, flavoring agents, coloring agents, fragrance agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavoring agents include peppermint oil, oil of Wintergreen, cherry, orange or raspberry flavoring.
  • Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • compositions suitable for oral administration may be presented as discrete units (i.e., dosage forms), each containing a predetermined amount of each component of the composition as a powder, tablet, capsule, granules, as a solution or a suspension in an aqueous liquid or non-aqueous liquid, or as an emulsion.
  • Oral administration has been demonstrated to be an effective administration route for both CBD and THC (reviewed by Millar et al., 2018, Frontiers in Pharmacology, 9: 1365 and Poyatos et al., 2020, Medicina (Kaunas), 56(6): 309).
  • the pharmaceutical composition is a full spectrum composition.
  • full-spectrum it is meant that the pharmaceutical composition comprises THC, CBD and other cannabinoids, terpenes, flavonoids, plant lipids, etc., for example, as derived from cannabis plant material.
  • plant material is to be understood to mean any part of the cannabis plant, including the leaves, stems, roots, and inflorescence, or parts thereof, as described elsewhere herein, as well as extracts, illustrative examples of which include keif or hash, which includes trichomes and glands.
  • the plant material is female inflorescence.
  • inflorescence means the complete flower head produced by the cannabis plant, comprising stems, stalks, bracts, flowers and trichomes (i.e., glandular, sessile and stalked trichomes).
  • the term "cannabis plant” means a plant of the genus Cannabis, illustrative examples of which include Cannabis sativa, Cannabis indica and Cannabis ruderalis.
  • Cannabis is an erect annual herb with a dioecious breeding system, although monoecious plants exist. Wild and cultivated forms of cannabis are morphologically variable, which has resulted in difficulty defining the taxonomic organization of the genus.
  • the cannabis plant is C. sativa.
  • plant The terms "plant”, “cultivar”, “variety”, “strain” or “race” are used interchangeably herein to refer to a plant or a group of similar plants according to their structural features and performance (i.e., morphological and physiological characteristics).
  • extract is to be understood as including a whole cannabis extract, such as resin, hash and keif, as well as substantially purified compounds isolated from the harvested plant material, such as cannabinoids, terpenes, flavonoids and/or plant lipids.
  • substantially purified refers to a compound or molecule that has been isolated from other components with which it is typically associated in its native state (i.e., within the plant material).
  • the substantially purified molecule is at least 60% free, more preferably at least 75% free, and more preferably at least 90% free from other components with which it is naturally associated.
  • isolated is meant material that is substantially or essentially free from components that normally accompany it in its native state.
  • SFE supercritical fluid extraction
  • the pharmaceutical composition is for use in the treatment of pain.
  • pain refers to an unpleasant sensory and emotional experience associated with, or resembling that associated with actual or potential tissue damage.
  • pain - nociceptive pain There are three clinically recognized types of pain - nociceptive pain, neuropathic pain and nociplastic pain (Merskey and Bogduk, 1994, Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy).
  • Nociceptive pain is the result of stimulation of the sensory nerve fibers, as detected by nociceptors around the body that respond to mechanical or physical damage. Nociceptive pain serves a protective function by warning of tissue damage, to cause withdrawal from the noxious stimulus, such as thermal damage (e.g., burns or frostbite) or mechanical trauma (e.g., laceration or pressure).
  • Neuroopathic pain is caused by a primary lesion, malfunction or dysfunction in the peripheral or central nervous system. Neuropathic pain has no protective effect and can develop days or months after an injury or after resolution of a disease state, and is frequently long lasting and chronic.
  • Nociplastic pain is caused by altered nociception with no corresponding or clear evidence or actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.
  • the pain is nociceptive pain.
  • the pain is neuropathic pain.
  • the pain is nociplastic pain.
  • Acute pain usually lasts for short periods (e.g., a few hours or days), and will typically disappear upon cessation of the underlying stimulus.
  • “Chronic pain” lasts for longer periods (e.g., weeks or months), and can persist even in the absence of an underlying stimulus.
  • the pharmaceutical composition is for use in the treatment of acute pain.
  • the acute pain is acute nociceptive pain.
  • the acute pain is acute neuropathic pain.
  • the acute pain is acute nociplastic pain.
  • the pharmaceutical composition is for use in the treatment of chronic pain.
  • the chronic pain is chronic nociceptive pain.
  • the chronic pain is chronic neuropathic pain.
  • the chronic pain is chronic nociplastic pain.
  • the pharmaceutical composition is for use in the treatment of chronic back pain.
  • the composition is for use in the treatment of chronic neck pain.
  • the composition is for use in the treatment of chronic back and neck pain.
  • treat refers to any and all methods that remedy, prevent, hinder, retard, ameliorate, reduce, delay or reverse or otherwise inhibit the severity of the condition (e.g., pain) or of one or more symptoms thereof in a subject.
  • Treatment does not necessarily imply that a patient is treated until total recovery. Pain is characterized by multiple symptoms/comorbidities (e.g., sleep quality, anxiety, quality of life), and thus the treatment need not necessarily remedy, prevent, hinder, retard, ameliorate, reduce, delay or reverse all of said symptoms/comorbidities.
  • Methods of the present disclosure may involve “treating” pain in terms of reducing, preventing or ameliorating the occurrence of a highly undesirable event or symptom associated with pain or an outcome of the progression or increase in the perception of pain, but may not of itself prevent the initial occurrence of the event, symptom, comorbidity or outcome. Accordingly, treatment includes amelioration of the symptoms of pain or preventing or otherwise reducing the risk of developing symptoms/comorbidities of pain.
  • subject refers to any mammal, including livestock and other farm animals (such as cattle, goats, sheep, horses, pigs and chickens), performance animals (such as racehorses), companion animals (such as cats and dogs), laboratory test animals and humans.
  • livestock and other farm animals such as cattle, goats, sheep, horses, pigs and chickens
  • performance animals such as racehorses
  • companion animals such as cats and dogs
  • laboratory test animals such as cats and dogs
  • compositions comprising THC and CBD at a ratio of 1:2.5 (THC : CBD) will suitably be administered to the subject in need thereof in a therapeutically effective amount.
  • therapeutically effective amount typically refers to an amount of THC and CBD that is sufficient to affect one or more beneficial or desired therapeutic outcomes (e.g., reduction or amelioration of the symptoms of pain).
  • beneficial or desired therapeutic outcomes may be subjectively measured using clinical instruments known in the art, illustrative examples of which include the Numerical Rating Scale (NRS) of Pain Intensity (2000, Spine, 25: 3200-3202), Brief Pain Inventory - Short Form (Cleeland, 1991).
  • NRS Numerical Rating Scale
  • the reduction or amelioration of the symptoms/comorbidities of pain may also be assessed using secondary indicators of beneficial or desired therapeutic outcomes (i.e., secondary indicia), e.g., improvements to physical functioning, sleep quality, emotional function, and quality of life.
  • secondary indicators of beneficial or desired therapeutic outcomes may be subjectively measured using clinical instruments known in the art, illustrative examples of which include the Depression Anxiety Stress Scale (Lovibond and Lovibond, 1995, Manual for the Depression Anxiety Stress Scales, 2 nd edition, Sydney: Psychology Foundation), Medical Outcomes of Sleep Survey (Shahid et al., in Shahid et al.
  • An effective amount can be provided in one or more administrations. The exact amount required may vary depending on factors such as the nature and severity of the pain to be treated, the age and general health of the subject.
  • a pharmaceutical composition comprising THC or a pharmaceutically acceptable salt or functional derivative thereof and CBD or a pharmaceutically acceptable salt or functional derivative thereof at a ratio of about 1:2.5 (THC : CBD) in the manufacture of medicament for the treatment of pain.
  • test compositions were stored in an upright bottle position under (1) ambient conditions at 25°C ⁇ 2°C, 60% ⁇ 5% relative humidity; or (2) under elevated temperature conditions at 40°C ⁇ 2°C, 75% ⁇ 5% relative humidity.
  • THC in Test Composition A Given the surprisingly improved stability of THC in Test Composition A, it was selected for further analysis. Appearance, UPLC identification, density and THC/THCA and CBD/CBDA concentration analyses were conducted. Microbial analyses were also performed (i.e., total aerobic microbial count (TAMC), total combined yeast and mould count (TYMC), bile-tolerant gram-negative bacteria, Salmonella, Escherichia coli, and Staphylococcus aureus). The results after 3 months and 6 months of storage are presented in Table 6.
  • TAMC total aerobic microbial count
  • TYMC total combined yeast and mould count
  • bile-tolerant gram-negative bacteria Salmonella, Escherichia coli, and Staphylococcus aureus
  • Test Composition A in comparison to Test Compositions B-D was maintained in the extended storage period through to 6 months.
  • the rate of degradation of THC remained relatively constant, with a reduction of -1.4% in THC observed from the 3 month time point to the 6 month time point.
  • the concentration of CBD also remained relatively stable in Test Composition A from the 3 month time point to the 6 month time point.
  • Test Composition A The improved stability observed for Test Composition A was maintained in the extended storage period through to 18 months. Consistent with the data collected from the 3 month time point and the 6 month time point, the concentration of CBD remained very stable in Test Composition A at both ambient conditions and under elevated temperature conditions. The rate of degradation of THC also remained stable in Test Composition A under ambient conditions.
  • compositions comprising THC and CBD at a ratio of about 1:2.5 (THC : CBD) with unexpectedly improved stability.

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Abstract

La présente invention concerne de manière générale une composition pharmaceutique comprenant du Δ9-tétrahydrocannabinol (THC) ou un sel pharmaceutiquement acceptable ou un dérivé fonctionnel de celui-ci et du cannabidiol (CBD) ou un sel pharmaceutiquement acceptable ou un dérivé fonctionnel de celui-ci avec un rapport d'environ 1:2,5 (THC : CBD).
PCT/AU2022/050950 2021-08-24 2022-08-23 Composition comprenant du tétrahydrocannabinol et du cannabidiol et ses utilisations WO2023023723A1 (fr)

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Citations (5)

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WO2017091764A1 (fr) * 2015-11-24 2017-06-01 Constance Therapeutics, Inc. Compositions d'huile de cannabis et leurs procédés de préparation
WO2019051560A1 (fr) * 2017-09-15 2019-03-21 Zelda Therapeutics Operations Pty Ltd Composition et méthode de traitement de l'autisme
US20190110981A1 (en) * 2017-10-17 2019-04-18 Life Tech Global, Llc Cannabinoid Patch
WO2020093102A1 (fr) * 2018-11-09 2020-05-14 Agriculture Victoria Services Pty Ltd Plants de cannabis ayant un profil cannabïnoide enrichi pour le cannabidiol et le δ-9-t2trahydrocannabinol
WO2020232530A1 (fr) * 2019-05-22 2020-11-26 Canopy Growth Corporation Compositions comprenant des cannabinoïdes pour la gestion de la douleur

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WO2017091764A1 (fr) * 2015-11-24 2017-06-01 Constance Therapeutics, Inc. Compositions d'huile de cannabis et leurs procédés de préparation
WO2019051560A1 (fr) * 2017-09-15 2019-03-21 Zelda Therapeutics Operations Pty Ltd Composition et méthode de traitement de l'autisme
US20190110981A1 (en) * 2017-10-17 2019-04-18 Life Tech Global, Llc Cannabinoid Patch
WO2020093102A1 (fr) * 2018-11-09 2020-05-14 Agriculture Victoria Services Pty Ltd Plants de cannabis ayant un profil cannabïnoide enrichi pour le cannabidiol et le δ-9-t2trahydrocannabinol
WO2020232530A1 (fr) * 2019-05-22 2020-11-26 Canopy Growth Corporation Compositions comprenant des cannabinoïdes pour la gestion de la douleur

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