A COMPOSITION COMPRISING TETRAHYDROCANNABINOL AND CANNABIDIOL AND USES THEREOF

RELATED APPLICATIONS

[0001] This application claims priority from Australian Provisional Patent Application No. 2021902679 filed on 24 August 2021, the entire content of which is hereby incorporated by reference.

FIELD

[0002] The present disclosure relates generally to a pharmaceutical composition comprising cannabidiol (CBD) and A ⁹ -tetrahydrocannabinol (THC) at a ratio of about 1:2.5 (THC : CBD).

BACKGROUND

[0003] Cannabidiol (CBD) is the most common cannabinoid used in medicinal cannabis preparations. Several studies suggest that CBD can be effective for the treatment of epilepsy and other neuropsychiatric disorders, e.g., anxiety and schizophrenia (Rong et al., 2017, Pharmacology Research, 121: 213-218). Many patient groups have also reported a preference for CBD medicinal cannabis products, due to the characterization of CBD as a therapeutic, non-psychotropic cannabinoid, as compared with THC, which is more typically characterized as a psychotropic cannabinoid. However, studies have demonstrated that the adjunctive consumption of THC with CBD increases symptomatic relief in patients with anxiety, back pain and depression (Stith et al., 2019, Scientific Reports, 9: 2712).

[0004] The formulation of 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. However, 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). Labelling discrepancies may be exacerbated in the context of compositions comprising THC and CBD, as the degradation of THC and CBD may result in unintended increases in the level of psychotropic cannabinoids over time. For example, it has been shown that 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. Further, both CBD and THC may be degraded to cannabinol (CBN), which has been shown to elicit mild psychotropic effects (Kbguel et al., 2018, Adicciones, 30(2): 140-151).

[0005] Therefore, there remains an urgent need for the development of 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.

SUMMARY

[0006] In an aspect of the present disclosure, there is provided 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).

[0007] In another aspect of the present disclosure, there is provided a method for the treatment of pain comprising administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof.

[0008] In another aspect of the present disclosure, there is provided a use of 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. DETAILED DESCRIPTION

[0009] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Any materials and method similar or equivalent to those described herein can be used to practice the present invention.

[0010] Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of the stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0011] The phrase "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.

[0012] As used herein the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound, as well as two or more compounds; reference to "an agent" includes one agent, as well as two or more agents; and so forth.

[0013] The term “about” will be understood by persons skilled in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to persons skilled in the art, given the context which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0014] The present disclosure is predicated, at least in part, on the inventors' surprising finding that optimization of the ratio of THC and CBD (THC : CBD) in a pharmaceutical composition can improve the stability of THC over time. [0015] Accordingly, in an aspect disclosed herein, there is provided 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).

Cannabidiol (CBD)

[0016] "Cannabidiol" or "CBD" is a 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.

[0017] 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.

[0018] "Total CBD" as used herein refers to the total amount of CBD and CBDA in the pharmaceutical composition.

[0019] 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. For example, 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.

[0020] In an embodiment, the CBD is plant-derived CBD.

[0021] In another embodiment, the CBD is synthetic CBD. [0022] 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.

[0023] CBD is a chiral compound, although only the (-) CBD enantiomer is present in cannabis plants.

[0024] The term “enantiomer” as used herein 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 “+”).

[0025] In an embodiment, the synthesized CBD is a racemic mixture, comprising the (-) CBD enantiomer and the (+) CBD enantiomer.

[0026] In an embodiment, the synthetic CBD consists of the (-) CBD enantiomer.

[0027] The present disclosure 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.

[0028] The present disclosure further contemplates the use of functional derivatives of CBD. Suitable functional derivatives of CBD would be known to persons skilled in the art, illustrative examples of which include 7-OH-CBD (7-hydrocannabidiol), methoxylated CBD derivatives (e.g., CBDM, or 2-methoxycannabidiol and CBDD, or 2,6- dimethoxycannabidiol), cannabidiorcol (CBD-Ci) and the CBD derivatives described by Morales et al. (2017, Frontiers in Pharmacology, 8: 422). A-9-Tetrahydrocannabinol (THC)

[0029] "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. As a result, THC is also associated with relaxation, fatigue, appetite stimulation, and alteration of the visual, auditory and olfactory senses. Furthermore, more recent studies have indicated that 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).

[0030] "Total A ⁹ -tetrahydrocannabinol " or "total THC" as used herein refers to the total amount of THC and THCA in the composition.

[0031] 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. For example, 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.

[0032] In an embodiment, the THC is plant-derived THC.

[0033] In another embodiment, the THC is synthetic THC.

[0034] Synthesized 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.

[0035] The present disclosure contemplates 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.

[0036] The present disclosure further contemplates the use of functional derivatives of 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

[0037] The 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.

[0038] In accordance with certain embodiments, 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%. In certain embodiments, 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.

[0039] In an embodiment, 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.

[0040] In an embodiment, 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).

[0041] In another embodiment, 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).

[0042] Thus, in an embodiment 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.

[0043] In an embodiment, 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.

[0044] In an embodiment, 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).

[0045] In an embodiment, 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). [0046] Thus, in an embodiment 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.

[0047] In an embodiment, 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.

[0048] As described elsewhere herein, the pharmaceutical 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.

[0049] "Ambient conditions" as used herein refers to storage conditions comprising 25°C ± 2°C, 60% ± 5% relative humidity.

[0050] Elevated temperature conditions" as used herein refers to storage conditions comprising 40°C ± 2°C, 75% ± 5% relative humidity.

[0051] In an embodiment, 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) is maintained in the pharmaceutical composition after exposure to ambient conditions for at least three months (e.g., three, four, five, six, seven, eight, nine, ten, eleven or twelve months).

[0052] In an embodiment, 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) is maintained in the pharmaceutical composition after exposure to ambient conditions for at least six months (e.g., six, seven, eight, nine, ten, eleven or twelve months). [0053] In an embodiment, 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) is maintained in the pharmaceutical composition after exposure to elevated temperature conditions for at least three months (e.g., three, four, five, six, seven, eight, nine, ten, eleven or twelve months).

[0054] In an embodiment, 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) is maintained in the pharmaceutical composition after exposure to elevated temperature conditions for at least six months e.g., six, seven, eight, nine, ten, eleven or twelve months).

[0055] In an embodiment, 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.

[0056] Thus, in an embodiment, 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. [0057] In an embodiment, 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.

[0058] Thus, in an embodiment, 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 under elevated temperature conditions.

[0059] In an embodiment, the THC and CBD are solubilized in an oil.

[0060] 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.

[0061] MCT oils are made up of medium-length triglycerides, typically between 6 and 12 carbons long. In an embodiment, 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. [0062] In an embodiment, the oil is coconut oil.

[0063] Coconut oil comprises a mixture of MCTs, including C12, CIO and C8.

[0064] 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.

[0065] Accordingly, in an embodiment, 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).

[0066] The term “terpene” as used herein, 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. The term “terpene” includes “terpenoids” or “isoprenoids”, which are modified terpenes that contain additional functional groups.

[0067] 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. In an embodiment, 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.

[0068] 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. In an embodiment, 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. [0069] 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.

[0070] Pharmaceutical 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).

[0071] In an embodiment, the pharmaceutical composition is formulated for oral administration.

[0072] Pharmaceutical compositions suitable for oral administration would be known to persons skilled in the art, illustrative examples of which include liquid, oil, tablets and capsules. The term “oral administration” as used herein broadly encompasses formulations for sublingual and buccal administration.

[0073] Pharmaceutical 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.

[0074] Pharmaceutical 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. [0075] 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).

[0076] In an embodiment, the pharmaceutical composition is a full spectrum composition.

[0077] By "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.

[0078] As used herein, the term "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. In an embodiment, the plant material is female inflorescence.

[0079] The term “inflorescence” as used herein means the complete flower head produced by the cannabis plant, comprising stems, stalks, bracts, flowers and trichomes (i.e., glandular, sessile and stalked trichomes).

[0080] As used herein, 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. In an embodiment, the cannabis plant is C. sativa.

[0081] 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).

[0082] The term "extract", as used herein, 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.

[0083] As used herein, "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). Preferably, 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. By "isolated" is meant material that is substantially or essentially free from components that normally accompany it in its native state.

[0084] Methods of extracting cannabinoids from plant material would be known to persons skilled in the art, illustrative examples of which include supercritical fluid extraction (SFE). The principles of SFE relate to the disappearance of the gas-liquid boundary when the temperature of certain materials was increased by heating them in a closed glass container. This allows the material to reach its critical point, which is the temperature above which a substance or compound can co-exist in the gas, liquid and solid phases. By taking substances to their critical point and at pressure, SFE can be used as sophisticated solvents for extraction and fractionation of complex mixtures. SFE is commonly used in the processing of oil and has also been applied to the purification and separation of vegetable and fish oils. More recently SFE has been used to extract cannabinoids from plant material, for example, method for the extraction of pharmaceutically active cannabinoids from plant material is provided in WO/2004/016277.

Pain

[0085] In an embodiment, the pharmaceutical composition is for use in the treatment of pain.

[0086] The term “pain” as used herein refers to an unpleasant sensory and emotional experience associated with, or resembling that associated with actual or potential tissue damage. 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). [0087] “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).

[0088] “Neuropathic 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.

[0089] “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.

[0090] In an embodiment, the pain is nociceptive pain.

[0091] In an embodiment, the pain is neuropathic pain.

[0092] In an embodiment, the pain is nociplastic pain.

[0093] “Acute pain” usually lasts for short periods (e.g., a few hours or days), and will typically disappear upon cessation of the underlying stimulus.

[0094] “Chronic pain” lasts for longer periods (e.g., weeks or months), and can persist even in the absence of an underlying stimulus.

[0095] In an embodiment, the pharmaceutical composition is for use in the treatment of acute pain. In an embodiment, the acute pain is acute nociceptive pain. In an embodiment, the acute pain is acute neuropathic pain. In an embodiment, the acute pain is acute nociplastic pain.

[0096] In an embodiment, the pharmaceutical composition is for use in the treatment of chronic pain. In an embodiment, the chronic pain is chronic nociceptive pain. In an embodiment, the chronic pain is chronic neuropathic pain. In an embodiment, the chronic pain is chronic nociplastic pain. [0097] In an embodiment, the pharmaceutical composition is for use in the treatment of chronic back pain. In an embodiment, the composition is for use in the treatment of chronic neck pain. In an embodiment, the composition is for use in the treatment of chronic back and neck pain.

Methods of treatment

[0098] In an aspect disclosed herein there is provided a method for the treatment of pain comprising administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof.

[0099] The terms “treat”, "treating", “treatment”, and the like refer 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.

[0100] The term “subject” as used herein 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. In an embodiment, the subject is a human.

[0101] Pharmaceutical 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. As used herein, the term “therapeutically effective amount” or “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). Said 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). 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. Said 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. (eds), 2012 STOP, THAT and One Hundred Other Sleep Scales, Springer, New York, pp 219-222), Pittsburgh Sleep Quality Index (Buysse et al., 1989, Psychiatry Research, 28(2): 193-213), Roland Morris Disability Questionnaire (Roland and Morris, 1983, Spine, 8: 141-144), Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983, Acta Psychiatrica Scandinavia, 67(6): 361-70), EuroQol 5D (EuroQol Research Foundation, 2019, EQ-5D-5L User Guide), Short Form Medical Outcomes 12 (Ware et al., 1996, Med Care, 34: 220-233), and Patient Global Impression of Change (Hurst and Bolton, 2004, Journal of Manipulative & Physiological Therapeutics, 27: 26-35).

[0102] 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.

[0103] In another aspect disclosed herein, there is provided a use of 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.

[0104] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

[0105] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0106] All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entireties.

[0107] The various embodiments enabled herein are further described by the following non-limiting examples.

EXAMPLES

Materials

[0108] Full spectrum cannabinoid compositions for stability testing were prepared as shown in Table 3.

Stability testing

[0109] The 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.

[0110] The comparative analysis of the THC concentration in the test compositions under ambient and accelerated conditions after three months are presented in Tables 4 and 5.

[0111] 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.

[0112] The improved stability observed for 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. Beneficially, the concentration of CBD also remained relatively stable in Test Composition A from the 3 month time point to the 6 month time point.

[0113] 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.

[0114] These data demonstrate that optimization of the ratio of THC : CBD unexpectedly improves the stability of THC in pharmaceutical compositions comprising THC and CBD. Further, given that extracted THCA is unstable and will typically decarboxylate to THC even at low temperature, low concentrations of THCA in cannabinoid compositions (i.e., <1% (w/w) of the total THC) beneficially reduce or eliminate any increase in the concentration of THC in the compositions over time.

[0115] Accordingly, these data are enabling for compositions comprising THC and CBD at a ratio of about 1:2.5 (THC : CBD) with unexpectedly improved stability.

Table 1. Cannabidiol and related cannabinoids

Table 2. Tetrahydrocannabinol and related cannabinoids

Table 3. Cannabinoid compositions for stability testing Table 4. Comparative analysis of total THC in test compositions under ambient conditions

Table 5. Comparative analysis of total THC in test compositions under accelerated conditions Table 6. Three and six month stability analysis of Test Composition A

Table 7. Nine and twelve month stability analysis of Test Composition A

Table 8. Eighteen month stability analysis of Test Composition A