Cannabinoid formulations providing rapid onset of pharmaceutical and recreational effects

Abstract

Disclosed herein is a formulation comprising a cannabinoid component comprising a cannabinoid; a tocopheryl phosphate component comprising mono-(tocopheryl) phosphate and di-(tocopheryl) phosphate; an oil component comprising an oil that may dissolve or be miscible with the cannabinoid and tocopheryl phosphate components. The tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio enabling rapid absorption of the cannabinoid component.

Description

[0001] CANNABINOID FORMULATIONS PROVIDING RAPID ONSET OF PHARMACEUTICAL AND RECREATIONAL EFFECTS

[0002] Field of the invention

[0003] The invention relates to sublingual and buccal cannabinoid formulations, to methods of manufacture of sublingual and buccal cannabinoid formulations, and to uses thereof.

[0004] Background of the invention

[0005] Oral cannabinoid administration is presently being investigated across a wide range of indications, and there is evidence for a variety of treatment outcomes in indications including chronic pain, chemotherapy induced nausea and vomiting, spasticity symptoms associated with MS, Tourette syndrome symptoms, symptoms associated with dementia, brain injury & intracranial haemorrhage outcomes, anxiety symptoms, short term sleep outcomes in some individuals, post -traumatic stress disorder symptoms and potentially epilepsy (National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington (DC): National Academies Press (US); 2017 Jan 12. 4, Therapeutic Effects of Cannabis and Cannabinoids).

[0006] Oral cannabinoid formulations are also widely used recreationally to establish euphoria, feelings of well -being, spontaneous laughter and excitement, increased appetite and / or quiet or reflective mood in the consumer.

[0007] One limitation of oral cannabinoid formulations is that the pharmaceutical or recreational effects, including the user’s perception of strength and duration of these effects, may not be provided in the end user until about 1 to 2 hours after oral administration. This delay may increase the risk of cannabinoid overdose, particularly where the delay in obtaining the desired pharmaceutical or recreational effect induces the end user to consume a further oral cannabinoid formulation before the pharmaceutical or recreation effects established by an earlier consumed cannabinoid formulation are realised. Further, higher strength and / or longer duration of effect formulations are desirable to enable dose reduction and minimise exposure to a cannabinoid.

[0008] There is need for cannabinoid formulations that may provide for rapid onset of pharmaceutical or recreational effects of cannabinoids.

[0009] There is also a need for cannabinoid formulations that may provide for an improved strength of pharmaceutical or recreational effects of cannabinoids.

[0010] There is also a need for cannabinoid formulations that may provide for an improved duration of the pharmaceutical or recreational effects of cannabinoids.

[0011] Summary of the invention

[0012] The invention seeks to minimise an above -mentioned need or limitation, or to provide an improvement in the administration of cannabinoids and cannabinoid formulations.

[0013] Various (enumerated) embodiments of the present invention are described herein. It will be understood that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0014] Embodiment A cannabinoid formulation comprising:

[0015] -a cannabinoid component comprising:

[0016] - a cannabinoid, preferably a synthetic or naturally occurring cannabinoid, more preferably a synthetic cannabidiol (herein CBD), or synthetic tetrahydrocannabinol (herein THC), or synthetic cannabigerol (herein CBG), or synthetic cannabichromene (herein CBC); or synthetic cannabinodiol (herein CBND); or synthetic cannabinol (herein CBN), or synthetic cannabitriol (herein CBT), or synthetic cannabielsoin (herein CBE), or synthetic cannabicyclol (herein CBL), or synthetic cannabichromanone (herein CBCN), or synthetic tetrahydrocannabivarin (herein THCV), or synthetic cannabigerolic acid (herein CBGA), or synthetic cannabidiolic acid (herein CBDA), or synthetic cannabidivarin (herein CBDV), the cannabinoid in an amount to provide the cannabinoid formulation with a concentration of cannabinoid of about 1 to 333 mg / g, preferably 1 to 250 mg / g, or 50 to 200 mg / g, or about 75 mg / g, or 1 to 50 mg / g of the cannabinoid formulation of the cannabinoid formulation; - a tocopheryl phosphate component comprising:

[0017] - mono-(tocopheryl) phosphate (herein TP) and di-(tocopheryl) phosphate (herein T2P), preferably wherein the mass ratio of TP to T2P is about 6:4 to 8:2, preferably about 2:1 respectively, preferably wherein the TP and T2P are added to the formulation as acid forms of tocopheryl phosphates;

[0018] - optionally a solvent in the form of an alcohol, preferably ethanol for increasing the solubility of the tocopheryl phosphate component;

[0019] - an oil component comprising:

[0020] - an oil that may dissolve or be miscible with the cannabinoid and tocopheryl phosphate components, preferably in the form of medium chain triglcyerides (herein MCT), preferably a naturally occurring MCT extract or oil, more preferably a naturally occurring MCT extract or oil that comprises linear or branched alkyl chains comprising no more than about 12 carbon atoms; and wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio enabling rapid absorption of the cannabinoid component, preferably wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component to oil component of about 5:1 to 1 :5, more preferably 2:1 to 4:1 , or 2:1 to 3:1 (such as 2.1 :1 , or 2.2:1 , or 2.3:1 , or 2.4:1 , or 2.5:1 , or 2.6:1 , or 2.7:1 , or 2.8:1 , or 2.9:1 ), or 3:1 to 4:1 (such as 3.1 :1 , or 3.2:1 , or 3.3:1 , or 3.4:1 , or 3.5:1 , or 3.6:1 , or 3.7:1 , or 3.8:1 , or 3.9:1 ), or 4:1 to 5:1 , more preferably 2:1 or 4:1 ;

[0021] - preferably wherein the tocopheryl phosphate component, cannabinoid component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component, cannabinoid component and oil component of from 1 :1 :1 to 5:1 :1 , more preferably 2:1 :1 to 4:1 :1 , or 2:1 :1 to 3:1 :1 (such as

[0022] 2.1 :1 :1 , or 2.2:1 :1 , or 2.3:1 :1 , or 2.4:1 :1 , or 2.5:1 :1 , or 2.6:1 :1 , or 2.7:1 :1 , or 2.8:1 :1 , or 2.9:1 :1 ), or 3:1 :1 to 4:1 :1 (such as 3.1 :1 :1 , or 3.2:1 :1 , or 3.3:1 :1 , or 3.4:1 :1 , or 3.5:1 :1 , or 3.6:1 :1 , or 3.7:1 :1 , or 3.8:1 :1 , or 3.9:1 :1 ), or 4:1 :1 to 5:1 :1 , more preferably 2:1 :1 or 4:1 :1 ; or

[0023] - preferably wherein the tocopheryl phosphate component, cannabinoid component, oil component and solvent are provided in the formulation in a mass ratio of tocopheryl phosphate component to cannabinoid component to oil component to solvent of from 4:1 :1 :8.

[0024] Embodiment 2 A method for producing a cannabinoid formulation, the method comprising the step of:

[0025] - combining

[0026] -a cannabinoid component comprising:

[0027] - a cannabinoid, preferably a synthetic or naturally occurring cannabinoid, more preferably a synthetic cannabidiol (herein CBD), or synthetic tetrahydrocannabinol (herein THC), or synthetic cannabigerol (herein CBG), or synthetic cannabichromene (herein CBC); or synthetic cannabinodiol (herein CBND); or synthetic cannabinol (herein CBN), or synthetic cannabitriol (herein CBT), or synthetic cannabielsoin (herein CBE), or synthetic cannabicyclol (herein CBL), or synthetic cannabichromanone (herein CBCN), or synthetic tetrahydrocannabivarin (herein THCV), or synthetic cannabigerolic acid (herein CBGA), or synthetic cannabidiolic acid (herein CBDA), or synthetic cannabidivarin (herein CBDV), the cannabinoid in an amount to provide the cannabinoid formulation with a concentration of cannabinoid of about 1 to 333 mg / g, preferably 1 to 250 mg / g, or 50 to 200 mg / g, or about 75 mg / g, or 1 to 50 mg / g of the cannabinoid formulation;

[0028] - a tocopheryl phosphate component comprising:

[0029] - mono-(tocopheryl) phosphate (herein TP) and di-(tocopheryl) phosphate (herein T2P), preferably wherein the mass ratio of TP to T2P is about 6:4 to 8:2, preferably about 2:1 respectively, preferably wherein the TP and T2P are added to the formulation as acid forms of tocopheryl phosphates;

[0030] - optionally a solvent in the form of an alcohol, preferably ethanol for increasing the solubility of the tocopheryl phosphate component; and

[0031] - an oil component comprising:

[0032] - an oil that may dissolve or be miscible with the cannabinoid and tocopheryl phosphate components, preferably in the form of medium chain triglcyerides (herein MCT), preferably a naturally occurring MCT extract or oil, more preferably a naturally occurring MCT extract or oil that comprises linear or branched alkyl chains comprising no more than about 12 carbon atoms;

[0033] - to produce a cannabinoid formulation wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio enabling rapid absorption of the cannabinoid component, preferably wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component to oil component of about 5:1 to 1 :5, more preferably 2:1 to 4:1 , or 2:1 to 3:1 (such as 2.1 :1 , or 2.2:1 , or 2.3:1 , or 2.4:1 , or 2.5:1 , or 2.6:1 , or 2.7:1 , or 2.8:1 , or 2.9:1 ), or 3:1 to 4:1 (such as 3.1 :1 , or 3.2:1 , or 3.3:1 , or 3.4:1 , or 3.5:1 , or 3.6:1 , or 3.7:1 , or 3.8:1 , or 3.9:1 ), or 4:1 to 5:1 , more preferably 2:1 or 4:1 ;

[0034] - preferably wherein the tocopheryl phosphate component, cannabinoid component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component, cannabinoid component and oil component of from 1 :1 :1 to 5:1 :1 , more preferably 2:1 :1 to 4:1 :1 , or 2:1 :1 to 3:1 :1 (such as

[0035] 2.1 :1 :1 , or 2.2:1 :1 , or 2.3:1 :1 , or 2.4:1 :1 , or 2.5:1 :1 , or 2.6:1 :1 , or 2.7:1 :1 , or 2.8:1 :1 , or 2.9:1 :1 ), or 3:1 :1 to 4:1 :1 (such as 3.1 :1 :1 , or 3.2:1 :1 , or 3.3:1 :1 , or 3.4:1 :1 , or 3.5:1 :1 , or 3.6:1 :1 , or 3.7:1 :1 , or 3.8:1 :1 , or 3.9:1 :1 ), or 4:1 :1 to 5:1 :1 , more preferably 2:1 :1 or 4:1 :1 ; or

[0036] - preferably wherein the tocopheryl phosphate component, cannabinoid component, oil component and solvent are provided in the formulation in a mass ratio of tocopheryl phosphate component to cannabinoid component to oil component to solvent of from 4:1 :1 :8, thereby producing a cannabinoid formulation. A kit for forming a cannabinoid formulation comprising in separate compartments:

[0037] -a cannabinoid component comprising:

[0038] - a cannabinoid, preferably a synthetic or naturally occurring cannabinoid, more preferably a synthetic cannabidiol (herein CBD), or synthetic tetrahydrocannabinol (herein THC), or synthetic cannabigerol (herein CBG), or synthetic cannabichromene (herein CBC); or synthetic cannabinodiol (herein CBND); or synthetic cannabinol (herein CBN), or synthetic cannabitriol (herein CBT), or synthetic cannabielsoin (herein CBE), or synthetic cannabicyclol (herein CBL), or synthetic cannabichromanone (herein CBCN), or synthetic tetrahydrocannabivarin (herein THCV), or synthetic cannabigerolic acid (herein CBGA), or synthetic cannabidiolic acid (herein CBDA), or synthetic cannabidivarin (herein CBDV), the cannabinoid in an amount to provide the cannabinoid formulation with a concentration of cannabinoid of about 1 to 333 mg / g, preferably 1 to 250 mg / g, or 50 to 200 mg / g, or about 75 mg / g, or 1 to 50 mg / g of the cannabinoid formulation; with

[0039] - a tocopheryl phosphate component comprising:

[0040] - mono-(tocopheryl) phosphate (herein TP) and di-(tocopheryl) phosphate (herein T2P), preferably wherein the mass ratio of TP to T2P is about 6:4 to 8:2, preferably about 2:1 respectively, preferably wherein the TP and T2P are added to the formulation as acid forms of tocopheryl phosphates;

[0041] - optionally a solvent in the form of an alcohol, preferably ethanol for increasing the solubility of the tocopheryl phosphate component; and

[0042] - an oil component comprising:

[0043] - an oil that may dissolve or be miscible with the cannabinoid and tocopheryl phosphate components, preferably in the form of medium chain triglcyerides (herein MCT), preferably a naturally occurring MCT extract or oil, more preferably a naturally occurring MCT extract or oil that comprises linear or branched alkyl chains comprising no more than about 12 carbon atoms;

[0044] - written instructions for comprising the method of Embodiment 2 described above for the production of a formulation according to Embodiment 1 described above.

[0045] Embodiment 4: A cannabinoid containing dosage unit in the form of a lozenge, troche, gummy, hard candy, chewable tablet, chewing gum or the like comprising:

[0046] - a cannabinoid formulation according to Embodiment 1

[0047] - a base for use in a composition for sublingual or buccal administration of a compound; preferably wherein the base comprises one or more carriers selected from the group consisting of gelatin, pectin, sucrose, glucose, water, polyethylene glycol, resin, humectant, elastomer, wax and emulsifier; preferably wherein the dosage unit comprises the cannabinoid formulation according to Embodiment 1 in an amount to achieve an intended dose of cannabinoid per dosage unit, more preferably wherein the dosage unit comprises a cannabinoid in an amount of 1 to 200mg of cannabinoid / dosage unit, or 1 to 50mg of cannabinoid / dosage unit, or 1 to 30mg of cannabinoid / dosage unit;

[0048] -optionally including a further component for modifying the taste, flavour or rheology characteristic of the cannabinoid formulation or component thereof.

[0049] Embodiment 5: A method for producing a cannabinoid -containing dosage unit in the form of a lozenge, troche, gummie, hard candy, chewable tablet, chewing gum or the like, the method comprising the step of:

[0050] - combining:

[0051] - a cannabinoid formulation according to Embodiment 1 ; with

[0052] - a base for use in a composition for sublingual or buccal administration of a compound; preferably wherein the base comprises one or more carriers selected from the group consisting of gelatin, pectin, sucrose, glucose, water, polyethylene glycol, resin, humectant, elastomer, wax and emulsifier; and optionally

[0053] -a further component for modifying the taste, flavour or rheology characteristic of the cannabinoid formulation or component thereof; in conditions enabling integration of the cannabinoid formulation according to Embodiment 1 into the base;

[0054] - preferably wherein the dosage unit comprises the cannabinoid formulation according to Embodiment 1 in an amount to achieve an intended dose of cannabinoid per dosage unit; more preferably wherein the dosage unit comprises a cannabinoid in an amount of 1 to 200mg of cannabinoid / dosage unit, or 1 to 50mg of cannabinoid / dosage unit, or 1 to 30mg of cannabinoid / dosage unit; thereby producing a cannabinoid -containing dosage unit in the form of a lozenge, troche, gummie, hard candy, chewable tablet, chewing gum or the like.

[0055] Embodiment 6 A kit for forming a cannabinoid formulation comprising in separate compartments:

[0056] - a cannabinoid formulation according to Embodiment 1 described above;

[0057] - a base for use in a composition for sublingual or buccal administration of a compound;

[0058] - written instructions comprising the method of Embodiment 5 described above for the production of a dosage unit according to Embodiment 4 described above.

[0059] Embodiment 7: A use of a cannabinoid formulation of Embodiment or a dosage unit of

[0060] Embodiment 4 described above in the administration of a cannabinoid to a buccal and / or sub-lingual cavity to improve the onset of a pharmaceutical or recreational effect of a cannabinoid. A method for treating an individual for a condition preferably a condition selected from the group consisting of conditions including pain, inflammation, anxiety, depression, insomnia, sleep disorders, lack of energy, lack of alertness, weight gain, obesity, diabetes, metabolic syndrome, nausea (acute or anticipatory), epilepsy, spasticity, schizophrenia, bi-polar disorder, cancer and neoplasia, chronic pain, osteoarthritic pain, bacterial and / or fungal infection, fibromyalgia, appetite enhancement and / or appetite suppression, Alzheimer’s disease, autism and developmental disorders, the method comprising step of:

[0061] - administration of a therapeutically effective amount of a cannabinoid formulation of Embodiment 1 or a dosage unit of Embodiment 4 to the sublingual or buccal cavities or mucosa of an individual in need of said treatment.

[0062] Embodiment 9 A cannabinoid formulation of Embodiment 1 or a dosage unit of

[0063] Embodiment 4 in the administration of a cannabinoid to a buccal and / or sub-lingual cavity or mucosal for preventing or treating an individual for a condition, preferably a condition selected from the group consisting of conditions including pain, inflammation, anxiety, depression, insomnia, sleep disorders, lack of energy, lack of alertness, weight gain, obesity, diabetes, metabolic syndrome, nausea (acute or anticipatory), epilepsy, autism, Alzheimer’s, development disorders, spasticity, schizophrenia, bi-polar disorder, cancer and neoplasia, chronic pain, osteoarthritic pain, bacterial and / or fungal infection, fibromyalgia, appetite enhancement and / or appetite suppression, Alzheimer’s disease, autism and developmental disorders, preferably wherein the formulation or dosage unit comprises a therapeutically effective amount of a cannabinoid formulation of Embodiment 1 .

[0064] Detailed description of the embodiments

[0065] 1. Definitions

[0066] For the purpose of interpreting this specification, the following definitions will apply and whenever appropriate, terms use in the singular will also include the plural and vice versa.

[0067] As used herein, the term “about” in relation to a numerical value X means + / - 10%, unless the context dictates otherwise.

[0068] As used herein, the term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).

[0069] As used herein, the term “treat”, “treating” or “treatment” in connection to a disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e. , slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, "treating" or "treatment" refers to modulating the disease or disorder, either physically, {e.g. , stabilization of a discernible symptom), physiologically, {e.g., stabilization of a physical parameter), or both. The term “alleviating” or “alleviation”, for example in reference to a symptom of a condition, as used herein, refers to reducing at least one of the frequency and amplitude of a symptom of a condition in a patient. In one embodiment, the terms “method for the treatment” or “method for treating”, as used herein, refer to “method to treat”.

[0070] As used herein, the term "therapeutically effective amount" refers to an amount of cannabinoid which is sufficient to achieve the stated effect. Accordingly, a therapeutically effective amount of cannabinoid will be an amount sufficient for the treatment or prevention of the relevant condition.

[0071] By “therapeutic regimen” is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during the treatment of the disease or disorder.

[0072] As used herein, a subject or individual is “in need of a treatment” if such subject would benefit biologically, medically or in quality of life from such treatment. An individual is generally a mammal, typically a human, and may be a companion animal, livestock or performance animal.

[0073] The words “comprise”, “comprises”, “comprising” and “comprised” are used in an inclusive sense, unless the context requires otherwise.

[0074] 2. Modes of carrying out the invention

[0075] 2.1 Cannabinoid -containing formulations

[0076] The invention provides a cannabinoid - containing formulation comprising:

[0077] -a cannabinoid component comprising:

[0078] - a cannabinoid;

[0079] - a tocopheryl phosphate component comprising:

[0080] - mono-(tocopheryl) phosphate (herein TP) and di-(tocopheryl) phosphate (herein T2P);

[0081] - an oil component comprising:

[0082] - an oil that may dissolve or be miscible with the cannabinoid and tocopheryl phosphate components; wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio enabling rapid absorption of the cannabinoid component, preferably wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component to oil component of about 5:1 to 1 :5, more preferably 2:1 to 4:1 , or 2:1 to 3:1 (such as 2.1 :1 , or 2.2:1 , or 2.3:1 , or 2.4:1 , or 2.5:1 , or 2.6:1 , or 2.7:1 , or 2.8:1 , or 2.9:1 ), or 3:1 to 4:1 (such as 3.1 :1 , or 3.2:1 , or 3.3:1 , or 3.4:1 , or 3.5:1 , or 3.6:1 , or 3.7:1 , or 3.8:1 , or 3.9:1 ), or 4:1 to 5:1 , more preferably 2:1 or 4:1 .

[0083] The cannabinoid component may comprise a cannabinoid, or may consist of a cannabinoid.

[0084] The cannabinoid may be a synthetic compound or a naturally occurring compound, for example a phyto-cannabinoid. Neutral cannabinoids include cannabigerol (CBG) and related compounds (e.g., cannabigerol monomethyl ether, cannabigerovarin); cannabichromene (CBC) and related compounds (e.g., (±)-cannabichromene, (±)- cannabichromevarin); (-)- cannabidiol (CBD) and related compounds (e.g., cannabidiol momomethyl ether, cannabidiol-04, (-)-cannabidivarin, cannabidiorcol); cannabinodiol (CBND) and related compounds (e.g., cannabinodivarin); A9-tetrahydrocannabinol (THC) and related compounds (e.g., A9-tetrahydrocannabinol-C4, A9- tetrahydrocannabivarin, A9-tetrahydro-cannabiorcol, (-)-AS-trans- (6aR,10aR)-A8- tetrahydrocannabinol, (-)-(6aS,10aR)-A9-tetrahydro-cannabinol); cannabinol (CBN) and related compounds (e.g., cannabinol-C4, cannabivarin, cannabinol-C2, cannabiorcol, cannabinol methyl ether); (±)-cannabitriol (CBT) and related compounds (e.g., ( — )- (9R,1 OR)- trans- 10-O-ethyl-cannabitriol, (±)-(9R,10R / 9S,10S)-cannabitriol-C3); cannabielsoin (CBE) and related compounds (e.g., (5aS,6S,9R,9aR)-cannabielsoin, (5aS,6S,9R,9aR)-C3-cannabielsoin, cannabiglendol-C3, dehydrocannabifuran, cannabifuran); isocannabinoids (e.g., (-)-A7-trans- (1 R,3R,6R)-isotetrahydrocannabinol, (±)-A7-1 ,2-cis-(1 R,3R,6S)-isotetrahydrocannabivarin, (±)-A7- 1 ,2-cis-(1 S,3S,6R)- isotetrahydro-cannabivarin, (-)-A7-trans-(1 R.3R.6R)- isotetrahydrocannabivarin); cannabicyclol (CBL) and related compounds (e.g., (±)-(1 aS,3aR,8bR,8cR)- cannabicyclol CBL-C5, (±)-(1 aS,3aR,8bR,8cR)-cannabicyclovarin); cannabicitran (CBT) and related compounds; and cannabichromanone (CBCN) and related compounds (e.g., cannabichromanone-C3, cannabicoumaronone). Acidic cannabinoids include cannabigerolic acid A; cannabigerolic acid A monomethyl ether; cannabigerovarinic acid A; (±)-cannabichromenic acid A; (±)-cannabichromevarinic acid A; cannabidiolic acid; cannabidivarinic acid; A9- tetrahydrocannabinol ic acid A; A9-tetrahydrocannabinolic acid B; A9-tetrahydrocannabinolic acidC4 A; A9-tetrahydrocannabinolic acid-C4 B; A9- tetrahydro-cannabivarinic acid A; A95 -tetrahydrocannabiorcolic acid A; A9- tetrahydrocannabiorcolic acid B; (-)-A8-trans-(6aR,10aR)- tetrahydrocannabinolic acid A; cannabinolic acid A; (5aS,6S,9R,9aR)-cannabielsoic acid A; (5aS,6S,9R,9aR)- cannabielsoic acid B; (5aS,6S,9R,9aR)-C3-cannabielsoic acid B; and (±)- (1 aS,3aR,8bR,8cR)-cannabicyclolic acid A.

[0085] In one embodiment, the formulation comprises a heterogenous mixture of cannabinoid compounds. Preferably the formulation comprises at least cannabidiol (herein CBD) and / or tetrahydrocannabinol (herein THC).

[0086] The cannabinoid may be provided as an extract of a naturally occurring source of cannabinoid. More preferably the extract may comprise CBD and THC. Extracts of a naturally occurring source of cannabinoid may be obtained by extraction processes known to the skilled worker for extraction of phytocannabinoids, such as alcohol extraction, CO2 extraction or other solvent free extraction. An extract may take the form of an oil.

[0087] A cannabinoid may be predominantly a single compound, for example CBD or THC, as obtained by fractionation of an extract of a natural source of cannabinoid, or by cannabinoid synthesis.

[0088] A cannabinoid may be a synthetic cannabinoid such as dronabinol. In this embodiment, the cannabinoid formulation may not comprise a surfactant, or may not comprise more than about 1 % by mass of an alcohol.

[0089] In one embodiment the cannabinoid is provided as a racemic mixture (i.e. having both D & L stereochemistries), for example as obtainable by extraction of a natural source of cannabinoid.

[0090] A cannabinoid component of the formulation may comprise CBD and THC in a ratio of about 1 :1 , 2:3, 4:1 or 1 :20. In another embodiment the ratio of CBD to THC may be 5:1 or 10:1.

[0091] In one embodiment, the cannabinoid component may further comprise other components commonly found in a naturally derived cannabinoid product such as a terpene. The tocopheryl phosphate component may comprise or consist of a particular species of tocopheryl phosphate, or comprise or consist of a combination of a particular species of tocopheryl phosphate in a particular ratio of tocopheryl phosphate species.

[0092] Tocopheryl phosphate is a phosphorylated tocopherol compound, where a covalent bond is formed between an oxygen atom (typically originating from a hydroxyl group) of the tocopherol compound and the phosphorous atom of a phosphate group (PO4).

[0093] The phosphorylated tocopherol compound may be a phosphate mono-ester, phosphate diester, phosphate tri-ester, pyrophosphate mono-ester, pyrophosphate di-ester, or a salt or derivative thereof, or a mixture thereof.

[0094] Salts of tocopheryl phosphate may include metal salts such as alkali or alkaline earth metal salts, for example sodium, magnesium, potassium and calcium salts. Other pharmaceutically or veterinary acceptable salts of the tocopheryl phosphate may be used, such as other alkali metal salts. Other pharmaceutically acceptable salts are well known in the art, and include the acceptable salts described in detail in S. M. Berge, et al., J. Pharmaceutical Sciences, 66:1 -19, 1977. Sodium and potassium salts are preferred.

[0095] The tocopheryl phosphate may be selected from, but not limited to, a mono-(tocopheryl) phosphate, a mono-(tocopheryl) phosphate monosodium salt, a mono-(tocopheryl) phosphate disodium salt, a di-(tocopheryl) phosphate, a di-(tocopheryl) phosphate monosodium salt, or a mixture thereof.

[0096] It is preferred that the TP and T2P are added to the formulation as an acid form of tocopheryl phosphate.

[0097] In particular embodiments, the composition comprises a mixture of TP and T2P in mass ratio of at about 2:1 , within the range of about 4:1 to about 1 :4, or within the range of about 6:4 to about 8:2. In some embodiments, the ratio is about 6:4 or about 8:2.

[0098] As described further herein, the tocopheryl phosphate component may further comprise an organic solvent, such as an alcohol, preferably ethanol, for increasing the solubility of the tocopheryl phosphate component in the cannabinoid component of the formulation. In one embodiment the oil component comprises medium chain tri-glycerides (MCT) or consists of medium chain tri-glycerides (MCT)

[0099] The MCT may be obtained from a naturally occurring source, or it may be synthetic.

[0100] The MCT may be provided as a naturally occurring MCT extract or oil. Examples of oils include palm kernel oil and coconut oil.

[0101] Typically, the MCT comprises linear or branched alkyl chains comprising no more than about 12 carbon atoms.

[0102] The MCT may be a naturally occurring oil or extract that has been purified or fractionated thereby increasing the relative abundance of one or more linear or branched alkyl chains comprising 1 or less carbon atoms in the oil or extract. For example, the MCT may be derived from a plant oil such as palm kernel oil or coconut oil. The oil is fractionated or otherwise processed so that the amount of a given fatty acid, for example, 6:0 (caproic), 8:0 (caprylic), 10:0 (capric), 12:0 (lauric) acid chain has a higher relative amount in the fractionated or processed oil than is observed in the plant oil from which the fractionated or processed oil is derived. In a preferred embodiment, the fatty acids of the fractionated or processed oil may consist of the following fatty acid chains in the following stated amounts: caproic acid (6%), caprylic acid (55-85%), capric acid (15-40%), lauric acid (4%).

[0103] The MCT may consist of saturated fatty acid chains.

[0104] The MCT may comprise or consist of one or more fatty acid chains selected from the group consisting of caproic acid, caprylic acid, capric acid and lauric acid.

[0105] The MCT may consist of unsaturated fatty acid chains, for example fatty acid chains having one or more double bonds.

[0106] The MCT may consist of a mixture of saturated fatty acid chains and unsaturated fatty acid chains, said fatty acid chains having 12 or less carbon atoms.

[0107] The MCT oil may consist of a mixture of tri-, di- and mono-glycerides, or a mixture of tri - and mono-glycerides, or a mixture of tri- and di-glycerides or a mixture di- and monoglycerides, or tri- glcyerides, or di-glcyerides, or mono-glycerides. In a preferred embodiment the MCT oil consists of tri-, di-, and mono- glycerides that comprise fatty acid chains that are 6:0, 8:0, 10:0, or, 12:0 carbon chains.

[0108] The MCT may be obtained from commercial sources, examples including Labrafac CC, Wabrafac WL1349, Captex 300, Captex 355 as described in the examples herein.

[0109] The cannabinoid -containing formulation may take the form of a liquid, solid or semisolid that is amenable for sublingual or buccal administration of cannabinoid i.e. it may be located adjacent mucosal tissue under the tongue, or adjacent mucosal tissue that lines the cheek.

[0110] The formulation may further comprise an aqueous component, or the formulation may be mixed with an aqueous component prior to sublingual or buccal administration.

[0111] Where the formulation further comprises an aqueous component, it may present as an emulsion, a colloidal suspension or a bi-phasic solution.

[0112] In one embodiment, the cannabinoid formulation may take the form of a liquid adapted for sublingual or buccal administration such as a syrup, suspension or spray.

[0113] 2.2 Preferred solid formulations

[0114] The formulation may be provided in the form of one unit, or a plurality of dosage units adapted for sublingual or buccal administration.

[0115] A cannabinoid -containing dosage unit may comprise:

[0116] - a cannabinoid formulation as described under sub-heading 2.1 above;

[0117] - a base for use in a composition for sublingual or buccal administration of a compound.

[0118] Each dosage unit may comprise an amount of cannabinoid of about 1 to 200 mg, or 1 to 50 mg, or 1 to 30mg.

[0119] In a preferred embodiment, a dosage unit may be presented as a lozenge, troche, gummie or the like.

[0120] A lozenge or hard candy may contain concentrated aqueous liquid sucrose, concentrated aqueous corn syrup, calcium carbonate, and flavouring. A troche may contain Polyethylene glycol 1450, silicon dioxide, polyethylene glycol 400, gelatin, sweetener, and flavouring. A chewable tablet may contain gelatin, sucrose, glucose, water, fumaric acid, citric acid, sucralose, flavouring, and colouring. A chewing gum may contain a gum base composed of an insoluble gum base (resins, humectants, elastomers, emulsifiers, fillers, waxes, antioxidants, and softeners), sweeteners, and flavoring agents. The coating may be composed of, for example, sweeteners, flavoring agents, coloring agents, and fruit acids.

[0121] In one embodiment, the dosage unit is a ‘gummie’. A gummie may otherwise be known as a 'gummy candy’ or 'jelly sweet’. A gummie may be a gelatin -based chewable confectionery. A gummie may be sugar free or otherwise unsweetened.

[0122] A dosage unit may further comprise components including thickeners, gelling agents, buffers, emollients, sweeteners, disintegrators, flavours, colours, electrolytes, pH modifiers, appearance modifiers, sustained-release agents, and the like. Such additional components may be added to either of the cannabinoid or tocopheryl phosphate components, during any step during the formulation process.

[0123] In one embodiment, a base may be useful to adapt the dosage unit to the form of a solid composition that is suitable sublingual or buccal administration, such as a muco- adhesive tablet, film, gel or ointment.

[0124] Mucoadhesive tablets allow for drinking and speaking without major discomfort. These are placed directly onto the mucosal surface for local or systemic drug delivery. These soften, adhere to the mucosa, and are retained in position until dissolution and or release is complete. Mucoadhesive tablets, in general, have the potential to be used for controlled release drug delivery, but coupling of mucoadhesive properties to tablet has additional advantages. For example, it offers efficient absorption and enhanced bioavailability of the drugs due to a high surface-to-volume ratio and facilitates a much more intimate contact with the mucous layer. Mucoadhesion arises as a result of dehydration of an area of the mucosa.

[0125] Mucoadhesive films may be preferred over tablets in terms of flexibility and comfort. In addition, they can circumvent the relatively short residence time of oral gels on the mucosa, which are easily washed away and removed by saliva. An ideal film should be flexible, elastic, and soft, yet adequately strong to withstand breakage due to stress from mouth movements. It must also possess good mucoadhesive strength in order to be retained in the mouth for the desired duration of action.

[0126] Buccal patches are described as laminates comprised of an impermeable backing layer, a drug containing reservoir layer which releases the drug in a controlled manner, and a mucoadhesive surface for mucosal attachment.

[0127] Semisolid dosage forms, such as gels and ointments, have the advantage of easy dispersion throughout the oral mucosa. Certain mucoadhesive polymers, for example, sodium carboxymethylcellulose, carbopol, hyaluronic acid, and xanthan gum, undergo a phase change from liquid to semisolid. This change enhances the viscosity, which results in sustained and controlled release of drugs. Hydrogels are also a promising dosage form for buccal drug delivery.

[0128] 2.3 Rapid onset of cannabinoid dosing effects

[0129] A principal advantage of the invention is that it enables rapid onset of pharmacological effects of a cannabinoid than could be previously obtained at the relevant dose of cannabinoid. Other advantages may include an improved strength and / or duration of the pharmacological effect of a cannabinoid.

[0130] Without wanting to be bound by hypothesis, it is believed that the tocopheryl phosphate component of the cannabinoid formulation of the invention, when present in a higher mass ratio to the oil component, results in the oil component being encapsulated by the tocopheryl phosphate component. This results in cannabinoid -containing nanoparticles that are rapidly absorbed across the sublingual and buccal mucosal. In contrast, when tocopheryl phosphate is present at a lower mass ratio to the oil component, it is believed that the oil encapsulates the tocopheryl phosphate component and this is associated with a preference for oral consumption, resulting in mucosal uptake in the gut or intestine and ultimately, a relative slower onset of the pharmacological effect. This is exemplified in the Examples described below where improved onset, strength and / or duration of the pharmacological effect of a cannabinoid is established for formulations having a tocopheryl phosphate component to oil component ratio in the range of 2:1 to 4:1 . Thus, in one embodiment there is provided use of a cannabinoid formulation of Embodiment 1 or a dosage unit of Embodiment 4 described above in the administration of a cannabinoid to a buccal and / or sub-lingual cavity to improve the onset of a pharmaceutical or recreational effect of a cannabinoid.

[0131] The onset, strength and / or duration of a pharmaceutical or recreational effect of a cannabinoid is improved or greater than that obtained by a same or similar dose of cannabinoid in a formulation that has a lower mass ratio of tocopheryl phosphate component to oil component.

[0132] 2.4 Methods of treatment

[0133] The rapid onset, improved strength and / or duration of cannabinoid dosing effects arising from the cannabinoid formulations of the invention enables and potentially enhances the treatment of a range of conditions for which cannabinoids have been suggested. As mentioned herein, some of these conditions include pain, inflammation, anxiety, depression, insomnia, sleep disorders, lack of energy, lack of alertness, weight gain, obesity, diabetes, metabolic syndrome, nausea (acute or anticipatory), epilepsy, spasticity, schizophrenia, bi-polar disorder, cancer and neoplasia, chronic pain, osteoarthritic pain, bacterial and / or fungal infection, fibromyalgia, appetite enhancement and / or appetite suppression, Alzheimer’s disease, autism and developmental disorders.

[0134] Thus, in one embodiment there is provided a method of prevention or treatment of one of the above -mentioned conditions comprising the step of administering an cannabinoid formulation or dosage unit described herein, thereby preventing or treating an above - mentioned condition. While it will be understood that the cannabinoid formulation of the invention is physically received in the oral cavity, the rapid onset, strength and / or duration characteristic is understood to be achieved predominantly by a sustained contact of the cannabinoid formulation of the invention of the sublingual and / or buccal mucosa. This sustained contact may be achieved by locating the cannabinoid formulation under the tongue, and / or against the mucosal lining of the cheek as explained under the previous sub-heading.

[0135] In another embodiment there is provided a cannabinoid formulation or dosage unit for use in the prevention or treatment of one of the above -mentioned conditions.

[0136] In another embodiment there is provided a use of a cannabinoid formulation or dosage unit described herein for prevention or treatment of one of the above -mentioned conditions. In another embodiment there is provided a use of a cannabinoid formulation or dosage unit described herein, in the manufacture of a medicament for prevention or treatment of one of the above -mentioned conditions.

[0137] In a particularly preferred embodiment, the condition is insomnia or other sleep disorder. In this embodiment it is preferred that the formulation is provided in the form of a plurality of dosage units, each individual unit comprising a cannabinoid component that comprises a cannabinoid, preferably CBD or THC in amounts of about 1 to 200 mg, 1 to 50 mg, or 1 to 30 mg. The mass ratio of TPM to MCT is about 5 :1 to 2:1 respectively, about 2:1 or 4:1 . The mass ratio of TP to T2P is about 2:1 , within the range of about 4:1 to about 1 :4, or within the range of about 6:4 to about 8:2.

[0138] In another embodiment, the condition is episodic or chronic and selected from the group consisting of anxiety, depression, epilepsy, spasticity, schizophrenia, bi-polar disorder.

[0139] In this embodiment it is preferred that the formulation is provided in the form of a plurality of dosage units, each individual unit comprising a cannabinoid component that comprises a cannabinoid, preferably CBD or THC in amounts of about 1 to 200 mg, 1 to 50 mg, or 1 to 30 mg. The mass ratio of TPM to MCT is about 5 :1 to 2:1 respectively, about 2:1 or 4:1 . The mass ratio of TP of TP to T2P is about 2:1 , within the range of about 4:1 to about 1 :4, or within the range of about 6:4 to about 8:2.

[0140] In another embodiment, the condition is acute or chronic pain which may be managed by activation of cannabinoid receptors in the individual in need of treatment. Examples include acute pain associated with trauma or surgical intervention, or chronic pain associated with inflammation, osteoarthritis, or neoplasia. In these embodiments, the cannabinoid formulation may be given to prevent perception of incident pain, or to manage ongoing pain. In this embodiment it is preferred that the formulation is provided in the form of a plurality of dosage units, each individual unit comprising a cannabinoid component that comprises a cannabinoid, preferably CBD or THC in amounts of about 1 to 200 mg, 1 to 50 mg, or 1 to 30 mg. The mass ratio of TPM to MCT is about 5 :1 to 2:1 respectively, about 2:1 to 4:1 . The mass ratio of TP to T2P is about 2:1 , within the range of about 4:1 to about 1 :4, or within the range of about 6:4 to about 8:2.

[0141] The number of dosage units to be given may be determined by individual characteristics including sex, age, weight, other conditions and medications, these factors being with the purview of the skilled worker, and determinable my measuring the plasma level of cannabinoids by standard techniques, including those described above.

[0142] 2.5 Methods of manufacture

[0143] The invention provides methods for the production of cannabinoid formulations, including formulations that comprise a base for facilitating sublingual and / or buccal administration of a pharmaceutical.

[0144] Turning to the tocopheryl phosphate component, this comprises TP and T2P.

[0145] The combination or mixture of TP and T2P (herein TPM), may be obtained by forming a composition of tocopheryl and P4O10 and heating the composition to a temperature at which an exothermic reaction occurs between the tocopheryl and P4O10. This temperature is referred to as an 'exotherm temperature’. At this point, the temperature of the reaction mixture is allowed to continue to rise and the reaction is completed by the formation of TP and T2P when the temperature of the reaction falls below the exotherm temperature. The phosphorylation of tocopheryl occurs at and above the exotherm temperature. The reaction products may further include poly phosphate complexes. These may be removed by hydrolysis reaction. The process is generally described in WO2018 / 112512.

[0146] Preferably the mass ratio of TP and T2P in the tocopheryl phosphate component is about 10:1 to 1 :10, preferably 5:1 to 1 :5, more preferably 2:1 to 1 :2. A component comprising this ratio may be directly obtained as a product of the above -described phosphorylation reaction, by modifying the amount of reaction substrate and or reaction conditions. Alternatively, or additionally, TP or T2P could be added to the product of the phosphorylation reaction to provide the preferred mass ratio of TP to T2P.

[0147] The TP and T2P reaction products arising from the above describe phosphorylation reaction are in the acid form and have a pH of about 2 to 4. These reaction products may be added to the formulation as acids, or as a salt (in which case they are neutral), although it is preferred that the reaction products are added as acids.

[0148] The mixture of TP and T2P, referred to herein as TPM, arising from the above described reaction process may have a brittle, wax-like or less malleable texture which makes working the TPM with other constituents of the tocopheryl phosphate component (if any) and the cannabinoid component more difficult. To improve the workability of the TPM, an alcohol, such as ethanol or other organic solvent may be added to decrease the solid character of TPM. The alcohol or organic solvent may be provided in a mass ration of alcohol to tocopheryl phosphate of up to 2:1 , although, generally, an alcohol or organic solvent is provided in no more than an amount of about 100% by weight of the tocopheryl phosphate component.

[0149] As described above, the cannabinoid of the cannabinoid component of the cannabinoid formulation may be derived from a synthetic source, or from a natural source, for example a phyto-cannabinoid. It is preferred that it is provided in a form which is miscible with MCT, or dissolvable in oil. In certain embodiments, the cannabinoid may be provided in the form of a powder.

[0150] The MCT of the cannabinoid component may be provided in a substantially unextracted form, for example, in the form of a whole oil i.e. an oil that contains components derived from the MCT source that are other than MCT. For example, MCT may be provided in the form of a whole palm kernel oil or coconut oil. In certain embodiments it is preferred that MCT is provided as an extract in which the only triglycerides are medium chain - i.e. generally 12 carbons or less. Highly purified extracts of MCT are preferred and may be obtained from a variety of commercial sources.

[0151] The MCT generally acts as a carrier for the cannabinoid, which is to say that in one embodiment it bulks the cannabinoid, thereby making working with and formulating the cannabinoid easier. Thus, generally the cannabinoid is provided for use as an ingredient for production of the cannabinoid formulation in MCT. As described herein, it has been found that a relatively lower mass ratio of MCT to TPM is associated with one or more of rapid onset, improved strength and duration of pharmacological effect of the pharmaceutical and recreational effects of a cannabinoid, suggesting sublingual and / or buccal administration is facilitated by a lower relative amount of MCT in the cannabinoid formulations of the invention. For example, rapid onset of these effects is more pronounced at ratios approaching 5:1 of TPM to MCT and the Examples herein demonstrated rapid onset at a preferred ratio of 4:1 . In the circumstances where cannabinoid is provided for use in the invention in the form of an oil, for example MCT, the mass ratio of cannabinoid in the MCT is relatively high and may approach 5:1 . In preferred embodiments of the manufacture process, the tocopheryl phosphate component is contacted with the cannabinoid component (comprising the MCT carrier / cannabinoid composition) to form the cannabinoid composition. This may be achieved by blending the tocopheryl phosphate with the cannabinoid component.

[0152] It is important that the blending process should result in the equal and consistent distribution of the TPM throughout the cannabinoid component, ostensibly providing for dissolution of the TPM throughout the cannabinoid component.

[0153] In one embodiment, TPM and MCT may be combined and stirred with gentle heating to enable the TPM to dissolve into the MCT to form a first solution of TPM dissolved in MCT. Cannabinoid, which may be in the form of a powder, may then be added to the first solution and mixed to dissolve the cannabinoid into the first solution.

[0154] The product of the process may have a range of physical properties, depending on the properties of the tocopheryl phosphate and cannabinoid components utilised as ingredients to form the product, and the reaction conditions. Generally, the product is hydrophobic, or otherwise oil-like in nature.

[0155] In one embodiment, the product may be a liquid, such as a liquid oil, and in this form the product may require no further substantial modification, thereby taking the form of the cannabinoid formulation that is ready for use in sublinqual or buccal administration. In other embodiments it may be necessary to add reagents to modify viscosity (i.e. to reduce or increase viscosity), depending on whether the cannabinoid composition is to take a liquid, solid, or semi solid form for sublinqual or buccal use. Viscosity modifying agents may be added to either the tocopheryl phosphate or cannabinoid components prior to blending those components to from the cannabinoid composition of the invention. Alternatively, these modifying agents may be added after these components have been combined.

[0156] A range of other pharmacologically accepted excipients, carriers, flavouring agents, stability modifiers can be added to the product of the manufacture process, or to the tocopheryl phosphate or cannabinoid components before those components are combined.

[0157] As described herein, in certain embodiments, the cannabinoid formulation may be provided in a dosage unit form that is adapted for sublingual or buccal administration of the cannabinoid component. The manufacture process generally involves the formation of a cannabinoid formulation according to Embodiment 1. A base is then provided in substantially molten or liquified form and contacted with the cannabinoid formulation to enable the cannabinoid formulation to mix and integrate with the base. The resultant composition is then allowed to cool, enabling the composition to set, preferably into a solid or gel state.

[0158] Examples

[0159] Example 1 - Manufacture of a gummie for sublingual or buccal absorption of a cannabinoid

[0160] SOP 3: Manufacture of TPM gummies with a 4:1 ratio of TPM to THC

[0161] Material

[0162] 1 - THC Concentrate (~90%)

[0163] 2- TPM

[0164] 3- Gelatin Puck

[0165] 4- Medium chain triglyceride (MCT) oil

[0166] 5- Ethanol (absolute)

[0167] Procedure

[0168] This SOP makes a gummy with a 4:1 ratio of TPM to THC.

[0169] 1 . Manufacture of TPM THC (4:1 ) Oil mixture: a. In a 7 ml scintillation vial (or similar air-tight container; choose size to minimise empty headspace), accurately weigh 800 mg of TPM, 222 mg THC concentration (-90% THC), 200 mg of MCT and 1 .44g absolute ethanol. Close the lid and heat in a water bath at 70°C. The ethanol is a dissolution aid for the TPM, much of which will be lost upon heating / mixing with the gummy. b. Stir / shake until complete dissolution of the TPM and a uniform transparent liquid is formed. At this point, it is ready to use. Maintain at 70°C until use. c. The amount of TPM THC Oil added to the gelatin mixture will determine the amount of THC (mg) per gummy. d. The volume of the TPM THC Oil that is manufactured can be scaled up / down depending on the amount required (i.e.. batch size / gummy size). Calculate the required amount of TPM THC oil required prior to manufacturing.

[0170] 2. Formulation: a. Cut the gelatin puck into small pieces and place in a beaker. For reference, each individual puck weighs ~100g. b. Place the beaker in a water bath at 70°C until the gelatin puck melts. c. Once molten, add the required amount (by weight) of molten TPM THC oil at 70°C to the gummy base and mix well using a glass stirring rod for 2-5 minutes. Example amounts of oil are provided below in Table 1 and 2. d. Pour the base into molds and allow to cool / cure.

[0171] Table 1 . Amounts required for 3g gummies. Amounts can be scaled up or down for a given batch size. The examples below assume the mixture is used to make ~40 x 3g gummies.

[0172] Table 2. Amounts required for 4g gummies. Amounts can be scaled up or down for a given batch size. The examples below assume the mixture is used to make ~30 x 4g gummies.

[0173] SOP 2: Manufacture of TPM gummies with a 2:1 ratio of TPM to THC

[0174] Material

[0175] 1 - THC Concentrate (~90%)

[0176] 2- TPM

[0177] 3- Gelatin Puck

[0178] 4- Medium chain triglyceride (MCT) oil Procedure

[0179] This SOP makes a gummy with a 2:1 ratio of TPM to THC.

[0180] 1 . Manufacture of TPM THC (2:1 ) Oil mixture: a. In a 7 ml scintillation vial (or similar air-tight container; choose size to minimise empty headspace), accurately weigh 800 mg of TPM, 444 mg THC concentration (-90% THC) and 400 mg of MCT. Close the lid and heat in a water bath at 70°C. b. Stir until complete dissolution of the TPM and a uniform transparent liquid is formed. At this point, it is ready to use. Maintain at 70°C until use. c. The amount of TPM THC Oil added to the gelatin mixture will determine the amount of THC (mg) per gummy (Tables 3 and 4). d. The volume of the TPM THC Oil that is manufactured can be scaled up / down depending on the amount required (i.e.. batch size / gummy size). Calculate the required amount of TPM THC oil required prior to manufacturing.

[0181] 2. Formulation: a. Cut the gelatin puck into small pieces and place in a beaker. For reference, each individual puck weighs -100g. b. Place the beaker in a water bath at 70°C until the gelatin puck melts. c. Once molten, add the required amount (by weight) of molten TPM THC oil at 70°C to the gummy base and mix well using a glass stirring rod for 2-5 minutes. Example amounts of oil are provided below in Tables 3 and 4. d. Pour the base into molds and allow to cool / cure. Table 3. Amounts required for 3g gummies. Amounts can be scaled up or down for a given batch size. The examples below assume the mixture is used to make ~40 x 3g gummies.

[0182] Table 4. Amounts required for 4g gummies. Amounts can be scaled up or down for a given batch size. The examples below assume the mixture is used to make ~30 x 4g gummies.

[0183] Example 2 - Cannabinoid formulations

[0184] The following cannabinoid formulations were manufactured A. 1 :1 mass ratio of TPM:THC; 140mg MCT oil; volume gummy 3.5mL; THC 2.5mg

[0185] B. 1 :1 mass ratio of TPM:THC; 140mg MCT oil; volume gummy 3.5mL; THC 5mg

[0186] C. 1 :1 mass ratio of TPM:THC; 140mg MCT oil; volume gummy 3.5mL; THC 10mg

[0187] D. 2:1 mass ratio of TPM:THC; 140mg MCT oil; volume gummy 3.5mL; THC 5mg E. 2:1 :1 mass ratio of TPM:THC:MCT ; 5mg MCT oil; volume gummy 3.5mL; THC 5mg

[0188] F. 2:1 :1 mass ratio of TPM:THC:LCT (corn oil); 5mg LCT oil; volume gummy 3.5mL; THC 5mg G. 4:1 :1 :8 mass ratio of TPM:THC:MCT:ethanol; 5mg MCT oil; volume gummy 3.5mL; THC 5mg

[0189] H. 4:1 :1 :8 mass ratio of TPM:THC:MCT:ethanol; 2.5mg MCT oil; volume gummy 3.5mL; THC 2.5mg

[0190] L 4:1 :1 :8 mass ratio of TPM:THC:MCT:ethanol; 1 mg MCT oil; volume gummy 3.5mL; THC 1 mg / ml

[0191] Example 3 - Assessment of cannabinoid formulations

[0192] Gummies were subjectively assessed for the kinetics and strength of effect using gummies including THC. Subjects were asked to consume the gummies at night, approximately 30 minutes after their evening meal. Subjects monitored the time course of effect using a timer on their smart phone and recorded notes with respect to the subjective sensation (nausea, dizzyness, euphoria, etc) and perceived strength of the various gummies relative to each other.

[0193] Example 4 - Results - onset

Claims

Claims1 . A formulation comprising:-a cannabinoid component comprising:- a cannabinoid;- a tocopheryl phosphate component comprising:- mono-(tocopheryl) phosphate (herein TP) and di-(tocopheryl) phosphate (herein T2P); an oil component comprising: an oil that may dissolve or be miscible with the cannabinoid and tocopheryl phosphate components; wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio enabling rapid absorption of the cannabinoid component.

2. The formulation of claim 1 wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component to oil component of about 5:1 to 1 :5.

3. The formulation of any one of the preceding claims wherein the tocopheryl phosphate component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component to oil component of about 2:1 to 4:1 , preferably 4:1.

4. The formulation of any one of the preceding claims wherein the tocopheryl phosphate component and cannabinoid component are provided in the formulation in a mass ratio of tocopheryl phosphate component to cannabinoid component of about 5:1 to 1 :5.

5. The formulation of any one of the preceding claims wherein the tocopheryl phosphate component and cannabinoid component are provided in the formulation in a mass ratio of tocopheryl phosphate component to cannabinoid component of about 2:1 to 4:1 , preferably 4:1 .

6. The formulation of any one of the preceding claims wherein the tocopheryl phosphate component, cannabinoid component, and oil component are provided inthe formulation in a mass ratio of tocopheryl phosphate component to cannabinoid component to oil component of from 1 :1 :1 to 5:1 :1 .

7. The formulation of any one of the preceding claims wherein the tocopheryl phosphate component, cannabinoid component and oil component are provided in the formulation in a mass ratio of tocopheryl phosphate component to cannabinoid component to oil component of from 2:1 :1 to 4:1 :1 , preferably 4:1 :1 .

8. The formulation of any one of the preceding claims further comprising an alcohol for facilitating solubility of the tocopheryl phosphate component and oil component.

9. The formulation of claim 8 wherein the alcohol and tocopheryl phosphate component are provided in the formulation in a mass ratio of alcohol to tocopheryl phosphate component of 2:1 .

10. The formulation of any one of claims 8 and 9 wherein the tocopheryl phosphate component, cannabinoid component, oil component and alcohol are provided in the formulation in a mass ratio of tocopheryl phosphate component to cannabinoid component to oil component to alcohol of 4:1 :1 :8.11 .The formulation of any one of the preceding claims wherein the mass ratio of TP to T2P in the tocopheryl phosphate component is about 2:1 .

12. The formulation of any one of the preceding claims wherein the cannabinoid component comprises cannabinoid in amount of about 1 to 333 mg / g, preferably 1 to 250 mg / g, or 50 to 200 mg / g, or about 75 mg / g, or 1 to 50 mg / g of the cannabinoid formulation13. The formulation of any one of the preceding claims wherein the cannabinoid component comprises cannabidiol (CBD) or tetrahydrocannabinol (THC).

14. The formulation of claim 13 wherein the cannabinoid component comprises THC.

15. The formulation of any one of the preceding claims wherein the oil component comprises medium chain triglyceride (herein MCT), preferably a naturally occurring MCT extract or oil, more preferably a naturally occurring MCT extract or oil that comprises linear or branched alkyl chains comprising no more than about 12 carbon atoms.

16. The formulation of claim 8 wherein the alcohol is ethanol.

17. A dosage unit comprising:- a formulation of any one of the preceding claims;- a base for use in a composition for sublingual or buccal administration of a compound.

18. The dosage unit of claim 17 wherein the dosage unit comprises a cannabinoid in an amount of 1 to 200mg of cannabinoid / dosage unit, or 1 to 50mg of cannabinoid / dosage unit, or 1 to 30mg of cannabinoid / dosage unit.

19. The dosage unit of claim 17 or 18 wherein the tocopheryl phosphate component, cannabinoid component and oil component comprise from 0.1 to 4.0% by weight of the base.

20. The dosage unit of claim 19 wherein the tocopheryl phosphate component, cannabinoid component and oil component comprise 0.1 to 1 .5% by weight of the base.21 .The dosage unit of any one of claims 17 to 20 wherein the base comprises gelatin or pectin.

22. The dosage unit of any one of claims 17 to 21 wherein the dosage unit is provided in the form of a gummie or lozenge.

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