Oral cannabinoid preparations containing tocopheryl phosphate and long-chain triglycerides or long-chain fatty acids

Abstract

The present invention relates to an oral cannabinoid formulation comprising a cannabinoid component and a tocopheryl phosphate component, wherein the cannabinoid component comprises a cannabinoid and a carrier in the form of a long-chain triglyceride (LCT) or a long-chain fatty acid (LCFA), the tocopheryl phosphate component comprises mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), and the mass ratio of the cannabinoid to the tocopheryl phosphate component is between about 10:1 and 1:10.

Description

Technical Field

[0001] The present invention relates to an oral cannabinoid formulation.

Background Art

[0002] Cannabinoids have been proposed to be used in various conditions such as pain, inflammation, anxiety, depression, insomnia, sleep disorders, lack of energy, reduced arousal, weight gain, obesity, diabetes, metabolic syndrome, nausea (acute nausea or anticipatory nausea), epilepsy, convulsions, schizophrenia, bipolar disorder, cancer and tumor formation, chronic pain, pain due to osteoarthritis, bacterial and / or fungal infections, fibromyalgia, increased appetite and / or decreased appetite.

[0003] In some of these conditions, it is preferred to administer cannabinoids via the oral administration route.

[0004] One problem with oral cannabinoid formulations is that absorption tends to be sub-optimal, with characteristics such that at a specific dose, bioavailability, cMax, tMax, absorption duration, and / or the area under the plasma drug concentration-time curve (AUC) are sub-optimal.

[0005] The reasons for sub-optimal bioavailability are thought to be the low solubility and absorbability of cannabinoids in the stomach and / or the fact that orally administered oral cannabinoid formulations are subject to first-pass metabolism or second-pass metabolism.

[0006] In US Patent Publication No. 2019015329(A), an oil-in-water emulsion formulation has been studied, and by using a surfactant, which is a main component, in an amount of 1 to 30% w / w based on the whole emulsion formulation, a dispersion in which a hydrophobic phase containing an active agent is stably dispersed in water is formed in the presence of tocopherol phosphate.

[0007] U.S. Patent Publication 2006281716(A) describes an alkaloid formulation containing a reaction product of one or more alkaloids and one or more phosphate derivatives of one or more electron transport agents.

[0008] U.S. Patent Publication 2015110924(A) describes a composition comprising recombinant dietary starch and one or more nonpolar compounds. Depending on the context, this composition may include a water-soluble derivative of a vitamin E mixture, which contains a relatively high concentration of a dimerized form of a PEG derivative of vitamin E.

[0009] U.S. Patent Publication 2021260143(A) describes an oil-in-water microemulsion containing a water-soluble pharmaceutical composition designed to prepare a medium-chain triglyceride-based oil phase in an underwater microemulsion. This water-soluble pharmaceutical composition uses sucrose ester as an emulsifier and lecithin as a coemulsifier.

[0010] WO21046628(A1) describes a cannabidiol composition for use in oral delivery, which comprises synthetic cannabidiol (CBD) of at least 99.8% purity and β-caryophyllene (BCP) acting as a solvent and antioxidant. This cannabidiol composition further comprises at least one other lipophilic solvent (e.g., medium-chain triglycerides (MCT) and coconut oil) and at least one other antioxidant (e.g., α-tocopherol (vitamin E)).

[0011] U.S. Patent Publication 2021069103(A) describes a self-emulsifying drug delivery system for oral delivery of cannabinoids. To improve the solubility, stability, and bioavailability of the cannabinoids, the cannabinoids are dissolved in an oily medium (e.g., a medium-chain triglyceride) along with at least one surfactant.

[0012] U.S. Patent Publication No. 2021046438(A) describes a nanoemulsion material of cannabidiol (CBD) and a method for processing the same, the nanoemulsion material comprising a formulation containing at least lecithin or lecithin mixture, one or more carrier oils, and TPGS derived from sunflower or soy as vitamin E.

[0013] U.S. Patent Publication No. 2020129463(A) describes cannabidiol, β-hydroxybutyric acid, and related compounds for the purpose of improving health conditions, including amino acids, short-chain fatty acids, short-chain triglycerides, medium-chain fatty acids, medium-chain triglycerides, long-chain fatty acids, long-chain triglycerides, berberine, berberine metabolites (e.g., dihydroberberine), and / or combinations thereof.

[0014] U.S. Patent Publication 2020138772(A) describes a formulation containing a stable aqueous emulsion of refined cannabis oil and the use of this formulation in the treatment of a disease. This aqueous emulsion contains a) CBD and THC with a weight ratio of 1,050:1 to 1:1,050, and b) poloxamer 188, polysorbate 80, polysorbate 20, vitamin E-TPGS (TPGS), TPGS-1000, TPGS-750-M, Solutol HS 15, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-8 glyceryl caprylate / caprate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, polysorbate 85, polyglyceryl-6-dioleate, sorbitan monooleate, Capmul MCM, and Maisine. 35-1 comprises at least one emulsifier selected from the group consisting of glyceryl monooleate, glyceryl monolinoleate, PEG-6 glyceryl oleate, PEG-6 glyceryl linoleate, oleic acid, linoleic acid, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyglyceryl-3 diisostearate, lecithin with added bile salts, lecithin without added bile salts, and mixtures thereof.

[0015] Chinese Patent Publication No. 110638756(A) describes a preparation made from 0.1 to 10 parts by weight of cannabidiol, 5 to 15 parts by weight of medium-chain triglycerides (MCT), 1 to 15 parts by weight of soy lecithin, 1 to 20 parts by weight of γ-cyclodextrin, 10 to 20 parts by weight of glycerol-10 stearate, 10 to 45 parts by weight of glycerol, and the remainder being distilled water. According to the preparation method described in this patent document, cannabidiol is prepared into a highly stable preparation using nanoencapsulation technology.

[0016] U.S. Patent Publication 2019104750(A) explores the preparation of emulsified or blended oils by emulsifying oils selected from coconut oil, coconut blend oils with a high MCT content (e.g., LouAna® Liquid Coconut Oil), pure MCT oil, and omega-3 oils. The emulsification of these oils and / or blended oils may be carried out using an emulsifier, which may be selected from sunflower lecithin, sodium stearoyl lactylate (SSL), and a combination of sunflower lecithin and SSL.

[0017] U.S. Patent Publication 2007104741(A) describes a self-emulsifying drug delivery system for improving the solubility, stability, and bioavailability of dronabinol and other cannabinoid drug compounds. These drug compounds are dissolved in an oily medium (e.g., triglycerides and / or mixed glycerides and / or free fatty acids, including medium-chain saturated free fatty acids, long-chain saturated free fatty acids, monounsaturated free fatty acids, and / or polyunsaturated free fatty acids) along with at least one surfactant. The surfactant promotes self-emulsification, thereby facilitating the delivery of chylomicrons targeting the mammalian intestinal lumen and achieving optimal bioavailability in the mammalian intestinal lumen.

[0018] U.S. Patent Publication 2002107265(A) describes an oil-in-water pharmaceutical emulsion for the delivery of a multifunctional active ingredient. This emulsion comprises an aqueous phase, an emulsifier, and an oil phase, the oil phase comprising structured triglycerides substantially free of triglycerides having three C6-C12 fatty acid moieties, or a combination of long-chain triglycerides and a polarity modifier to increase polarity.

[0019] U.S. Patent Publication 2009005348(A) describes a method for modulating one or more immunomodulatory cytokines, such as pro-inflammatory cytokines and / or anti-inflammatory cytokines, comprising administering a therapeutically effective amount of one or more phosphate derivatives or complexes of one or more hydroxychromans.

[0020] U.S. Patent Publication 2009239827(A) describes a therapeutic method for lowering blood levels of lipids selected from the group including LDL cholesterol, triglycerides, total cholesterol, and mixtures thereof, the method comprising the step of administering an effective amount of one or more phosphate derivatives of one or more electron transport agents.

[0021] U.S. Patent Publication 2009233881(A) describes a method for alleviating symptoms or treating or preventing cancer, comprising administering a pharmaceutical formulation containing an effective amount of one or more phosphate derivatives of one or more hydroxychromans selected from the group consisting of 7,8-dimethyl-6-hydroxychroman, 8-methyl-6-hydroxychroman, and mixtures thereof, to a subject with cancer or at risk of developing cancer.

[0022] U.S. Patent Publication 2009004166(A) describes a carrier for use in the intestinal administration of bioactive compounds, the carrier comprising an effective amount of one or more phosphate derivatives of one or more electron transport agents.

[0023] In US Patent Publication No. 2006 / 241085 (A), a method for suppressing the occurrence of one or more of monocyte / macrophage proliferation, smooth muscle cell proliferation, CD36 receptor expression, and oxidized LDL uptake, the method comprising administering an effective amount of one or more phosphate derivatives of one or more electron transfer agents, has been considered.

[0024] In US Patent Publication No. 2006 / 257459 (A), a method for improving the effectiveness and / or transdermal transport of topically administered pharmaceuticals and pharmacologically active compounds, the method comprising incorporating a pharmaceutical or pharmacologically active compound into a carrier comprising an effective amount of one or more complexes of a pharmaceutically acceptable lipophilic compound's phosphate derivative, has been considered.

[0025] In US Patent Publication No. 2005 / 009787 (A), nutritional supplements or health supplements have been considered, and these nutritional supplements or health supplements contain an effective amount of micronutrients selected from the group consisting of phosphate derivatives of tocopherol, phosphate derivatives of ubiquinol, phosphate derivatives of ascorbic acid, phosphate derivatives of tocotrienol, phosphate derivatives of retinol, and mixtures thereof, and these micronutrients are delivered by an acceptable carrier.

[0026] There is a need for an oral cannabinoid formulation with improved bioavailability of cannabinoids.

Summary of the Invention

Means for Solving the Problems

[0027] The present invention relates to an oral cannabinoid formulation; the use of an oral cannabinoid formulation for improving the bioavailability of cannabinoids in an individual who needs cannabinoids; the use of an oral cannabinoid formulation for treating a condition; and a method for manufacturing an oral cannabinoid formulation.

[0028] In this specification, various embodiments of the present invention are described (enumeratively). The features specifically described in each embodiment may be combined with the other specifically described features to provide further embodiments of the present disclosure.

[0029] Embodiment 1: An oral cannabinoid formulation, preferably an oral cannabinoid liquid formulation, more preferably an oral cannabinoid liquid oil formulation, comprising a cannabinoid component, a tocopheryl phosphate component, and an aqueous component as an optional component; wherein the cannabinoid component comprises a cannabinoid and a carrier; the cannabinoid is preferably a synthetic cannabinoid, more preferably synthetic cannabidiol (referred to as CBD in this specification) and / or synthetic tetrahydrocannabinol (referred to as THC in this specification), and the content of the cannabinoid in the oral cannabinoid formulation is at a concentration of about 1 - 250 mg / ml or 10 - 250 mg / ml with respect to the whole oral cannabinoid formulation; the carrier is in the form of long-chain triglycerides (referred to as LCT in this specification) or long-chain fatty acids (referred to as LCFA in this specification), preferably an extract or oil of naturally derived LCT or LCFA, more preferably an extract or oil of naturally derived LCT or LCFA containing a straight-chain or branched-chain alkyl chain having 13 or more carbon atoms; Preferably, the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract has an increased relative amount of one or more straight-chain or branched-chain alkyl chains having 13 or more carbon atoms after purification or fractionation; Preferably, the mass ratio of the cannabinoid to the carrier is about 1:3 to about 1:1000, about 1:3 to about 1:500, or about 1:3 to about 1:100; The tocopheryl phosphate component comprises mono(tocopheryl) phosphate (referred to as TP herein) and di(tocopheryl) phosphate (referred to as T2P herein), and optionally includes a solvent that increases the solubility of the tocopheryl phosphate component; Preferably, the mass ratio of TP to T2P is about 6:4 to 8:2, preferably about 2:1; Preferably, the TP and the T2P are added to the formulation as acidic tocopheryl phosphate; The mass ratio of the cannabinoid to the tocopheryl phosphate component is about 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2. The formulation may be provided in the form of multiple dosage units suitable for oral administration, each dosage unit containing approximately 1 to 250 mg or approximately 10 to 250 mg of cannabinoids; and Preferably, the oral cannabinoid preparation does not contain dronabinol, does not contain surfactants, or contains less than 1% by weight of alcohol. A formulation characterized by the following.

[0030] Embodiment 2: A method for producing an oral cannabinoid formulation which may contain an aqueous component, preferably an oral cannabinoid liquid formulation, more preferably an oral cannabinoid liquid oil formulation, The process includes a step of combining a tocopheryl phosphate component and a cannabinoid component to produce an oral cannabinoid preparation containing the cannabinoid and the tocopheryl phosphate component in a mass ratio of approximately 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2; The tocopheryl phosphate component comprises mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), and an optional solvent that increases the solubility of the tocopheryl phosphate component, wherein the mass ratio of TP to T2P is preferably about 6:4 to 8:2, preferably 2:1, and the TP and T2P are preferably added to the formulation as acidic tocopheryl phosphate; The cannabinoid component comprises a cannabinoid and a carrier in the form of a long-chain triglyceride (LCT) or long-chain fatty acid (LCFA); The cannabinoid is preferably a synthetic cannabinoid, more preferably synthetic cannabidiol (CBD) and / or synthetic tetrahydrocannabinol (THC), and the cannabinoid content in the oral cannabinoid preparation is at a concentration of about 1 to 250 mg / ml or 10 to 250 mg / ml relative to the entire oral cannabinoid preparation; The carrier in the form of LCT or LCFA is preferably an extract or oil of naturally derived LCT or LCFA, and more preferably an extract or oil of naturally derived LCT or LCFA containing a linear or branched alkyl chain having 13 or more carbon atoms; Preferably, the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract has been purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms; Preferably, the mass ratio of the cannabinoid to the carrier is 1:3 to about 1:1000, about 1:3 to about 1:500, or about 1:3 to about 1:100; and Preferably, the oral cannabinoid preparation does not contain dronabinol, does not contain surfactants, or contains less than 1% by weight of alcohol. A method characterized by the following.

[0031] Embodiment 3: A kit for manufacturing the oral cannabinoid preparation described in Embodiment 1, The component comprises a tocopheryl phosphate component, instructions for using the tocopheryl phosphate component in the method of Embodiment 2, and a cannabinoid component as an optional component; The tocopheryl phosphate component comprises mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), and an optional solvent that reduces the viscosity of the tocopheryl phosphate component, wherein the mass ratio of TP to T2P is preferably about 6:4 to 8:2, preferably 2:1, and the TP and T2P are preferably added to the formulation as acidic tocopheryl phosphate; The cannabinoid component as the optional component comprises a cannabinoid, preferably a synthetic cannabinoid, more preferably synthetic cannabidiol (CBD) and / or synthetic tetrahydrocannabinol (THC), and the content of the cannabinoid in the oral cannabinoid preparation is at a concentration of about 1 to 250 mg / ml or about 10 to 250 mg / ml relative to the entire oral cannabinoid preparation; and In the aforementioned kit, the cannabinoid component as the optional component and the tocopheryl phosphate component are either included separately, or the cannabinoid component as the optional component and the tocopheryl phosphate component are included in a mixture. A kit featuring the following characteristics.

[0032] The kit described in Embodiment 3 may further include, separately from the tocopheryl phosphate component, a cannabinoid component as an optional component and a carrier in the form of LCT or LCFA, wherein the carrier in the form of LCT or LCFA is preferably an extract or oil of naturally derived LCT or LCFA, more preferably an extract or oil of naturally derived LCT or LCFA containing a linear or branched alkyl chain having 13 or more carbon atoms, wherein the LCT or LCFA is a naturally derived oil or extract, and wherein the naturally derived oil or extract has been purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms.

[0033] Embodiment 4: An oral cannabinoid preparation, preferably an oral cannabinoid liquid preparation, more preferably an oral cannabinoid liquid oil preparation, It comprises a cannabinoid component, a tocopheryl phosphate component, and an aqueous component as an optional component; The cannabinoid component comprises a cannabinoid and a carrier; The cannabinoid is preferably a synthetic cannabinoid, more preferably synthetic cannabidiol (CBD) and / or synthetic tetrahydrocannabinol (THC), and the cannabinoid content in the oral cannabinoid preparation is at a concentration of about 1 to 250 mg / ml or about 10 to 250 mg / ml relative to the entire oral cannabinoid preparation; The carrier comprises long-chain triglycerides (LCTs) or long-chain fatty acids (LCFAs) and medium-chain triglycerides (MCTs); The LCT or LCFA is preferably an extract or oil of naturally derived LCT or LCFA, and more preferably an extract or oil of naturally derived LCT or LCFA containing a linear or branched alkyl chain having 13 or more carbon atoms; Preferably, the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract has been purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms; The MCT is preferably a naturally derived MCT extract or oil, and more preferably a naturally derived MCT extract or oil containing a linear or branched alkyl chain with 12 or fewer carbon atoms; The ratio of the LCT or LCFA to the MCT is 1:3 to 3:1, preferably 1:1; Preferably, the mass ratio of the cannabinoid to the carrier is about 1:3 to about 1:1000, about 1:3 to about 1:500, or about 1:3 to about 1:100; The tocopheryl phosphate component comprises mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), and an optional solvent that increases the solubility of the tocopheryl phosphate component; The mass ratio of TP to T2P is approximately 6:4 to 8:2, preferably approximately 2:1; Preferably, the TP and the T2P are added to the formulation as acidic tocopheryl phosphate; The mass ratio of the cannabinoid to the tocopheryl phosphate component is about 10:1 to 1:10, preferably 5:1 to 1:5, more preferably 2:1 to 1:2; and The formulation may be provided in the form of multiple dosage units suitable for oral administration, each dosage unit containing approximately 1 to 250 mg or approximately 10 to 250 mg of cannabinoids. A formulation characterized by the following.

[0034] Embodiment 5: An oral cannabinoid preparation, preferably an oral cannabinoid liquid preparation, more preferably an oral cannabinoid liquid oil preparation, It comprises a cannabinoid component, a tocopheryl phosphate component, and an aqueous component as an optional component; The cannabinoid component comprises a cannabinoid and a carrier in the form of a long-chain triglyceride (LCT) or long-chain fatty acid (LCFA); The cannabinoid is preferably a synthetic cannabinoid, more preferably synthetic cannabidiol (CBD) and / or synthetic tetrahydrocannabinol (THC), and the cannabinoid content in the oral cannabinoid preparation is at a concentration of about 1 to 250 mg / ml or about 10 to 250 mg / ml relative to the entire oral cannabinoid preparation; The carrier in the form of LCT or LCFA is preferably an extract or oil of naturally derived LCT or LCFA, and more preferably an extract or oil of naturally derived LCT or LCFA containing a linear or branched alkyl chain having 13 or more carbon atoms; Preferably, the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract has been purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms; Preferably, the mass ratio of the cannabinoid to the carrier is 1:3 to about 1:1000, about 1:3 to about 1:500, or about 1:3 to about 1:100; The tocopheryl phosphate component comprises mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), and an optional solvent that increases the solubility of the tocopheryl phosphate component; The mass ratio of TP to T2P is approximately 6:4 to 8:2, preferably approximately 2:1; Preferably, the TP and the T2P are added to the formulation as acidic tocopheryl phosphate; The mass ratio of the LCT or LCFA to the tocopheryl phosphate component is 5:1 to 250:1. The mass ratio of the cannabinoid to the tocopheryl phosphate component is about 10:1 to 1:10, preferably 5:1 to 1:5, more preferably 2:1 to 1:2; and The formulation may be provided in the form of multiple dosage units suitable for oral administration, each dosage unit containing approximately 1 to 250 mg or approximately 10 to 250 mg of cannabinoids. A formulation characterized by the following.

[0035] Embodiment 6: It is a cannabinoid oil, Cannabinoids and Tocopheryl phosphate components in the form of mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), Long-chain triglycerides (LCTs) or long-chain fatty acids (LCFAs), Medium-chain triglycerides (MCTs) as optional components and Includes, Preferably, the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract has been purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms; The amount of LCT or LCFA in the cannabinoid oil is such that the cMax of the cannabinoid increases in an individual who receives the cannabinoid oil orally, compared to when an individual receives a cannabinoid oil containing the tocopheryl phosphate component but without LCT or LCFA orally; Preferably, the mass ratio of LCT or LCFA to tocopheryl phosphate in the cannabinoid oil is 5:1 to 250:1; and The mass ratio of the LCT or LCFA to the MCT may be 1:1. Cannabinoid oil characterized by [this feature].

[0036] Embodiment 7: It is a cannabinoid oil, Cannabinoids and Tocopheryl phosphate components in the form of mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), Long-chain triglycerides (LCTs) or long-chain fatty acids (LCFAs), Medium-chain triglycerides (MCTs) as optional components and Includes, Preferably, the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract has been purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms; The amount of LCT or LCFA in the cannabinoid oil is such that the area under the plasma drug concentration-time curve (AUC) of the cannabinoid increases in an individual who receives the cannabinoid oil orally, compared to when an individual receives a cannabinoid oil containing the tocopheryl phosphate component but without LCT or LCFA orally. Preferably, the mass ratio of LCT or LCFA to tocopheryl phosphate in the cannabinoid oil is 5:1 to 250:1; and The mass ratio of the LCT or LCFA to the MCT may be 1:1. Cannabinoid oil characterized by [this feature].

[0037] Embodiment 8: A capsule for oral administration, It contains cannabinoid oil and hydrogel, The cannabinoid oil comprises a cannabinoid, a tocopheryl phosphate component in the form of mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), and an optional further component selected from the group consisting of emulsifiers, buffers, aqueous solvents, antioxidants, and flow improvers; The cannabinoid is preferably a synthetic cannabinoid, more preferably synthetic cannabidiol (CBD) and / or synthetic tetrahydrocannabinol (THC), and the cannabinoid content in the capsule is about 1 to 250 mg or about 10 to 250 mg; The cannabinoid is contained in a carrier in the form of LCT or LCFA, wherein the LCT or LCFA is preferably an extract or oil of naturally derived LCT or LCFA, and more preferably an extract or oil of naturally derived LCT or LCFA containing a linear or branched alkyl chain having 13 or more carbon atoms; Preferably, the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract has been purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms; Preferably, the carrier further comprises medium-chain triglycerides (MCTs); Preferably, the mass ratio of the LCT or LCFA to the MCT is 1:3 to 3:1, and more preferably 1:1; Preferably, the mass ratio of TP to T2P is about 6:4 to 8:2, preferably about 2:1, and the TP and T2P are preferably added to the capsule as acidic tocopheryl phosphate; The mass ratio of the cannabinoid to the tocopheryl phosphate is about 10:1 to 1:10, preferably 5:1 to 1:5, more preferably 2:1 to 1:2; and The hydrogel is preferably gelatin for encapsulating cannabinoid oil. A capsule formulation characterized by the following:

[0038] Embodiment 9: A method for providing cannabinoids to an individual to achieve a specific plasma concentration, The process includes the step of orally administering the therapeutic formulation described in any of Embodiments 1 and 4 to 8 to an individual, Oral administration of the therapeutic formulation results in a plasma cannabinoid concentration in the individual that is higher than the plasma cannabinoid concentration obtained by oral administration of the control formulation; and The control formulation is the same as the therapeutic formulation except that it does not contain the tocopheryl phosphate component. A method characterized by the following.

[0039] Embodiment 10: A method for extending the duration of therapeutically effective plasma cannabinoid concentrations in the plasma of an individual, The process includes the step of orally administering the therapeutic formulation described in any of Embodiments 1 and 4 to 8 to an individual, The duration of therapeutically effective plasma cannabinoid concentrations in the plasma of an individual who has been orally administered the therapeutic formulation is longer than the duration of therapeutically effective plasma cannabinoid concentrations obtained by oral administration of the control formulation; and The control formulation is the same as the therapeutic formulation except that it does not contain the tocopheryl phosphate component. A method characterized by the following.

[0040] Embodiment 11: A method for treating a condition in an individual, The process includes administering a therapeutically effective dose of the cannabinoid preparation described in Embodiment 1 or 4-8 orally. Preferably, the method is characterized in that the condition is selected from the group consisting of conditions such as pain, inflammation, anxiety, depression, insomnia, sleep disorders, lack of energy, decreased alertness, weight gain, obesity, diabetes, metabolic syndrome, nausea (acute or anticipatory nausea), epilepsy, spasticity, schizophrenia, bipolar disorder, cancer and tumor formation, chronic pain, pain due to osteoarthritis, bacterial and / or fungal infections, fibromyalgia, increased appetite and / or decreased appetite.

[0041] Embodiment 12: An oral cannabinoid preparation according to Embodiment 1 or 4-8 for use in the prevention or treatment of a condition in an individual, Preferably, the condition is selected from the group consisting of conditions such as pain, inflammation, anxiety, depression, insomnia, sleep disorders, lack of energy, decreased alertness, weight gain, obesity, diabetes, metabolic syndrome, nausea (acute or anticipatory nausea), epilepsy, spasticity, schizophrenia, bipolar disorder, cancer and tumor formation, chronic pain, pain due to osteoarthritis, bacterial and / or fungal infections, fibromyalgia, increased appetite and / or decreased appetite; and The formulation is preferably characterized in that it contains a therapeutically effective amount of the cannabinoid formulation described in Embodiment 1 or 4 to 8.

[0042] Embodiment 13: A method for increasing the cMax or AUC of cannabinoids in an individual, The process includes orally administering a cannabinoid formulation according to any one of embodiments 1 and 4-8 to an individual requiring an increase in the cMax or AUC of a cannabinoid, A method characterized in that the cMax or AUC of cannabinoids in individuals orally administered the formulation described in Embodiment 1 or 4-8 increases compared to the cMax or AUC of cannabinoids when a cannabinoid formulation according to the above embodiment that does not contain long-chain triglycerides (LCTs) or tocopheryl phosphate components is orally administered. [Brief explanation of the drawing]

[0043] [Figure 1] This shows the solubilization of CBD when a carrier oil (MCT, LCT / LCFA, or a mixture of MCT and LCT / LCFA) is digested in vitro in fasted artificial intestinal fluid (pH 6.5). The total lipid content was 110 mg (100 mg of carrier oil + 10 mg of CBD). Data are shown as mean ± SD, with n=3. A. Shows the concentration of CBD (mg) during the digestion process when MCT is used as the carrier oil. B. Shows the concentration of CBD (mg) during the digestion process when LCT / LCFA (Maisine CC) is used as the carrier oil. C. Shows the concentration of CBD (mg) during the digestion process when a mixture of MCT and LCT / LCFA (Maisine CC) is used as the carrier oil. [Figure 2] This shows the solubilization of CBD when a carrier oil (MCT, LCT / LCFA, or a mixture of MCT and LCT / LCFA) is digested in vitro in an empty intestinal fluid in the presence of a mixture of mono(tocopheryl) phosphate and di(tocopheryl) phosphate (TPM). The total lipid content was 110 mg (80-90 mg of carrier oil + 10 mg of CBD + 10-20 mg of TPM). Data are shown as mean ± SD, with n=3. A. Shows the concentration of CBD (mg) during the digestion process when MCT is used as the carrier oil in the presence of TPM. B. Shows the concentration of CBD (mg) during the digestion process when LCT / LCFA (Maisine CC) is used as the carrier oil in the presence of TPM. C. Shows the concentration of CBD (mg) during the digestion process when a mixture of MCT and LCT / LCFA (Maisine CC) is used as the carrier oil in the presence of TPM. [Figure 3]This shows the solubilization of CBD when a carrier oil (MCT, LCT / LCFA, or a mixture of MCT and LCT / LCFA) is digested in vitro in fasted artificial intestinal fluid (pH 6.5) in the presence of TPM. The total lipid content was 110 mg (80-90 mg of carrier oil + 10 mg of CBD + 10-20 mg of TPM). Data are shown as mean ± SD, with n=3. A. Shows the concentration of CBD (mg) during the digestion process when a mixture of MCT and LCT / LCFA in a ratio of 3:1 is used as the carrier oil in the presence of TPM. B. Shows the concentration of CBD (mg) during the digestion process when a mixture of MCT and LCT / LCFA in a ratio of 1:1 is used as the carrier oil in the presence of TPM. C. Shows the concentration of CBD (mg) during the digestion process when a mixture of MCT and LCT / LCFA in a ratio of 1:3 is used as the carrier oil in the presence of TPM. [Figure 4] This shows the in vitro solubility of CBD under simulated stomach conditions (0-30 minutes) and simulated intestinal conditions (30-90 minutes). Group 1: MCT only. Group 2: MCT with 50 mg / ml TPM added. Group 3: MCT with 100 mg / ml TPM added. Group 4: 1:1 mixture of MCT with 100 mg / ml TPM added and Maisine CC. Group 5: 1:1 mixture of MCT with 200 mg / ml TPM added and Maisine CC. [Figure 5] This shows the average Cmax of CBD after a single forced oral administration of a CBD-containing preparation. [Figure 6] This shows the average AUC of CBD after a single forced oral administration of a CBD-containing preparation. [Modes for carrying out the invention]

[0044] 1. Definition of Terms For the purposes of interpreting this specification, the following definitions are used, and where appropriate, singular terms include plural terms and plural terms include singular terms.

[0045] In this specification, the term "approximately" in relation to a numerical value X means the mean ± 10% unless otherwise specified.

[0046] In this specification, "pharmaceutically acceptable" means a non-toxic material that does not inhibit the efficacy of the biological activity of the active ingredient.

[0047] In this specification, “to treat,” “to treat,” or “treatment” with respect to a disease or disorder means, in one embodiment, the alleviation of the disease or disorder (i.e., delaying, preventing, or suppressing the onset of the disease or at least one of its clinical symptoms). In another embodiment, “to treat,” “to treat,” or “treatment” means the reduction or alleviation of at least one physical parameter, such as a physical parameter that may not be identifiable to the patient himself. In yet another embodiment, “to treat,” “to treat,” or “treatment” means the physical modification of a disease or disorder (e.g., stabilization of identifiable symptoms) or physiological modification (e.g., stabilization of physical parameters) or both. In this specification, for example, “to alleviate” or “alleviate” with respect to the symptoms of a condition means reducing at least one of the frequency and severity of the occurrence of the symptoms of the condition in the patient. In this specification, “method of treatment” or “method of treatment” means, in one embodiment, “method for treatment.”

[0048] In this specification, “therapeutic dose” refers to the amount of cannabinoid sufficient to achieve the effects described herein. Therefore, a therapeutic dose of cannabinoid is an amount sufficient to treat or prevent the condition in question.

[0049] A "treatment regimen" refers to a pattern of treatment for a disease, such as a pattern of medication used during the treatment of a disease or disorder.

[0050] In this specification, a subject or individual is a subject or individual that “needs” such treatment if such treatment provides a biological benefit, medical benefit or benefit in quality of life. An individual is generally a mammal, usually a human, and may be a pet, livestock or a performing animal.

[0051] The terms "include," "contains," and "included" are used in a comprehensive sense unless the context requires a different interpretation.

[0052] 2. Modes for carrying out the present invention 2.1 Formulation The present invention relates to an oral cannabinoid formulation, A cannabinoid component comprising a cannabinoid and a carrier in the form of a long-chain triglyceride (hereinafter referred to as LCT) or a long-chain fatty acid (hereinafter referred to as LCFA); A tocopheryl phosphate component comprising mono(tocopheryl) phosphate (referred to as TP herein) and di(tocopheryl) phosphate (referred to as T2P herein) Includes, The mass ratio of the cannabinoid to the tocopheryl phosphate component is approximately 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2. We provide a formulation characterized by the following.

[0053] Cannabinoids may be synthetic compounds or natural compounds, for example, plant-derived cannabinoids. Examples of neutral cannabinoids include cannabigerol (CBG) and related compounds (e.g., cannabigerol monomethyl ether, cannabigerovaline); cannabichromene (CBC) and related compounds (e.g., (±)-cannabichromene, (±)-cannabiclomevalin); (-)-cannabidiol (CBD) and related compounds (e.g., cannabidiol monomethyl ether, cannabidiol-C4, 20(-)-cannabidivaline, cannabidiorcol); and cannabinodiol (C BND) and related compounds (e.g., cannabinodivarin); Δ9-tetrahydrocannabinol (THC) and related compounds (e.g., Δ9-tetrahydrocannabinol-C4, Δ9-tetrahydrocannabivarin, Δ9-tetrahydro-cannabiorcol, (-)-Δ8-trans-(6aR,10aR)-Δ8-tetrahydrocannabinol, (-)-(6aS,10aR)-Δ9-tetrahydrocannabinol); cannabinol (CBN) and related compounds (e.g., cannabinodivarin); Cannabino-C4, cannabivarin, cannabinol-C2, cannabiorcol(25), cannabinol methyl ether; (±)-cannabinotriol (CBT) and related compounds (e.g., (-)-(9R,10R)-trans-10-O-ethyl-cannabinotriol, (±)-(9R,10R / 9S,10S)-cannabinotriol-C3); cannabiersoin (CBE) and related compounds (e.g., (5aS,6S,9R,9aR)-cannabiersoin, (5aS,6S,9R,9a (R)-C3-cannabielsoin, cannabiglendol-C3, dehydrocannabifuran, cannabifuran); isocannabinoids (e.g., (-)-Δ7-trans-(1R,3R,6R)-isotetrahydrocannabinol, (±)-Δ7-1,2-cis-(1R,3R,6S)-isotetrahydrocannabivarin, (±)-Δ7-1,2-cis-(1S,3S,6R)-isotetrahydrocannabivarin, (-)-Δ7-30-trans-(1R,3R,6R)-isotetrahydrocannabivarin);Examples include cannabicyclol (CBL) and its related compounds (e.g., (±)-(1aS,3aR,8bR,8cR)-cannabicyclol (CBL-C5), (±)-(1aS,3aR,8bR,8cR)-cannabicyclovaline); cannabicitran (CBT) and its related compounds; and cannabichromanone (CBCN) and its related compounds (e.g., cannabichromanone-C3, cannabicoumaronone). Acidic cannabinoids include cannabigerol acid A; cannabigerol acid A monomethyl ether; cannabigerovalic acid A; (±)-cannabichromenic acid A; (±)-cannabichromemevalic acid A; cannabidiolic acid; cannabidivalic acid; Δ9-tetrahydrocannabinolic acid A; Δ9-tetrahydrocannabinolic acid B; Δ9-tetrahydrocannabinolic acid C4 A; Δ9-tetrahydrocannabinolic acid C4 B; Δ9-tetrahydrocannabivaric acid A; Δ9-5-tetrahydrocannabiorcolic acid A; Δ9-tetrahydrocannabiorcolic acid Examples include B;(-)-Δ8-trans-(6aR,10aR)-tetrahydrocannabinolate A; cannabinolate A; (5aS,6S,9R,9aR)-cannabiellsonic acid A; (5aS,6S,9R,9aR)-cannabiellsonic acid B; (5aS,6S,9R,9aR)-C3-cannabiellsonic acid B; and (±)-(1aS,3aR,8bR,8cR)-cannabicycloalate A.

[0054] In one embodiment, the oral cannabinoid preparation of the present invention comprises a heterogeneous mixture of cannabinoid compounds. Preferably, the oral cannabinoid preparation of the present invention comprises at least cannabidiol (hereinafter referred to as CBD) and / or tetrahydrocannabinol (hereinafter referred to as THC).

[0055] Cannabinoids may be provided as extracts of naturally derived cannabinoid raw materials. More preferably, the extract may contain CBD and THC. Extracts of naturally derived cannabinoid raw materials may be obtained by extraction methods for plant-derived cannabinoids known to those skilled in the art, such as alcohol extraction, CO2 extraction, or other solvent-free extraction methods. The extract may also be in the form of an oil.

[0056] Cannabinoids may consist primarily of a single compound (e.g., CBD or THC) obtained by fractionating extracts of natural cannabinoid raw materials, or they may consist primarily of a single compound (e.g., CBD or THC) obtained by synthesizing cannabinoids.

[0057] The cannabinoid may be a synthetic cannabinoid such as dronabinol. In this embodiment, the oral cannabinoid formulation of the present invention may not contain a surfactant and may not contain an amount of alcohol exceeding about 1% by mass.

[0058] In one embodiment, the cannabinoid is provided as a racemic mixture (i.e., a mixture containing both the stereochemical isomers D and L) which can be obtained, for example, by extracting natural raw materials of cannabinoid.

[0059] In one embodiment, the cannabinoid component contains about 1 to 250 mg / ml, preferably 10 to 100 mg / ml, and preferably about 75 mg / ml of CBD relative to the total oral cannabinoid preparation.

[0060] In one embodiment, the cannabinoid component contains about 1 to 50 mg / ml, preferably about 20 to 40 mg / ml of THC.

[0061] The ratio of CBD to THC in the cannabinoid component of an oral cannabinoid preparation may be approximately 1:1, approximately 2:3, approximately 4:1, or approximately 1:20. In another embodiment, the ratio of CBD to THC may be 5:1 or 10:1.

[0062] In one embodiment, the cannabinoid component may further include other components commonly found in naturally derived cannabinoid products (e.g., terpenes).

[0063] As described herein, long-chain triglycerides appear to aid in the solubilization of tocopheryl phosphate components in oil, and improved solubilization of tocopheryl phosphate components was observed to improve the solubilization of cannabinoids in the gastrointestinal environment. Furthermore, improvements in the cMax and area under the plasma drug concentration-time curve (AUC) of oral cannabinoid oil formulations containing LCT or LCFA were observed in in vitro digestion models and in vivo studies. While we do not wish to be bound by any hypothesis, the improvement in cannabinoid cMax and AUC observed in this study may be due to improved solubilization of the total product (TPM) of mono(tocopheryl) and di(tocopheryl) phosphate mixture by the action of LCT or LCFA.

[0064] LCT or LCFA may be obtained from naturally derived raw materials or may be synthesized.

[0065] LCT or LCFA may be provided as an extract or oil of naturally derived LCT or LCFA.

[0066] LCTs or LCFAs typically contain linear or branched alkyl chains with 13 or more carbon atoms. The total number of carbon atoms in LCTs or LCFAs may be 28 or less.

[0067] In one embodiment, LCT or LCFA is a naturally derived oil or extract, which may have been refined or fractionated to increase the relative amount of linear or branched alkyl chains with 13 or more carbon atoms. For example, LCT or LCFA may be derived from vegetable oil, for example, from corn oil. The vegetable oil is a fractionated or other treated oil in which the amount of a predetermined fatty acid chain, such as an 18:1 fatty acid chain (oleic acid) or an 18:2 fatty acid chain (linoleic acid), has been increased compared to the vegetable oil before fractionation or other treatment. In a preferred embodiment, the fractionated or treated oil may consist of 18:1 and 18:2 carbon chain fatty acid chains, or 18:1 or 18:2 carbon chain fatty acid chains.

[0068] LCT or LCFA may consist of saturated fatty acid chains.

[0069] LCT or LCFA may contain one or more fatty acid chains selected from the group consisting of myristic acid, palmitic acid, arachidic acid, behenic acid, lignoceric acid, and serotic acid, or may consist of one or more fatty acid chains selected from this group.

[0070] LCT or LCFA may consist of unsaturated fatty acid chains, for example, fatty acid chains having one or more double bonds.

[0071] LCT or LCFA may contain one or more fatty acid chains selected from the group consisting of myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoleidic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid, or may consist of one or more fatty acid chains selected from this group.

[0072] LCT or LCFA may consist of a mixture of saturated and unsaturated fatty acid chains, with these fatty acid chains having at least 13 to less than 28 carbon atoms.

[0073] LCT or LCFA may consist of a mixture of triglycerides, diglycerides and monoglycerides, a mixture of triglycerides and monoglycerides, a mixture of triglycerides and diglycerides, a mixture of diglycerides and monoglycerides, triglycerides only, diglycerides only, or monoglycerides only. In a preferred embodiment, the LCT oil consists of triglycerides, diglycerides and monoglycerides containing fatty acid chains that are 18:1 carbon chains and 18:2 carbon chains, or consists of triglycerides, diglycerides and monoglycerides that are 18:1 carbon chains or 18:2 carbon chains.

[0074] LCT may be obtained from a distributor, and examples include Maisine CC, Peceol (C18:2), Gelucire 48 / 16, Labrafil M 1944 CS, Sterotex, BBS-C, sesame oil, and peanut oil, as described in the examples of this specification.

[0075] As described herein, in an in vitro gastrointestinal digestion model, carriers containing long-chain and medium-chain triglycerides were observed to increase the solubility of cannabinoids in the aqueous phase. Furthermore, in in vivo pharmacokinetic (pK) studies, improvements in the cMax and AUC of cannabinoids were observed in oil formulations containing LCT and MCT. While we do not wish to be bound by any hypothesis, as described in the embodiments herein, this improvement was attributed to the combination of LCT and MCT in the carrier oil component of the cannabinoid oil formulation.

[0076] Therefore, in one embodiment, the cannabinoid component may further include a carrier in the form of medium-chain triglycerides (MCTs). The MCTs may be obtained from naturally occurring MCT extracts or oils. Examples of naturally occurring MCT oils include palm kernel oil and coconut milk. Typically, MCTs contain linear or branched alkyl chains with about 12 or fewer carbon atoms. In this embodiment, the MCTs are provided in the form of a carrier oil in which the ratio of MCTs to LCTs is about 1:3 to 3:1, preferably 1:1.

[0077] The mass ratio of cannabinoid to carrier is approximately 1:3 to 1:1000, 1:3 to 1:500, or 1:3 to 1:100.

[0078] Tocopheryl phosphate is a phosphorylated tocopherol compound in which a covalent bond is formed between the oxygen atom (usually derived from the hydroxyl group) of the tocopherol compound and the phosphorus atom of the phosphate group (PO4).

[0079] The phosphorylated tocopherol compound may be a monophosphate ester, diphosphate ester, triester phosphate, monopyrophosphate ester, dipyrophosphate ester, salts or derivatives thereof, or mixtures thereof.

[0080] Examples of salts of tocopheryl phosphate include metal salts such as alkali metal salts and alkaline earth metal salts, such as sodium salt, magnesium salt, potassium salt, and calcium salt. Other pharmaceutically acceptable or veterinarily acceptable salts of tocopheryl phosphate may be used, such as other alkali metal salts. Other pharmaceutically acceptable salts are also well known in the art, including those detailed in SM Berge, et al., J. Pharmaceutical Sciences, 66:1-19, 1977. Sodium salt and potassium salt are particularly preferred.

[0081] Tocopheryl phosphate may be selected from, but is not limited to, mono(tocopheryl) phosphate, monosodium mono(tocopheryl) phosphate, disodium mono(tocopheryl) phosphate, di(tocopheryl) phosphate, monosodium di(tocopheryl) phosphate, and mixtures thereof.

[0082] Mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P) are preferably added to the formulation as acidic tocopheryl phosphates.

[0083] In certain embodiments, the compositions of the present invention include mixtures in which the mass ratio of TP to T2P is about 2:1, mixtures in which the mass ratio of TP to T2P is about 4:1 to about 1:4, or mixtures in which the mass ratio of TP to T2P is about 6:4 to about 8:2. In some embodiments, the mass ratio of TP to T2P is about 6:4 or about 8:2.

[0084] Furthermore, as described herein, the tocopheryl phosphate component may further include an organic solvent, such as an alcohol, preferably ethanol, that increases the solubility of the tocopheryl phosphate component in the cannabinoid component of the formulation.

[0085] Oral cannabinoid preparations may be in liquid, solid, or semi-solid form.

[0086] Oral cannabinoid preparations may further contain an aqueous component, which may be mixed with the aqueous component before oral administration. This aqueous component may be used to introduce a hydrophilic component (drug, additive) into the oral cannabinoid preparation, and this aqueous component may contain a buffer to adjust the pH.

[0087] If the oral cannabinoid preparation further contains an aqueous component, the oral cannabinoid preparation may exist as an emulsion, colloidal suspension, or two-phase solution.

[0088] In one embodiment, the oral cannabinoid preparation contains about 2.5% by weight or less of water.

[0089] Oral cannabinoid preparations may further contain ingredients such as thickeners, gelling agents, buffers, emollients, sweeteners, disintegrants, flavorings, pigments, electrolytes, pH adjusters, appearance enhancers, and sustained-release agents. Such additional ingredients may be added to the cannabinoid component or to the tocopheryl phosphate component at any step in the formulation process.

[0090] Oral cannabinoid preparations may be provided in the form of multiple dosage units suitable for oral administration.

[0091] Suitable dosage units for oral administration of the formulation may contain approximately 1-250 mg / ml or 10-250 mg / ml of cannabinoids.

[0092] The dosage unit may be a tablet, caplet, capsule, or liquid suitable for oral administration, and the liquid may be, for example, a syrup, suspension, or spray.

[0093] In one embodiment, the dosage unit is a "gummy candy." The gummy candy is also known as a "gummy candy" or "jelly sweet." The gummy candy may be a chewable confectionery made with gelatin. The gummy candy may not contain sugars or other sweeteners.

[0094] In a first embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBD (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0095] A second embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBD (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0096] A third embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBG (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0097] A fourth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBG (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0098] A fifth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBC (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0099] A sixth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBC (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0100] A seventh embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBN (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0101] An eighth embodiment of the cannabinoid oil formulation of the present invention is provided, which is a cannabinoid oil formulation for oral administration, comprising CBN (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0102] A ninth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBND (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0103] A tenth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBND (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0104] In an eleventh embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising THC (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0105] In a twelfth embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising THC (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0106] A thirteenth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising THCV (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0107] A fourteenth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising THCV (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0108] In a fifteenth embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBGA (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0109] A sixteenth embodiment of the cannabinoid oil formulation of the present invention provides a cannabinoid oil formulation for oral administration comprising CBGA (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0110] In a 17th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBT (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0111] In an eighteenth embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBT (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0112] In a 19th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBE (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0113] In a 20th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBE (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0114] In a 21st embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBL (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0115] In a 22nd embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBL (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0116] In a 23rd embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBCN (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0117] In a 24th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBCN (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0118] In a 25th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBDA (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0119] In a 26th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBDA (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0120] In a 27th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBDV (about 10% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 35% w / w), MCT (about 35% w / w), TPM (7.50% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0121] In a 28th embodiment of the cannabinoid oil formulation of the present invention, a cannabinoid oil formulation for oral administration is provided, comprising CBDV (about 1% w / w), refined or fractionated corn oil (i.e., LCT or LCFA) (about 42% w / w), MCT (about 42% w / w), TPM (about 2% w / w), tromethamine (about 1.40% w / w), water (about 2.5% w / w), lecithin (about 7.5% w / w), simethicone (about 0.02%), and butylated hydroxytoluene (about 0.2% w / w).

[0122] 2.2 Capsule Formulations In a first embodiment of the capsule formulation of the present invention, a capsule formulation, preferably a softgel capsule (also known as a "soft gelatin capsule"), is provided, comprising the cannabinoid oil formulation described in subheading 2.1.

[0123] A second embodiment of the capsule formulation of the present invention is a capsule formulation for oral administration, Cannabinoids, A carrier of the cannabinoid in the form of a long-chain triglyceride (LCT) or long-chain fatty acid (LCFA), Tocopheryl phosphate components in the forms of mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P), Emulsifier as an optional ingredient, Buffering agents as optional components, Aqueous solvent as an optional component, Antioxidants as optional components, and Fluidity improver as an optional component Cannabinoid oil containing, A gelatin or starch-containing outer film, preferably in the form of a soft gel, for encapsulating the cannabinoid oil. A capsule containing [the specified ingredient] is provided.

[0124] In a second embodiment of the capsule formulation of the present invention, the carrier may further contain medium-chain triglycerides (MCTs), and the mass ratio of LCT or LCFA to MCT is 1:3 to 3:1, more preferably 1:1. The mass ratio of TP to T2P is about 6:4 to 8:2, preferably about 2:1, and the mass ratio of cannabinoid to tocopheryl phosphate is about 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2.

[0125] Water may be homogeneously dispersed in the oil phase using an emulsifier, which may be selected from the group consisting of neutral surfactants (Span and Tween) and phospholipids (lecithin and Phospholipon G). The emulsifier may be provided in the minimum amount necessary to homogeneously disperse water in the oil.

[0126] A buffer may be used to inhibit the breakdown of cannabinoids, or to inhibit the conversion of one cannabinoid to another, for example, to inhibit the conversion of CBD to THC. The buffer may be selected from the group consisting of tromethamine, Tris, and PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)). The buffer may be provided in the minimum amount appropriate to maintain the pH of the capsule formulation during storage.

[0127] Furthermore, a buffer may be used to inhibit the conversion of one cannabinoid to another, and this buffer may be selected from the group consisting of hydrolyzed gelatin and pectin. This buffer may be provided in an amount necessary to prevent changes in pH during storage.

[0128] A water-soluble component may be added to the capsule formulation using an aqueous solvent. This water-soluble component may be another active ingredient or additive, or a buffer for adjusting the pH. The aqueous solvent may be provided in the minimum amount necessary to dissolve the buffer.

[0129] Antioxidants may be used to prevent oxidation of CBD, and these antioxidants may be selected from butylhydroxytoluene, butylhydroxyanisole, and α-tocopherol. These antioxidants may be supplied in amounts of 0.01 to 5% w / w.

[0130] A flow modifier may be used to prevent the precipitation of polymerization buffers (gelatin or pectin) and maintain the homogeneity of the capsule formulation. This flow modifier may be selected from simethicone, alginate, and PVP (polyvinylpyrrolidone). This flow modifier may be provided in the amount necessary to maintain the homogeneity of the capsule formulation.

[0131] In a second embodiment of the capsule formulation of the present invention, the cannabinoid is preferably a synthetic cannabinoid, more preferably synthetic CBD and / or synthetic THC, and the cannabinoid content in the capsule is preferably about 1 to 250 mg.

[0132] In a second embodiment of the capsule formulation of the present invention, the LCT or LCFA is preferably an extract or oil of naturally derived LCT or LCFA, and more preferably an extract or oil of naturally derived LCT or LCFA containing a linear or branched alkyl chain having 13 or more carbon atoms.

[0133] A third embodiment of the capsule of the present invention is a capsule for oral administration, The cannabinoids comprise TPM (referred herein to a mixture of mono(tocopheryl) phosphate (referred herein to as TP) and di(tocopheryl) phosphate (referred herein to as T2P)), MCT and LCT or LCFA; The cannabinoid is selected from the group consisting of CBG, CBC, CBND, THC, CBN, CBT, CBE, CBL, CBT, CBCN, THCV, CBGA, CBCN, CBDA, and CBDV, and is preferably CBD or THC; The mass ratio of the cannabinoid to the TPM is approximately 2:1 to 1:2, preferably 1:1; The mass ratio of the MCT to the LCT or LCFA is about 3:1 to 1:3, preferably 1:1; and The ratio of the combined mass of the MCT and the LCT or LCFA to the combined mass of the cannabinoid and the TPM is approximately 1000:3 to 10:3. A capsule formulation characterized by the above is provided.

[0134] A fourth embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, wherein the oil formulation contains, per 1000 mg of total filling weight, 75 mg of CBG, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0135] A fifth embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, characterized in that the oil formulation contains, per 1000 mg of total filling weight, 75 mg of CBC, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0136] A sixth embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, characterized in that the oil formulation contains, per 1000 mg of total filling weight, 75 mg of CBND, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0137] A seventh embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, characterized in that the oil formulation contains, per 1000 mg of total filling weight, 75 mg of THC, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0138] An eighth embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, characterized in that the oil formulation contains, per 1000 mg of total filling weight, 75 mg of CBN, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0139] A ninth embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, wherein the oil formulation contains, per 1000 mg of total filling weight, 75 mg of CBT, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0140] A tenth embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, characterized in that the oil formulation contains, per 1000 mg of total filling weight, 75 mg of CBE, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0141] In an eleventh embodiment of the capsule of the present invention, a softgel capsule comprising an oil formulation is provided, characterized in that the oil formulation comprises, per 1000 mg of total filling weight, 75 mg of CBL, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0142] In a twelfth embodiment of the capsule of the present invention, a softgel capsule comprising an oil formulation is provided, characterized in that the oil formulation comprises, per 1000 mg of total filling weight, 75 mg of CBCN, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0143] A thirteenth embodiment of the capsule of the present invention provides a softgel capsule comprising an oil formulation, characterized in that the oil formulation contains, per 1000 mg of total filling weight, 75 mg of CBD, 75 mg of TPM, 350 mg of MCT, 350 mg of glyceryl monolinoleate, 75 mg of phospholipon 90G, 13.5 mg of tromethamine, 21.1 mg of pure water, 0.4 mg of butylhydroxytoluene, 0.2 mg of simethicone, and 39.8 mg of hydrolyzed gelatin.

[0144] In the embodiments described under the subheading "Capsule Formulation," the outer membrane may be composed of gelatin. The gelatin matrix may contain gelatin, a plasticizer, a solvent, and optional components (such as flavorings and colorings). The gelatin may be derived from cattle, pigs, or fish. The bloom strength of the gelatin may vary, but a bloom strength of 150 is preferred. Glycerin or sorbitol may be used as the plasticizer, with glycerin being preferred. A potato starch matrix may be used instead of gelatin. The potato starch matrix is ​​a smooth, transparent substance very similar to gelatin, tasteless and colorless, easily digestible, and plant-derived.

[0145] 2.3 Bioavailability of orally administered cannabinoids A major advantage of the present invention is that it is possible to obtain higher plasma concentrations and higher AUC values ​​of cannabinoids via the oral administration route than those previously achievable with clinically significant cannabinoid doses.

[0146] While we do not wish to be bound by any particular hypothesis, it is believed that the tocopheryl phosphate component contained in the oral cannabinoid formulation of the present invention, specifically TPM, helps to increase the dispersion and solubility of cannabinoids in the gastrointestinal tract, thereby increasing the bioavailability of cannabinoids and minimizing first-pass metabolism and excretion of cannabinoids absorbed from the intestines. This is demonstrated in the examples described below. In the examples described below, it was found that the addition of TPM increased the solubility of cannabinoids in aqueous solvents in in vitro models, and increased the plasma concentration and area under the curve of cannabinoids in in vivo animal models.

[0147] Furthermore, surprisingly, it was found that TPM increases the bioavailability of cannabinoids.

[0148] Therefore, in one embodiment, a method for providing cannabinoids to an individual to a specific plasma concentration, The process includes administering the formulation described in any of Embodiments 1 and 4 to 8 orally to an individual, Oral administration of the formulation described in Embodiments 1 and 4-8 results in a plasma cannabinoid concentration in the individual that is higher than the plasma cannabinoid concentration obtained by oral administration of a formulation that does not contain TPM but has the same or similar dose of cannabinoids. A method characterized by the above is provided.

[0149] Furthermore, in the evaluation of the pharmacokinetic (PK) profile described herein, it has been demonstrated that the oral cannabinoid formulation of the present invention extends the exposure time to pharmacologically effective concentrations of cannabinoids in plasma. This is advantageous because it allows the protective effect of the drug to be sustained even in long administration cycles of 4 to 8-10 hours.

[0150] Therefore, in another embodiment, a method for extending the duration of pharmaceutically effective plasma cannabinoid concentrations in the plasma of an individual, The process includes administering the formulation described in any of Embodiments 1 and 4 to 8 orally to an individual, The duration of the pharmaceutically effective cannabinoid concentration in the plasma of an individual to whom the formulation described in any of Embodiments 1 and 4-8 has been orally administered is longer than the duration of the pharmaceutically effective cannabinoid concentration obtained by orally administering a formulation that does not contain TPM but has the same or similar dose of cannabinoids. A method characterized by the above is provided.

[0151] Furthermore, this specification demonstrates that the solubility of TPM is improved by using LCT or LCFA compared to its solubility in MCT. With the improvement in TPM solubility, it is readily predictable that the Cmax and AUC of cannabinoids in a cannabinoid-containing composition containing TPM solubilized in LCT or LCFA will be improved compared to the Cmax and AUC of cannabinoids in a cannabinoid-containing composition containing TPM solubilized in MCT. Accordingly, in one embodiment, a method is provided for increasing the cMax or AUC of cannabinoids in an individual. This method involves orally administering an MCT-free formulation according to Embodiments 1 and 5-8 to an individual requiring an increase in the cMax or AUC of cannabinoids. The amount of increase in the cMax or AUC of cannabinoids by administration of the MCT-free cannabinoid oil according to Embodiments 1 and 5-8 is determined against the cMax or AUC of cannabinoids typically obtained by administering an oral composition without TPM or an oral composition without either LCT or LCFA. Administering the MCT-free formulations described in Embodiments 1 and 5-8 increases the cannabinoid cMax or AUC in an individual compared to the cannabinoid cMax or AUC obtained when a cannabinoid-containing formulation without LCT or LCFA or without TPM is orally administered. The increase in cannabinoid cMax or AUC is typically at least 0.25 to 20 times that of the control.

[0152] Furthermore, it has been demonstrated that the solubility of TPM in carrier oils containing MCT and LCT in a ratio of approximately 1:1 is improved by the use of LCT or LCFA, and that the Cmax and AUC of the cannabinoids contained in such formulations are also improved along with the improved solubility of TPM. Accordingly, in one embodiment, a method is provided for increasing the cMax or AUC of a cannabinoid in an individual. This method involves orally administering the formulation described in Embodiment 1 or 4-8 to an individual who requires an increase in the cMax or AUC of a cannabinoid. The amount of increase in the cMax or AUC of a cannabinoid by administration of the formulations described in Embodiment 1 and 4-8 is determined by comparing it to the cMax or AUC of a cannabinoid typically obtained by administering an oral composition that does not contain TPM or an oral composition that does not contain either LCT or LCFA. By administering the formulations described in Embodiment 1 and 4-8, the cMax or AUC of a cannabinoid in an individual is increased compared to the cMax or AUC of a cannabinoid obtained by orally administering a cannabinoid oil that does not contain either LCT or LCFA or a cannabinoid oil that does not contain TPM. The increase in cMax or AUC for cannabinoids is typically at least 0.25 to 40 times that of the control.

[0153] In one embodiment, the cMax or AUC of the cannabinoid may be improved by adding LCT or LCFA to an oil containing TPM and cannabinoids, or by increasing the relative amount of LCT or LCFA in an oil containing LCT or LCFA, TPM and cannabinoids. In another embodiment, the cMax or AUC of the cannabinoid may be improved by adding TPM to an oil containing LCT or LCFA and cannabinoids, or by increasing the relative amount of TPM in an oil containing LCT or LCFA, TPM and cannabinoids. In yet another embodiment, the cMax or AUC of the cannabinoid may be improved by adding MCT to an oil containing LCT or LCFA, TPM and cannabinoids, or by increasing the relative amount of MCT in an oil containing MCT, LCT or LCFA, TPM and cannabinoids. In one embodiment, the cMax or AUC of a cannabinoid may be improved by adding TPM to an oil containing LCT or LCFA, MCT and cannabinoid, or by increasing the relative amount of TPM in an oil containing LCT or LCFA, MCT, TPM and cannabinoid. Methods for measuring the plasma concentration and area under the curve of cannabinoids are known to those skilled in the art. The examples herein illustrate in vitro methods and in vivo models for evaluating the cMax and AUC of cannabinoids in formulations containing carrier oil, tocopheryl phosphate and cannabinoids in various proportions. By using these methods, improvements in the cMax or AUC of a cannabinoid-containing composition resulting from an increase in the relative amount of one or more of TPM, LCT or LCFA, cannabinoids and MCT as an optional component in a cannabinoid-containing formulation according to the embodiments described herein can be evaluated and measured.

[0154] 2.4 Treatment method Oral administration of the formulations of the present invention improves the bioavailability of cannabinoids, making it possible to treat a variety of conditions for which the use of cannabinoids has been proposed. As described herein, some of these conditions include pain, inflammation, anxiety, depression, insomnia, sleep disorders, lack of energy, decreased alertness, weight gain, obesity, diabetes, metabolic syndrome, nausea (acute or anticipatory nausea), epilepsy, spasticity, schizophrenia, bipolar disorder, cancer and tumorigenesis, chronic pain, pain due to osteoarthritis, bacterial and / or fungal infections, fibromyalgia, increased appetite and / or decreased appetite.

[0155] Accordingly, in one embodiment, a method is provided for preventing or treating any of the aforementioned conditions, the method comprising the step of preventing or treating any of the aforementioned conditions by administering an oral cannabinoid preparation described herein.

[0156] In another embodiment, an oral cannabinoid formulation is provided for use in the prevention or treatment of any of the aforementioned conditions.

[0157] In another embodiment, the use of the oral cannabinoid formulation described herein for the prevention or treatment of any of the aforementioned conditions is provided.

[0158] In another embodiment, the use of the oral cannabinoid formulation described herein in the manufacture of a pharmaceutical product for the prevention or treatment of any of the aforementioned conditions is provided.

[0159] In one particularly preferred embodiment, the condition is insomnia or other sleep disorder. In this embodiment, it is preferable to provide the formulation in multiple dose units, each dose unit comprising a cannabinoid component, the cannabinoid being preferably about 1 to 250 mg / ml of CBD or 1 to 50 mg / ml of THC. The mass ratio of carrier to cannabinoid is 1:3 to 1:1000, 1:3 to 1:500, or 1:3 to 1:100. The mass ratio of TP to T2P is about 2:1, or in the range of about 4:1 to about 1:4 or about 6:4 to about 8:2, and the mass ratio of cannabinoid to tocopheryl phosphate component is about 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2. One or more dose units may be orally administered to the individual 15 minutes to 1 hour before sleep onset.

[0160] In another embodiment, the condition is intermittent or chronic and is selected from the group consisting of anxiety, depression, epilepsy, spasticity, schizophrenia, and bipolar disorder. In this embodiment, it is preferable to provide the formulation in multiple dose units, each dose unit comprising a cannabinoid component, the cannabinoid being preferably about 1 to 250 mg / ml of CBD or 1 to 50 mg / ml of THC. The mass ratio of carrier to cannabinoid is 1:3 to 1:1000, 1:3 to 1:500, or 1:3 to 1:100. The mass ratio of TP to T2P is about 2:1, or in the range of about 4:1 to about 1:4 or about 6:4 to about 8:2, and the mass ratio of cannabinoid to tocopheryl phosphate component is about 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2. In this embodiment, the oral cannabinoid preparation is administered orally to the individual every 4 to 8 hours, and in this case, up to 4 doses may be administered daily.

[0161] In another embodiment, the condition is acute or chronic pain, and in individuals requiring pain treatment, the pain may be manageable by activating cannabinoid receptors. Examples of pain include acute pain associated with trauma or surgical intervention, or chronic pain associated with inflammation, osteoarthritis, or tumor formation. In these embodiments, the administration of an oral cannabinoid preparation may prevent the perception of associated pain or manage persistent pain. In this embodiment, it is preferable that the preparation be provided in the form of multiple dosage units, each dosage unit containing a cannabinoid component, the cannabinoid preferably being about 1 to 250 mg / ml of CBD or 1 to 50 mg / ml of THC. The mass ratio of carrier to cannabinoid is 1:3 to 1:1000, 1:3 to 1:500, or 1:3 to 1:100. The mass ratio of TP to T2P is approximately 2:1, or within the range of approximately 4:1 to approximately 1:4 or approximately 6:4 to approximately 8:2, and the mass ratio of cannabinoid to tocopheryl phosphate component is approximately 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2. The oral cannabinoid preparation of the present invention may be administered to the individual before the onset of pain or during the onset of pain. Administration of the oral cannabinoid preparation is continued until the individual no longer requires analgesia.

[0162] The number of units to be administered may be determined according to individual characteristics such as sex, age, weight, other conditions, and other medications, which are understandable to those skilled in the art, and the number of units to be administered can be determined by measuring plasma cannabinoid concentration using standard techniques such as the methods described above.

[0163] 2.5 Manufacturing method The present invention provides a method for producing an oral cannabinoid preparation according to the present invention.

[0164] The tocopheryl phosphate component contains TP and T2P.

[0165] The combination or mixture of TP and T2P (hereinafter referred to as TPM) is tocopheryl and P4O 10 After forming a composition consisting of the above, the obtained composition is divided into tocopheryl and P4O 10 The reaction may also be obtained by heating to a temperature at which an exothermic reaction occurs. This temperature is called the "exothermic temperature." At this point, the temperature of the reaction mixture continues to rise, and when the reaction temperature falls below the exothermic temperature, TP and T2P are formed, and the reaction is complete. Tocopheryl phosphorylation occurs above the exothermic temperature. The reaction product may further contain a polyphosphate complex. The polyphosphate complex may be removed by hydrolysis. Such a method is outlined in WO2018 / 112512.

[0166] The mass ratio of TP to T2P in the tocopheryl phosphate component is preferably about 10:1 to 1:10, preferably 5:1 to 1:5, and more preferably 2:1 to 1:2. Components containing TP and T2P in such ratios may be obtained directly as the product of the phosphorylation reaction by partially changing the amount of the reaction substrate and / or the reaction conditions of the phosphorylation reaction described above. Alternatively, or in addition to this method, a tocopheryl phosphate component containing TP and T2P in a preferred mass ratio can also be obtained by adding TP or T2P to the product of the phosphorylation reaction described above.

[0167] The reaction product of TP and T2P obtained by the phosphorylation reaction described above is acidic, with a pH of approximately 2-4. This reaction product may be added to the formulation as an acid or salt (in which case the reaction product is neutral), but it is preferable to add it as an acid.

[0168] The mixture of TP and T2P obtained by the aforementioned reaction process (hereinafter referred to as TPM) may have a brittle, waxy, or poorly ductile texture, and TPM with such a texture is difficult to process with other components of the tocopheryl phosphate component (if any) and the cannabinoid component. To improve the processability of TPM, alcohol or other organic solvents may be added to suppress the solid properties of TPM. Typically, the amount of alcohol or organic solvent added is about 50% by weight or less of the total amount of the tocopheryl phosphate component, or about 1% by weight or less of the total amount of the oral cannabinoid preparation.

[0169] As mentioned above, the cannabinoid components in oral cannabinoid preparations may be obtained from synthetic raw materials or from natural raw materials (e.g., plant-derived cannabinoids). The cannabinoid is preferably provided in a form that is miscible with LCT or LCFA and / or MCT, or in an oil-soluble form. In certain embodiments, the cannabinoid may be provided in powder form.

[0170] LCT, LCFA, or MCT may be provided in a form that is not substantially an extract, for example, in the form of an untreated oil, i.e., an oil containing components other than LCT, LCFA, and MCT, derived from the raw materials of LCT or LCFA or MCT. In certain embodiments, it is preferable to provide LCT or LCFA as an extract containing only long-chain glycerides, i.e., typically only glycerides with 13 or more carbon atoms. Highly purified extracts of LCT or LCFA are preferred, and highly purified extracts of LCT or LCFA may be obtained from various suppliers described below.

[0171] In certain embodiments where the MCT form of carrier is further used, the MCT is preferably provided as an extract containing only medium-chain triglycerides, i.e., only triglycerides typically having 12 or fewer carbon atoms. Highly purified extracts of MCT are preferred, and highly purified extracts of MCT may be obtained from various suppliers.

[0172] MCTs typically act as carriers for cannabinoids, which in one embodiment means increasing the bulk of the cannabinoid, thereby facilitating the processing and formulation of the cannabinoid. Therefore, cannabinoids are usually provided for use as components in the production of oral cannabinoid formulations supported by MCTs. The mass ratio of cannabinoids to MCTs is typically about 1:3 to 1:500.

[0173] When MCT is used in a formulation according to an embodiment of the present invention, the cannabinoid may be dissolved in the MCT and provided, in which case LCT or LCFA is then added to provide a formulation with an MCT to LCT or LCFA ratio of 1:3 to 3:1, preferably 1:1. Alternatively, the cannabinoid may be dissolved in the LCT or LCFA and provided, in which case MCT is then added to provide a formulation with an MCT to LCT or LCFA ratio of 1:3 to 3:1, preferably 1:1. In either case, TPM may be added to the MCT or to the LCT or LCFA. It is preferable to add TPM to the LCT or LCFA before combining the LCT or LCFA with the MCT.

[0174] In an embodiment of the manufacturing method of the present invention, a tocopheryl phosphate component is brought into contact with a cannabinoid component (including a composition comprising a carrier and a cannabinoid) to form an oral cannabinoid composition. This contact may be carried out by mixing the tocopheryl phosphate and the cannabinoid component.

[0175] When mixing cannabinoid components with TPM, it is important that the TPM is evenly and homogeneously distributed throughout the cannabinoid components, so that visually, the TPM appears to be dissolved throughout the entire cannabinoid component.

[0176] In one embodiment, TPM and a carrier are mixed and gently heated while stirring to dissolve the TPM in the carrier, forming a first solution in which TPM is dissolved in the carrier. Next, cannabinoids, which may be in powder form, are added to the first solution and mixed to dissolve the cannabinoids in the first solution.

[0177] The product obtained by the manufacturing method of the present invention may have various physical properties depending on the properties of the tocopheryl phosphate and cannabinoid components used as components for forming the product and the reaction conditions. Typically, the product is hydrophobic or essentially oily.

[0178] In one embodiment, the product may be a liquid, for example, a liquid oil, and such a product may not require substantially further modification, thus providing an oral cannabinoid formulation in a readily usable form. In another embodiment, depending on whether the oral cannabinoid composition is prepared in liquid, solid, or semi-solid form, it may be necessary to add reagents to adjust the viscosity (i.e., decrease or increase the viscosity). A viscosity modifier may be added to the tocopheryl phosphate component or the cannabinoid component before mixing the tocopheryl phosphate component and the cannabinoid component to form the oral cannabinoid composition of the present invention. Alternatively, the viscosity modifier may be added after combining the tocopheryl phosphate component and the cannabinoid component.

[0179] The product of the manufacturing method of the present invention may be molded or shaped to form tablets, caplets, gummies, chewable confectionery, or suppositories.

[0180] The product of the manufacturing method of the present invention may be encapsulated to form, for example, encapsulated oil, or coated to form an enteric coating, thereby minimizing the degradation of the formulation in the intestines.

[0181] Various types of other pharmaceutically acceptable additives, carriers, flavorings, and stability modifiers may be added to the product of the manufacturing method of the present invention, or various types of other pharmaceutically acceptable additives, carriers, flavorings, and stability modifiers may be added to the tocopheryl phosphate component or the cannabinoid component before combining the tocopheryl phosphate component and the cannabinoid component. [Examples]

[0182] Example 1 - Enteric solubility of cannabidiol in vitro The concentration in the aqueous phase during intestinal digestion is often considered a parameter that should be taken into account when estimating the bioavailability of lipid-based formulations. Furthermore, drug precipitation in the intestines has been proposed as an indicator of low bioavailability. Changes in the properties of solubilizing components such as micelles and vesicles in the aqueous phase of the intestines are considered important factors in determining the final bioavailability of drugs that are poorly water-soluble but sufficiently permeable when administered in the form of lipid-based formulations.

[0183] In vitro digestive experiments were conducted to investigate whether a mixture of mono(tocopheryl) and di(tocopheryl) phosphates (TPM) contained in various carrier oils could increase the water solubility of cannabidiol (CBD) in the intestines. This experiment used a digestive model of the intestinal environment with a pH of approximately 6.5. This digestive model allows for the estimation of the solubility of CBD or other cannabinoids (e.g., THC) in aqueous intestinal fluid.

[0184] In this digestion experiment, when CBD was dissolved in MCT, LCT / LCFA (Maisine CC), or a mixture of MCT and Maisine CC, the degree of CBD solubilization into the aqueous phase was low (Figure 1). When MCT was present, most of the CBD was detected as solid precipitate in the form of pellets, and when LCT / LCFA was present, it was detected in the immiscible oil phase (Figure 1C).

[0185] In this model, adding TPM to either the MCT carrier oil or the LCT / LCFA carrier oil did not increase the solubility of CBD during in vitro digestion (Figure 2).

[0186] Interestingly, adding TPM to a mixture of MCT and LCT / LCFA increased the water solubility of CBD during digestion (Figure 2C). This formulation was predicted to have better bioavailability in vivo than CBD dissolved in MCT alone.

[0187] When the ratio of MCT to LCT / LCFA was investigated, it was found that the water solubility of CBD was highest when a solvent containing MCT and LCT / LCFA in a 1:1 ratio was used (Figure 3). In formulations with an increased MCT ratio (MCT:LCT / LCFA=3:1), CBD precipitation occurred during the digestion process. In formulations with an increased LCT / LCFA ratio (MCT:LCT / LCFA=1:3), aqueous CBD increased slightly, but the majority of CBD dissolved in the immiscible oil phase. From these results, it was predicted that using an oily solvent with a 1:1 ratio of MCT to LCT / LCFA would yield the largest amount of aqueous CBD and thus the highest in vivo bioavailability.

[0188] Example 2 - In vitro lipolysis in rats The aforementioned model, which investigated the solubility of cannabidiol in the intestines, is limited to conditions that model the intestinal environment. In contrast, bioavailability is also affected by gastric digestion, which occurs earlier than intestines. The degree of dispersion of a drug solubilized under gastric conditions becomes a factor for estimating drug absorption and bioavailability in the intestines.

[0189] Furthermore, to investigate the dispersion and solubility of CBD, in vitro lipolysis experiments were performed in a gastrointestinal tract model. The effects of TPM and formulation solvents were evaluated by comparing them with CBD dissolved in MCT solvent at a concentration of 100 mg / ml. The rat gastrointestinal tract model was selected to obtain the best correlation with the subsequent in vivo pharmacokinetic (pk) study in rats.

[0190] This in vitro lipolysis experiment simulated the conditions of the rat gastrointestinal tract. The dispersion test was performed in a lipolysis vessel containing artificial gastric fluid with a pH of 2.4, which simulated rat gastric juice, and the gastric digestion of the formulation was evaluated over 30 minutes. Next, concentrated bile buffer and pancreatin were added to the artificial gastric fluid to adjust the final concentration to simulate the conditions in the rat intestines. Then, lipid digestion and drug solubilization were evaluated over 60 minutes.

[0191] When TPM was added to MCT containing CBD (100 mg / ml), the dispersion and solubility of CBD increased in both the simulated stomach and simulated intestine (Figure 4). In Group 3, it was observed that some of the TPM did not dissolve due to the high concentration of TPM, and for the same reason, no titration effect was observed in Group 2, especially at the end of intestinal digestion.

[0192] Even when TPM was added to a mixed solvent of MCT containing CBD (100 mg / ml) and LCT / LCFA, the dispersion and solubility of CBD increased in the simulated intestine. Since 100 mg / ml of TPM dissolved more readily in the preparation solvent containing LCT / LCFA (Group 4) than in the solvent without LCT / LCFA (Group 3), it was shown that TPM increases the solubility of CBD in preparations containing LCT / LCFA. This effect became less pronounced when the TPM concentration exceeded 200 mg / ml, suggesting that Group 5 did not show a clear titration effect compared to Group 4 at the end of intestinal digestion. These data suggest that a large amount of LCT / LCFA is necessary to reliably dissolve TPM at concentrations above 200 mg / ml, and in particular, a mixed solvent with an LCT / LCFA to MCT ratio higher than 1:1 is required. Alternatively, if the LCT / LCFA to MCT ratio is 1:1, it is thought that a larger amount of CBD can be added.

[0193] In all test groups (except for group 3 as mentioned above), CBD solubilization was generally increased at the end of 60 minutes of intestinal digestion compared to when CBD was added to MCT-only solvent. Therefore, since TPM increases CBD solubility in in vitro gastric and intestinal digestion, it was predicted that using TPM may also increase CBD intestinal absorption and bioavailability in vivo.

[0194] Example 3 - Bioavailability in vivo Next, the formulations whose CBD solubility had been tested in vitro were also tested in vivo.

[0195] Male Sprague-Dawley rats (301-353g at the time of the experiment) were given a standard diet and allowed free access to water for at least 7 days to allow them to acclimate. The rats were then housed in a reversed light-dark cycle (12 hours / 12 hours) under controlled environmental parameters (temperature: 22.1°C, relative humidity: 57%). Before starting the experiment, the rats were fasted for approximately 13 hours during their inactive period.

[0196] This experiment was conducted using rats divided into five groups of six, as shown in the table below. [Table 1]

[0197] Each formulation was administered to each rat by forced oral administration using a polyurethane feeding tube (Instech Laboratories Inc., Plymouth Meeting, USA). Blood samples (200 μL) were collected from the tail vein before administration and at 0, 0.5, 1, 2, 4, 6, and 8 hours after administration. After collecting the blood sample at 6 hours, the rats were fed a standard diet. At 23 hours, the rats were euthanized with gas, and a blood sample was collected from the heart immediately afterward. Each blood sample was collected in a tube coated with ethylenediaminetetraacetic acid (EDTA) tripotassium salt dihydrate (Sarstedt, Helsingborg, Sweden) and centrifuged at 10,000 rpm for 10 minutes. After centrifugation, the plasma was transferred to a polypropylene microtube and stored at -20°C until LC-MS analysis.

[0198] Adding TPM to the MCT carrier increased the mean Cmax compared to a control CBD formulation using MCT alone as the carrier (Figure 5 and Table 1). The increase in Cmax was dependent on the TPM concentration. Adding 50 mg / ml of TPM increased the mean Cmax by approximately 5 times, and adding 100 mg / ml of TPM increased the mean Cmax by approximately 14 times. The area under the curve also clearly increased in these MCT formulations containing TPM (Figure 6). Therefore, TPM was shown to increase the bioavailability of CBD in CBD / MCT carrier oil formulations.

[0199] Similar to the formulations containing CBD, TPM, and MCT, the addition of TPM to a mixed carrier of MCT and LCT / LCFA increased the mean Cmax compared to a control CBD formulation using only MCT as the carrier (Figure 5). The increase in Cmax was dependent on the concentration of TPM. Adding 100 mg / ml of TPM increased the mean Cmax by approximately 30 times compared to a control formulation using only MCT as the carrier, and adding 200 mg / ml of TPM increased the mean Cmax by approximately 40 times. It was clearly shown that the area under the curve also increased similarly in these MCT:LCT / LCFA formulations containing TPM (Figure 6).

[0200] Similar to Example 2, LCT was found to be able to dissolve a larger amount of TPM, and as a result, it was thought that a larger amount of CBD was dissolved in the formulation solvent containing TPM, thereby improving the bioavailability of CBD.

[0201] Furthermore, fatty acid chain length plays a crucial role in emulsification, permeability, and absorption pathways. While medium-chain esters are known to be rapidly absorbed into the liver, products consisting of unsaturated LCFAs tend to stimulate chylomicron secretion and increase uptake into the lymphatic system. Combining a mixture of MCT and LCT fatty acids with TPM can significantly increase the oral bioavailability of CBD in vivo.

[0202] Example 4 - In vitro digestion model for evaluating the solubility of cannabinoids in aqueous gastric juice and aqueous intestinal juice The solubility of various types of cannabinoids contained in the formulation of the present invention in aqueous gastric juice and aqueous intestinal juice was measured by in vitro digestion of the cannabinoid formulation in aqueous gastric juice and aqueous intestinal juice.

[0203] Cannabinoid formulations are prepared by dissolving an appropriate amount of cannabinoid in a carrier oil (a 1:1 mixture of MCT and LCT / LCFA or LCT) according to the composition shown in Table 2, and then adding TPM. To dissolve the TPM in the carrier oil, it is sonicated and briefly heated in a water bath set to 50°C. [Table 2]

[0204] Artificial gastric fluid (pH 2.4) should be prescribed according to the composition shown in Table 3 below. [Table 3] *To this composition, add 1 mL of pepsin stock (derived from porcine gastric mucosa (content in artificial gastric juice: 450 U / mL) (Sigma-Aldrich)) and 1 mL of lipase (derived from Rhizopus Oryzae (content in artificial gastric juice: 50 TBU / mL) (Sigma-Aldrich)).

[0205] The concentrated bile buffer (pH 8.1) should be formulated according to the composition shown in Table 4 below. [Table 4]

[0206] Add 5 mL of cannabinoid preparation to 18 mL of artificial gastric juice (pH 2.4) and maintain the mixture for 5 minutes to allow for dispersion. Add pepsin and lipase until the final pepsin activity reaches 450 U / mL and the final lipase activity reaches 50 U / mL, with the point at which pepsin and lipase are added being considered the zero point. Samples are collected at 0 minutes, 5 minutes, 15 minutes, and 30 minutes.

[0207] After 30 minutes, concentrate bile buffer and 5 mL of pancreatin (added to the medium-chain triglyceride level of 179 U / mL (Sigma-Aldrich)) are added to the artificial gastric fluid to prepare an artificial intestinal fluid with a pH of 7.5 as shown in Table 5 below. [Table 5]

[0208] Collect 0.55 mL of the sample at 31 minutes, 35 minutes, 45 minutes, 60 minutes, and 90 minutes.

[0209] The evaluation of the entire sample volume is performed as follows: 250 μL of homogeneous sample is pipetteed into a 1.5 mL Eppendorf tube containing 1000 μL of acetonitrile and 225 μL of 0.5 M HCl. Next, the sample is centrifuged at 10,000 rpm for 5 minutes, and the cannabinoid content in the supernatant is analyzed by HPLC-UV.

[0210] The solubilized drug sample is evaluated as follows: 250 μL of homogeneous sample is added to 7 μL of 4-bromobenzeneboronic acid solution (1 M methanol solution; enzyme inhibitor), and ultracentrifugation is performed using an Optima MAX-XP ultracentrifuge (Beckman Coulter, Blair, California, USA) at 100,000 rpm and 37°C for 30 minutes. Next, 200 μL of the supernatant is pipetteed into a 1.5 mL Eppendorf tube containing 1000 μL of acetonitrile and 225 μL of 0.5 M HCl. This Eppendorf tube is centrifuged at 10,000 rpm for 5 minutes, and the cannabinoid content in the supernatant is analyzed by HPLC-UV.

[0211] The samples were analyzed using a Dionex 3000 HPLC instrument equipped with a Phenomenex Luna 5μm C18(2) column (100Å, 150×4.60mm, 5μm (P / NO 00F-4252-E0)). Separation was performed by isocratic elution with an 80:20 mixture of acetonitrile and pure water using the settings described in Table 6 below. [Table 6]

[0212] The results for each cannabinoid test sample are compared to a corresponding cannabinoid control that has the same cannabinoid and carrier oil content as the test sample but does not contain TPM. If the solubility of the cannabinoid in the test sample, as measured by HPLC, is increased by at least 0.5 times compared to the corresponding control, it indicates an improvement in the solubility of the sample in the gastrointestinal tract, and is likely to be higher than that of the corresponding control in vivo, with a higher cMax and / or AUC.

[0213] In this model, the amount of cannabinoid being evaluated may be adjusted. Typically, using a higher amount of cannabinoid than those listed in Table 2 requires a higher TPM (e.g., 200 mg / mL or higher TPM) or a higher LCT / LCFA.

[0214] Example 5 - Solubility of TPM in oil formulations The solubility of TPM in various solvents was measured.

[0215] Experimental materials • Maisine CC [Gattefosse SAS, Saint-Priest, France] • Labrafac CC [Gattefosse SAS, Saint-Priest, France] Labrafac Lipohile WL 1349 [Gattefosse SAS, Saint-Priest, France] • Captex® 300 [Abitec Corp., Wisconsin, USA] • Captex 355 [Abitec Corp, Wisconsin, USA] • Soybean oil [Sigma, St. Louis, Missouri, USA] • Peanut oil [Sigma, St. Louis, Missouri, USA] • PEG 400 [Aldrich, St. Louis, Missouri, USA] · Propylene glycol [Sigma Aldrich, St. Louis, Missouri, USA] · Glycerol [Merck, Victoria, Australia] · Fractionated oil (MCT oil derived from coconut) [Coco earth, New South Wales, Australia] · Tocopheryl phosphate mixture (TPM) [Avecho Biotechnology, Victoria, Australia]

[0216] Laboratory equipment · Glass scintillation vial (20 mL) [Rowe Scientific, Victoria, Australia] · Teflon-coated magnetic rotor [Rowe Scientific, Victoria, Australia] · Multi-stirrer [Velp, Germany] · Balance (5-digit display) (Mettler Toledo, Excellence Plus XP205) · Positive displacement pipette (Rainin, Mettler Toledo, Victoria, Australia) · Positive displacement pipette tip [Mettler Toledo, BioClean disposable capillary / piston] · Stainless steel spatula [Rowe Scientific, Victoria, Australia] · Ratek water bath [Rowe Scientific, Victoria, Australia]

[0217] Solubility test According to the description in Table 1, TPM was accurately weighed and placed in a 20 ml glass scintillation vial. A magnetic stir bar was placed in this vial, and the total weight was recorded (TPM + vial + magnetic rotor). The vial was placed on a multi-magnetic stirrer.

[0218] To the TPM powder in the vial, 500 μL of the divided solvent was added dropwise at 25°C every 10 minutes while stirring. When the solution began to become clear, 100 μL of the divided solvent was added dropwise every 20 minutes. Solvent was added until the entire amount of TPM powder was completely dissolved. The vial was left to stand overnight at 25°C without stirring to prevent crystallization in the solution. The final weight of the vial (total weight) was recorded, and the amount of solvent required to dissolve X g of TPM was calculated from this weight.

[0219] The same procedure was performed while maintaining the temperature of the vial in the water bath at 45°C, and the solubility of TPM at 40°C was measured.

[0220] result The solubility of TPM in each test solvent is shown in Tables 7 and 8 below. At 25°C, the solubility of TPM ranged from 0.06 to 8.62% w / w. The solubility of TPM was highest in Maisine CC. The solubility of TPM in Captex, Labrafac, or MCT oil was 1.29 to 2.21% w / w. The solubility of TPM in soybean oil, peanut oil, PEG400, glycerol, or propylene glycol was less than 0.1% w / w.

[0221] When the solvent temperature was increased to 45°C, the solubility of TPM increased in all tested solvents. The absolute increase in solubility ranged from 0.10% to 2.13%. The greatest increase in solubility was observed when using Labrafac WL 1349, and the smallest increase was observed when using glycerol. When the TPM solution was returned to room temperature, precipitation of TPM occurred in PEG400, propylene glycol, or glycerol in less than 30 minutes, but in the other solvents, precipitation occurred after 24 hours.

[0222] [Table 7]

[0223] [Table 8]

Claims

1. Oral cannabinoid preparations, A cannabinoid component comprising a cannabinoid and a carrier in the form of a long-chain triglyceride (LCT) or long-chain fatty acid (LCFA); Tocopheryl phosphate components including mono(tocopheryl) phosphate (TP) and di(tocopheryl) phosphate (T2P) Includes, A formulation wherein the mass ratio of the cannabinoid to the tocopheryl phosphate component is 10:1 to 1:

10.

2. The formulation according to claim 1, wherein the mass ratio of the cannabinoid to the tocopheryl phosphate component is 5:1 to 1:

5.

3. The formulation according to claim 2, wherein the mass ratio of the cannabinoid to the tocopheryl phosphate component is 2:1 to 1:

2.

4. The formulation according to any one of claims 1 to 3, wherein the LCT or LCFA is a naturally derived oil or extract, and the naturally derived oil or extract is purified or fractionated to increase the relative amount of one or more linear or branched alkyl chains having 13 or more carbon atoms.

5. The formulation according to any one of claims 1 to 3, wherein the cannabinoid component further comprises a carrier in the form of a medium-chain triglyceride (MCT).

6. The formulation according to claim 5, wherein the mass ratio of the MCT to the LCT or LCFA is 3:1 to 1:

3.

7. The formulation according to claim 6, wherein the mass ratio of the MCT to the LCT or LCFA is 1:

1.

8. The formulation according to any one of claims 1 to 3, wherein the mass ratio of the LCT or LCFA to the tocopheryl phosphate component is 5:1 to 250:

1.

9. The preparation according to any one of claims 1 to 3, wherein the cannabinoid content in the preparation is 1 to 250 mg / ml.

10. The formulation according to any one of claims 1 to 3, wherein the mass ratio of the cannabinoid to the carrier is 1:3 to 1:1000.

11. The formulation according to any one of claims 1 to 3, wherein the cannabinoid is cannabidiol (CBD) or tetrahydrocannabinol (THC).

12. The formulation according to claim 11, wherein the cannabinoid is CBD.

13. The formulation according to any one of claims 1 to 3, wherein the mass ratio of the TP to the T2P is 2:

1.

14. The formulation according to any one of claims 1 to 3, provided in the form of multiple dosage units suitable for oral administration.

15. A formulation according to any one of claims 1 to 3, comprising a cannabinoid in a dose unit of 1 to 250 mg suitable for oral administration.

16. The formulation according to claim 15, which is a tablet, caplet, capsule, chewable gum, or liquid formulation suitable for oral administration.

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