Solid cannabinoid composition for parenteral use

Abstract

A solid cannabinoid composition comprising: (i) 0.3 to 10% by weight of one or more cannabinoids; (ii) 4 to 69% by weight of one or more nonionic surfactants having an HLB value of 10 to 25; (iii) at least 20% by weight of one or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and (iv) 0 to 5% by weight of water, wherein the combination of one or more nonionic surfactants and one or more carbohydrates accounts for at least 70% by weight of the composition. A sterile aqueous solution for use in medical treatment, comprising: (a) 0.1 to 10 mg / mL of one or more cannabinoids; (b) one or more nonionic surfactants having an HLB value of 10 to 25; (c) one or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and (d) at least 85% by weight of water, wherein one or more nonionic surfactants and one or more cannabinoids are present in the sterile aqueous solution in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in the sterile aqueous solution in a weight ratio of 3:1 to 300:1.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to a solid cannabinoid composition for parenteral use. The solid pharmaceutical composition of the present invention can be appropriately combined with a sterile aqueous solution to produce a liquid that can be administered parenterally.

[0002] The solid cannabinoid composition of the present invention is highly stable and dissolves very rapidly in aqueous solutions, thus enabling the rapid preparation of a parenterally administered liquid.

[0003] The cannabinoid composition of the present invention can be appropriately used in the treatment of neonates at risk of seizures and brain injury, particularly in the treatment of hypoxic-ischemic encephalopathy (HIE). [Background technology]

[0004] Background of the Invention Cannabinoids are highly hydrophobic substances with very poor water solubility. Cannabidiol, for example, has a water solubility of 0.0627 μg / mL. Tetrahydrocannabinol (THC), another cannabinoid with various therapeutic uses, has a water solubility of 0.0028 mg / mL (23°C). Therefore, it is necessary to increase the solubility of cannabinoids in order to prepare parenterally administered aqueous solutions containing enough cannabinoids to be therapeutically effective.

[0005] It is worth noting that cannabinoids exhibit limited stability as a result of oxidation, particularly when applied in water-containing formulations.

[0006] HIE is caused by a lack of oxygen and / or blood flow from the placenta to the newborn. There are currently no approved drugs or therapies for HIE, and the standard treatment is therapeutic hypothermia, which benefits only a select group of newborns. More than two million newborns worldwide die or develop permanent disabilities each year due to HIE.

[0007] Preclinical studies provide strong evidence of the neuroprotective effects of cannabidiol (CBD). These effects are observable in both the short and long term, as demonstrated by functional, neuroimaging, histological, and biochemical studies, and are associated with the modulation of excitotoxicity, inflammation, and oxidative stress—major components of HIE pathophysiology. CBD protects nerve and glial cells and has a significant effect on preserving normal myelin formation. Therefore, CBD is a valuable tool for HIE management because it is safe and effective. It is administered a posteriori (posteriori) via parenteral routes with a broad therapeutic window.

[0008] International Publication No. 2018 / 002636 includes: (i) Cannabinoids; (ii) tonicity agent; (iii) Surfactants; and (iv) One or more types of stability enhancers; The document describes parenteral aqueous formulations containing cannabinoids.

[0009] International Publication No. 2022 / 174352 relates to a single-phase, injectable cannabinoid formulation for parenteral administration. The formulation contains at least one cannabinoid completely dissolved in a cosolvent system. The cosolvent system comprises (i) an effective amount of at least one triglyceride; and (ii) an effective amount of at least one C6-C6 22 The preparation contains (iii) a fatty acid; (iii) at least one phosphatidylglycerol and / or a salt thereof in about 1 to about 3% (w / v); and (iv) an effective amount of at least one antioxidant (or preservative) to improve the shelf life (optionally). The preparation does not contain water or ethanol.

[0010] International Publication No. 2022 / 017911 relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes related to brain injury. The CBD formulations described contain more than 95% (w / w) CBD and 0.01 - 0.15% (w / w) tetrahydrocannabinol (THC). An injectable form is not mentioned.

[0011] U.S. Patent Application Publication No. 2019 / 015383 describes · a purified cannabinoid mixture; · at least one carrier oil; and · at least one water-soluble agent selected from complex carbohydrates, polyols, polysaccharides, oligosaccharides or combinations thereof, a water-soluble cannabinoid composition comprising being water-soluble at a temperature of about 20°C or lower; and a water-soluble cannabinoid composition in the form of aggregated particles is described.

[0012] U.S. Patent Application Publication No. 2023 / 030491 describes i) one or more cannabinoids and / or cannabinoid extracts; ii) one or more surfactants; and iii) one or more oils, a liquid emulsifiable formulation comprising a weight ratio of one or more surfactants: one or more cannabinoids and / or cannabinoid extracts of about 1:1 to about 20:1, and a weight ratio of one or more oils: one or more cannabinoids and / or cannabinoid extracts of about 1:1 to about 10:1, a liquid emulsifiable formulation is described. Summary of the Invention Means for Solving the Problems

[0013] Summary of the Invention The inventors have developed a solid cannabidiol composition that is highly stable and, when appropriately used, can prepare an injectable aqueous solution in a short period by simply mixing an aqueous solution such as a sterile isotonic aqueous solution with a solid composition.

[0014] The solid cannabidiol composition according to the present invention comprises: (i) 0.3 to 10% by weight of one or more cannabinoids; (ii) 4 to 69% by weight of one or more nonionic surfactants having an HLB value of at least 10, preferably 10 to 25 (iii) at least 20% by weight of one or more carbohydrates selected from mannitol, sucrose, trehalose and stachyose; (iv) 0 to 5% by weight of water; and The combination of one or more nonionic surfactants and one or more carbohydrates accounts for at least 70% by weight of the composition.

[0015] The solid cannabidiol composition of the present invention can be appropriately prepared by freeze-drying an aqueous solution containing one or more cannabinoids, one or more nonionic surfactants having an HLB of 10 to 25, and one or more carbohydrates selected from mannitol, sucrose, trehalose and stachyose at appropriate concentrations. The solid cannabidiol composition thus obtained is highly porous and mainly amorphous, and contains a glassy carbohydrate matrix. The inventors do not wish to be bound by theory, but the combination and presence of the characteristics of nonionic surfactants having an HLB in the range of 10 to 25 are thought to contribute to the high stability and rapid dissolution in water of the solid cannabidiol composition of the present invention.

[0016] A second aspect of the present invention relates to a method for preparing the solid cannabidiol composition of the present invention, said method comprising: a. 0.3 to 10 mg / mL of one or more cannabinoids; b. One or more nonionic surfactants having at least 10, preferably 10 to 25 HLB; c. One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; d. At least 85% by weight of water; This includes freeze-drying an aqueous solution containing the following: One or more nonionic surfactants and one or more cannabinoids are present in the aqueous solution in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in the aqueous solution in a weight ratio of 3:1 to 300:1.

[0017] A third aspect of the present invention relates to a vial or syringe containing a solid cannabinoid composition according to any one of the preceding claims, in an amount that provides 0.2 to 100 mg of cannabinoids.

[0018] A fourth aspect of the present invention is: (a) 0.1-10 mg / mL of one or more cannabinoids; (b) One or more nonionic surfactants having at least 10, preferably 10 to 25 HLB; (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; (d) at least 85% by weight of water; A sterile aqueous solution used in medical treatment, which includes, This invention relates to a sterile aqueous solution in which one or more nonionic surfactants and one or more cannabinoids are present in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in a weight ratio of 3:1 to 300:1. [Modes for carrying out the invention]

[0019] Detailed description of the present invention A first aspect of the present invention is: (i) 0.3 to 10% by weight of one or more cannabinoids; (ii) 4 to 69% by weight of one or more nonionic surfactants having an HLB value of 10 to 25; (iii) at least 20% by weight of one or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; (iv) Water 0-5% by weight; A solid cannabinoid composition containing, This invention relates to a solid cannabinoid composition in which a combination of one or more nonionic surfactants and one or more carbohydrates accounts for at least 70% by weight of the composition.

[0020] As used herein, the term “freeze-drying” means a process by which a material is dried by cooling it to a temperature below its triple point, a temperature at which the solid, liquid, and gas phases of the material can coexist, and then sublimating it under reduced pressure.

[0021] As used herein, the term "parenteral" refers to a mode of administration in which a pharmaceutically active ingredient is delivered by a route other than enteral administration. Examples of parenteral administration include intravenous, intraperitoneal, intramuscular, and subcutaneous administration.

[0022] The solid cannabinoid composition is preferably prepared by freeze-drying.

[0023] The solid cannabinoid composition is preferably provided in the form of pellets, powder, or granules. Most preferably, the composition is provided in pellet form. The pellets preferably have a weight in the range of 50 to 1,200 mg, more preferably in the range of 100 to 1,000 mg.

[0024] The solid cannabinoid composition provided in pellet form preferably has a density of 30 to 300 mg / mL, more preferably 40 to 200 mg / mL.

[0025] The solid cannabinoid composition, provided in powder or granular form, preferably has a density of 10 to 200 mg / mL, more preferably 20 to 160 mg / L.

[0026] The solid cannabinoid composition of the present invention preferably contains 0.4 to 8% by weight, more preferably 0.6 to 6% by weight, and most preferably 0.8 to 4% by weight of one or more cannabinoids.

[0027] The cannabinoids used in accordance with the present invention may be isolated from natural materials (e.g., cannabis plant materials) or obtained via synthetic routes. The one or more cannabinoids in the solid composition of the present invention are preferably selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, cannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, delta-11-tetrahydrocannabinol, and tetrahydrocannabivarin, levonantradiol, and nabilone. More preferably, the one or more cannabinoids are selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, and cannabinol. Even more preferably, the one or more cannabinoids are selected from cannabidiol and tetrahydrocannabinol. Most preferably, the solid cannabinoid composition of the present invention contains cannabidiol.

[0028] The solid cannabinoid composition preferably contains 5 to 40% by weight, more preferably 6 to 30% by weight, and most preferably 8 to 24% by weight of one or more nonionic surfactants.

[0029] One or more nonionic surfactants used in accordance with the present invention preferably have an HLB in the range of 11 to 20, more preferably 11 to 18, and most preferably 12 to 16.

[0030] According to a preferred embodiment, the one or more nonionic surfactants are fatty acid esters of polyethylene glycol, more preferably esters of glycerol polyethylene glycol and C 12 ~C 20 hydroxy fatty acids, esters of polyethylene glycol and C 12 ~C 20 hydroxy fatty acids, esters of polyethylene glycol sorbitol and C 12 ~C 20 fatty acids, and combinations thereof, which are fatty acid esters of polyethylene glycol.

[0031] In an advantageous embodiment, the one or more surfactants are esters of glycerol polyethylene glycol and C 12 ~C 20 hydroxy fatty acids, more preferably esters of C 16 ~C 18 hydroxy fatty acids. Most preferably, the nonionic surfactant is an ester of glycerol polyethylene glycol and ricinoleic acid. Kolliphor® ELP is a commercial example of such a surfactant.

[0032] In another advantageous embodiment, the one or more surfactants are esters of polyethylene glycol and C 12 ~C 20 hydroxy fatty acids, more preferably esters of C 16 ~C 18 hydroxy fatty acids. Most preferably, the nonionic surfactant is an ester of polyethylene glycol and 12-hydroxystearic acid. Kolliphor® HS15 is a commercial example of such a surfactant.

[0033] According to another advantageous embodiment, the one or more surfactants are esters of polyethylene glycol sorbitol and C 12 ~C 20 fatty acids, more preferably C 16 ~C 18It is an ester of a fatty acid. Most preferably, the nonionic surfactant is an ester of polyethylene glycol sorbitol and oleic acid. Polysorbate 80 is an example of such a surfactant.

[0034] The solid cannabinoid composition preferably contains at least 30% by weight, more preferably 40-95% by weight, even more preferably 60-93% by weight, and most preferably 75-92% by weight of one or more carbohydrates.

[0035] The carbohydrates, one or more types, are preferably selected from mannitol and sucrose. Most preferably, the carbohydrate used is mannitol.

[0036] In a particularly preferred embodiment, the solid cannabinoid composition contains at least 80% by weight of one or more carbohydrates in an amorphous state.

[0037] A combination of one or more nonionic surfactants and one or more carbohydrates constitutes at least 80% by weight, more preferably at least 85% by weight, of the solid cannabinoid composition.

[0038] Preferably, a combination of one or more cannabinoids, one or more nonionic surfactants, and one or more carbohydrates constitutes at least 75% by weight, more preferably at least 85% by weight, and most preferably at least 90% by weight of the solid cannabinoid composition.

[0039] One or more nonionic surfactants and one or more cannabinoids are preferably present in the solid cannabinoid composition in a weight ratio of 3:1 to 30:1, more preferably 4:1 to 25:1, and even more preferably 5:1 to 20:1.

[0040] Preferably, one or more carbohydrates and one or more cannabinoids are present in the solid cannabinoid composition in a weight ratio of 3:1 to 300:1, more preferably 15:1 to 200:1, even more preferably 20:1 to 150:1, and most preferably 30:1 to 120:1.

[0041] The solid cannabinoid composition of the present invention has a reconstitution time of preferably less than 180 seconds, more preferably less than 120 seconds, and most preferably less than 60 seconds, determined by an impedance-based method described by Werketal (An Impedance-Based Method to Determine Reconstitution Time for Freeze-Dried Pharmaceuticals, J. of Pharm. Sc. (2015) 104:2948-2955) using 300 mg of the solid cannabinoid composition and 5 mL of sterile water for injection at 20°C.

[0042] In addition to dissolving rapidly, the solid cannabinoid composition of the present invention preferably forms a clear solution. Therefore, medical staff can easily determine whether the solid composition has dissolved properly and is ready for parenteral administration.

[0043] According to a preferred embodiment, a clear solution is obtained by reconstituting 300 mg of the solid cannabinoid composition of the present invention with 5 mL of sterile water for injection at 20°C. The reconstituted composition is considered clear if its clarity is the same as that of Water R, or if its opalescence does not exceed that of Reference Suspension I, according to Table 2.2.1-2 of Chapter 2.2.1 of the European Pharmacopoeia.

[0044] In addition to one or more cannabinoids, the solid cannabinoid composition preferably does not contain a significant amount of lipophilic components. When the solid composition is reconstituted in an aqueous solution for parenteral use, the presence of such components in the composition may result in the formation of a turbid or cloudy emulsion.

[0045] Therefore, in a preferred embodiment, the solid cannabinoid composition contains 0 to 1% by weight of triglycerides, more preferably 0 to 0.5% by weight of triglycerides, even more preferably 0 to 0.3% by weight of triglycerides, and most preferably 0 to 0.1% by weight of triglycerides.

[0046] Preferably, the solid cannabinoid composition contains 0 to 1% by weight of oil, more preferably 0 to 0.5% by weight of oil, even more preferably 0 to 0.3% by weight of oil, and most preferably 0 to 0.1% by weight of oil, wherein the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

[0047] The solid cannabinoid composition of the present invention contains triglycerides and one or more cannabinoids in a weight ratio of triglycerides to one or more cannabinoids, preferably in the range of 0 to 1, more preferably in the range of 0 to 0.3, even more preferably in the range of 0 to 0.1, and most preferably in the range of 0 to 0.03.

[0048] The oil and one or more cannabinoids are present in the solid cannabinoid composition in a weight ratio of oil to one or more cannabinoids, preferably in the range of 0 to 1, more preferably in the range of 0 to 0.3, even more preferably in the range of 0 to 0.1, and most preferably in the range of 0 to 0.03, wherein the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

[0049] The water content of the solid cannabinoid composition is preferably in the range of 0 to 3% by weight, more preferably in the range of 0 to 2.5% by weight, and most preferably in the range of 0 to 2% by weight.

[0050] In addition to cannabinoids, nonionic surfactants, carbohydrates, and water, the solid cannabinoid composition of the present invention may optionally contain additional components. Examples of such components include salts, polymers (such as polyvinylpyrrolidone), antioxidants (e.g., ascorbic acid), and isotonic agents (e.g., glycerol).

[0051] In a particularly preferred embodiment, when dispersed in distilled water at a concentration of 10-200 mg / mL at a temperature of 37°C, the solid cannabinoid composition produces an aqueous solution having an osmolality in the range of 100-800 mOsm / L, more preferably 150-500 mOsm / L, and most preferably 200-400 mOsm / L.

[0052] A method for preparing a solid cannabinoid composition of the present invention is provided according to a second aspect of the present invention. The method is as follows: (a) 0.1-10 mg / mL of one or more cannabinoids; (b) One or more nonionic surfactants having an HLB value of 10 to 25; (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; (d) at least 85% by weight of water; This includes freeze-drying an aqueous solution containing the following: One or more nonionic surfactants and one or more cannabinoids are present in the aqueous solution in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in the aqueous solution in a weight ratio of 3:1 to 300:1.

[0053] One or more nonionic surfactants and one or more cannabinoids are preferably present in the aqueous solution in a weight ratio of 4:1 to 25:1, more preferably 5:1 to 20:1.

[0054] Preferably, one or more types of carbohydrates and one or more types of cannabinoids are present in the aqueous solution in a weight ratio of 15:1 to 200:1, more preferably 20:1 to 150:1, and most preferably 30:1 to 120:1.

[0055] Preferably, the aqueous solution freeze-dried by the method of the present invention contains 0.2 to 8 mg / mL, more preferably 0.4 to 4 mg / mL, of one or more cannabinoids.

[0056] Freeze-drying of aqueous solutions involves the following three consecutive phases: (1) freezing; (2) primary drying (sublimation); and (3) secondary drying (absorption).

[0057] Freeze-drying of aqueous solutions may involve additional process steps, such as one or more annealing steps.

[0058] In the primary drying phase, the pressure is reduced and heat is applied to the material to sublimate the water. Most of the water in the material is removed in this phase. In the secondary drying phase, ionically bonded water molecules are removed. By raising the temperature higher than in the primary drying phase, the bonds between the material and water molecules are broken. Once the freeze-drying process is complete, the vacuum is broken.

[0059] After freeze-drying, the solid cannabinoid composition is preferably introduced into a vial or syringe. In a particularly preferred embodiment, the solid cannabinoid composition is introduced into the vial or syringe under reduced pressure and sealed. The inventors have found that this embodiment offers the important advantage that foaming is effectively minimized when the solid cannabinoid composition is combined with an aqueous solvent. In a preferred embodiment, the solid cannabinoid composition is introduced into the vial or syringe and sealed at a pressure of less than 10 kPa, more preferably less than 5 kPa, and most preferably 0 to 1 kPa.

[0060] A third aspect of the present invention relates to a vial or syringe containing the solid cannabinoid composition of the present invention in an amount that provides 0.2 to 100 mg, more preferably 0.5 to 40 mg, even more preferably 1 to 20 mg, and most preferably 2 to 10 mg of cannabinoids.

[0061] In a preferred embodiment, the syringe comprises two chambers, the first chamber containing a solid cannabinoid composition and the second chamber containing a sterile isotonic aqueous solvent. Preferably, the syringe is configured such that the contents of the two chambers are mixed to produce an aqueous cannabinoid solution, and the aqueous cannabinoid solution is dispensed from the syringe by, for example, pressing the syringe plunger.

[0062] As already described above, the vial or chamber of the syringe containing the solid cannabinoid composition is preferably under reduced pressure. Preferably, the reduced pressure is up to 50 kPa, more preferably up to 30 kPa, and most preferably 0.0001 to 10 kPa.

[0063] A fourth aspect of the present invention is: (a) 0.1-10 mg / mL of one or more cannabinoids; (b) One or more nonionic surfactants having an HLB value of 10 to 25; (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; (d) at least 85% by weight of water; A sterile aqueous solution used in medical treatment, which includes, This invention relates to a sterile aqueous solution in which one or more nonionic surfactants and one or more cannabinoids are present in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in a weight ratio of 3:1 to 300:1.

[0064] In a particularly preferred embodiment, a sterile aqueous solution can be obtained by dispersing the solid cannabinoid composition of the present invention in water for injection.

[0065] Preferably, the sterile aqueous solution used in treatment contains 0.2 to 8 mg / mL, more preferably 0.4 to 4 mg / mL, of one or more cannabinoids.

[0066] The one or more cannabinoids in the sterile aqueous solution are preferably selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, cannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, delta-11-tetrahydrocannabinol, and tetrahydrocannabivarin, levonantradiol, and nabilone. More preferably, the one or more cannabinoids are selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, and cannabinol. Even more preferably, the one or more cannabinoids are selected from cannabidiol and tetrahydrocannabinol. Most preferably, the cannabinoid is cannabidiol.

[0067] The one or more nonionic surfactants used preferably have an HLB in the range of 11 to 20, more preferably in the range of 11 to 18, and most preferably in the range of 12 to 16.

[0068] The one or more nonionic surfactants in the sterile aqueous solution are preferably fatty acid esters of polyethylene glycol, more preferably glycerol polyethylene glycol and C 12 ~C 20 Hydroxy fatty acid esters, polyethylene glycol and C 12 ~C 20 Hydroxy fatty acid esters, polyethylene glycol sorbitol and C 12 ~C 20This is a fatty acid ester of polyethylene glycol selected from fatty acid esters and combinations thereof.

[0069] In a favorable embodiment, one or more surfactants include glycerol polyethylene glycol and C 12 ~C 20 It is an ester of a hydroxy fatty acid. Most preferably, the nonionic surfactant is an ester of glycerol polyethylene glycol and ricinoleic acid. Kolliphor® ELP is a commercially available example of such a surfactant.

[0070] In another advantageous embodiment, one or more surfactants are polyethylene glycol and C 12 ~C 20 It is an ester of a hydroxy fatty acid. Most preferably, the nonionic surfactant is an ester of polyethylene glycol and 12-hydroxystearic acid. Kolliphor® HS15 is a commercially available example of such a surfactant.

[0071] According to another advantageous embodiment, one or more surfactants include polyethylene glycol sorbitol and C 12 ~C 20 It is an ester of a fatty acid. Most preferably, the nonionic surfactant is an ester of polyethylene glycol sorbitol and oleic acid. Polysorbate 80 is an example of such a surfactant.

[0072] Preferably, one or more carbohydrates are selected from mannitol, sucrose, and combinations thereof. Most preferably, the carbohydrate used is mannitol.

[0073] One or more nonionic surfactants and one or more cannabinoids are preferably present in a sterile aqueous solution in a weight ratio of 4:1 to 25:1, more preferably 5:1 to 20:1.

[0074] Preferably, one or more types of carbohydrates and one or more types of cannabinoids are present in a sterile aqueous solution in a weight ratio of preferably 15:1 to 200:1, more preferably 20:1 to 150:1, and most preferably 30:1 to 120:1.

[0075] The sterile aqueous solution contains 0 to 10 mg / L of triglycerides, more preferably 0 to 6 mg / L of triglycerides, even more preferably 0 to 3 mg / L of triglycerides, and most preferably 0 to 1 mg / L of triglycerides.

[0076] The oil is preferably contained in a sterile aqueous solution at a concentration of 0 to 10 mg / L, more preferably 0 to 6 mg / L, even more preferably 0 to 3 mg / L, and most preferably 0 to 1 mg / L, and the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

[0077] The sterile aqueous solution preferably contains triglycerides and one or more cannabinoids in a weight ratio of triglycerides to one or more cannabinoids in the range of 0 to 1, more preferably 0 to 0.3, even more preferably 0 to 0.1, and most preferably 0 to 0.03.

[0078] The oil and one or more cannabinoids are preferably in the range of 0 to 1, more preferably in the range of 0 to 0.3, even more preferably in the range of 0 to 0.1, and most preferably in the range of 0 to 0.03, contained in a sterile aqueous solution in a weight ratio of oil to one or more cannabinoids, wherein the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

[0079] In a particularly preferred embodiment, the aqueous solution has a pH of 2 to 11, more preferably 4 to 9, and most preferably 6.5 to 8.0.

[0080] In a particularly preferred embodiment, the aqueous solution described above has an osmolality in the range of 100 to 800 mOsm / L, more preferably in the range of 180 to 500 mOsm / L, and most preferably in the range of 200 to 400 mOsm / L.

[0081] In a particularly preferred embodiment, a sterile aqueous solution is prepared by combining the solid cannabinoid composition of the present invention with a sterile solution. Preferably, the sterile solution used to prepare the sterile aqueous solution contains at least 90% by weight, more preferably at least 95% by weight, of water.

[0082] In a particularly preferred embodiment, the medical treatment includes parenteral administration of a sterile aqueous solution, more preferably intravenous, intraperitoneal, intramuscular, or subcutaneous administration, and most preferably intravenous administration.

[0083] The medical treatment of the present invention preferably involves administering a sterile aqueous solution to a newborn. Preferably, the sterile aqueous solution is administered to the newborn to provide cannabinoids in a dosage of 1 to 15 mg, more preferably 2 to 10 mg.

[0084] In a particularly preferred embodiment, the medical treatment of the present invention is for the treatment of neonates at risk of seizures and brain injury, in particular for the treatment of hypoxic-ischemic encephalopathy (HIE).

[0085] The present invention is further illustrated by the following non-limiting examples. [Examples]

[0086] Examples Example 1 An aqueous solution containing cannabidiol was prepared based on the formulation shown in Table 1.

[0087] [Table 1]

[0088] Before mixing the two solutions using an electromagnetic stirrer, cannabidiol was first dissolved in the surfactant, and mannitol was first dissolved in deionized water.

[0089] Five ml aliquots of cannabidiol solution were placed in clear glass tubular injection vials with crimped necks (8R: diameter = 22 mm, height = 45 mm), frozen, and then freeze-dried.

[0090] Freeze-drying was performed using a vacuum pump (2XZ-2 rotary vane vacuum pump (A4218)) and a freeze-dryer (Drawell Analytical, DW-10N series).

[0091] The freeze-drying procedure was configured as follows: • Cold trap temperature ~60℃, • Pressure 1.0~3.0 Pa, • Duration + / - 24 hours.

[0092] The glass vial containing the freeze-dried pellets was sealed by closing it with a screw-on cap equipped with a septum.

[0093] The dissolution rate (reconstitution time) of lyophilized cannabidiol pellets in a clear glass vial was evaluated by introducing 5 mL of deionized water at 20°C into a vial through the septum using a syringe, gently shaking the container by hand, and determining the time until a clear solution formed. The results are summarized in Table 2.

[0094] [Table 2]

[0095] Cannabinoid pellet 2 offers the advantage of being easily diluted with sterile water for injection to produce an isotonic intravenous solution that can be appropriately administered to neonates by injection, providing a dose of 2-10 mg of cannabinoids.

[0096] Example 2 Example 1 was repeated, starting with formulation number 3, except that sucrose was used instead of mannitol. This time, it took slightly more than 2 minutes to achieve complete dissolution of the pellet.

[0097] Example 3 Example 1 was repeated, starting with formulation number 3, except that the vial was freeze-dried and sealed at a pressure of 2 Pa. Dissolution tests yielded similar dissolution times to Example 1, but with significantly less foaming observed during shaking.

[0098] Example 4 Aqueous solutions containing cannabidiol were prepared based on the formulations shown in Table 3.

[0099] [Table 3]

[0100] Before mixing the two solutions using an electromagnetic stirrer, cannabidiol was first dissolved in a surfactant and mannitol was first dissolved in deionized water. All the resulting cannabidiol solutions were completely clear, indicating that after lyophilization, the lyophilized material would form a clear solution when reconstituted with water.

[0101] Example 5 Aqueous solutions containing cannabidiol were prepared based on the formulations shown in Table 4.

[0102] [Table 4]

[0103] Before mixing the two solutions using an electromagnetic stirrer, the cannabidiol was first dissolved in the surfactant, and each of the carbohydrates was first dissolved in deionized water.

[0104] Five ml aliquots of the resulting cannabidiol solution were filled into clear glass tubular injection vials with crimped necks (8R: diameter = 22 mm, height = 45 mm), frozen, and freeze-dried.

[0105] Freeze-drying was performed using a vacuum pump (2XZ-2 rotary vane vacuum pump (A4218)) and a freeze-dryer (Drawell Analytical, DW-10N series).

[0106] The freeze-drying procedure was configured as follows: • Cold trap temperature -60℃, • Pressure 1.0~3.0 Pa, • Duration + / - 24 hours.

[0107] The glass vial containing the freeze-dried pellets was sealed by closing it with a screw-on cap equipped with a septum.

[0108] The dissolution rate of lyophilized cannabidiol pellets in a clear glass vial was evaluated by introducing 5 mL of deionized water at 20°C into a vial through the septum using a syringe, gently shaking the container by hand, and determining the time elapsed until a clear solution formed, or the time until further dissolution ceased. The results are summarized in Table 2. Furthermore, the appearance of the lyophilized material and the reconstituted solution was also evaluated. The results obtained for the lyophilized cannabidiol solution in Table 4 are shown in Table 5.

[0109] [Table 5]

[0110] Example 6 An aqueous solution containing cannabidiol was prepared based on the formulation shown in Table 6.

[0111] [Table 6]

[0112] Before mixing the two solutions using an electromagnetic stirrer, cannabidiol was first dissolved in the emulsifier, and trehalose was first dissolved in deionized water.

[0113] The dissolution rate of the freeze-dried cannabidiol pellets, as well as the appearance of the freeze-dried product and the reconstituted solution, were evaluated using the same method as in Example 5. The results are shown in Table 7.

[0114] [Table 7]

[0115] Example 7 An aqueous solution containing cannabidiol was prepared based on the formulation shown in Table 8.

[0116] [Table 8]

[0117] Before mixing the two solutions using an electromagnetic stirrer, cannabidiol was first dissolved in the emulsifier, and stachyose was first dissolved in deionized water.

[0118] The dissolution rate of the freeze-dried cannabidiol pellets, as well as the appearance of the freeze-dried product and the reconstituted solution, were evaluated using the same method as in Example 5. The results are shown in Table 9.

[0119] [Table 9]

[0120] Example 8 An aqueous solution containing tetrahydrocannabinol was prepared based on the formulation shown in Table 10.

[0121] [Table 10]

[0122] Before mixing the two solutions using an electromagnetic stirrer, tetrahydrocannabinol was first dissolved in the emulsifier, and mannitol was first dissolved in deionized water.

[0123] The results show that all tetrahydrocannabinol solutions obtained are completely clear, and that after freeze-drying, the dried material will be reconstituted with water to form a clear solution.

[0124] Example 9 The tetrahydrocannabinol solution 2 from Example 7 was freeze-dried using the same method as described in Example 5.

[0125] The dissolution rate of the freeze-dried material, as well as the appearance of the freeze-dried material and the reconstituted liquid, were evaluated using the same method as in Example 5. It was found that the formed freeze-dried material formed a clear liquid in 23 seconds.

[0126] Comparative example A The mixture of SNEDD, water, and sorbitol from Example 11 of U.S. Patent Application Publication No. 2023 / 0030491 was prepared again. The resulting aqueous solution was turbid, and it is also shown that when the dried material is reconstituted with water after freeze-drying, a turbid liquid will be formed.

[0127] Comparative example B An aqueous solution containing cannabidiol was prepared based on the formulation shown in Table 11.

[0128] [Table 11]

[0129] All of the cannabidiol preparations obtained were turbid dispersions.

Claims

1. (i) 0.3 to 10% by weight of one or more cannabinoids; (ii) 4 to 69% by weight of one or more nonionic surfactants having an HLB value of 10 to 25; (iii) At least 20% by weight of one or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; (iv) Water 0-5% by weight; A solid cannabinoid composition containing, A solid cannabinoid composition in which the combination of one or more nonionic surfactants and one or more carbohydrates constitutes at least 70% by weight of the composition.

2. The solid cannabinoid composition according to claim 1, wherein the solid composition has a density of 10 to 200 mg / mL.

3. The solid cannabinoid composition according to claim 1 or 2, wherein the one or more cannabinoids are selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, cannabinol, 11-hydroxytetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, delta-11-tetrahydrocannabinol, and tetrahydrocannabivarin, levonantradol, and nabilone, preferably selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, and cannabinol, and most preferably selected from cannabidiol and tetrahydrocannabinol.

4. The solid cannabinoid composition according to claim 3, wherein the cannabinoid is selected from cannabidiol, tetrahydrocannabinol, and combinations thereof.

5. A solid cannabinoid composition according to any one of claims 1 to 4, comprising at least 4% by weight of a nonionic surfactant having an HLB value in the range of 11 to 18, preferably in the range of 12 to 16.

6. The solid cannabinoid composition according to any one of claims 1 to 5, wherein the one or more nonionic surfactants are fatty acid esters of polyethylene glycol.

7. The fatty acid ester of polyethylene glycol is glycerol polyethylene glycol and C １２ ~C ２０ Hydroxy fatty acid esters, polyethylene glycol and C １２ ~C ２０ Hydroxy fatty acid esters, polyethylene glycol sorbitol and C １２ ~C ２０ A solid cannabinoid composition according to any one of claims 1 to 6, selected from fatty acid esters and combinations thereof.

8. The solid cannabinoid composition according to any one of claims 1 to 7, wherein the one or more carbohydrates are selected from mannitol, sucrose, trehalose, and stachyose.

9. The solid cannabinoid composition according to claim 8, wherein the one or more carbohydrates are mannitol.

10. A solid cannabinoid composition according to any one of claims 1 to 9, containing 0 to 1% by weight of triglycerides.

11. The solid cannabinoid composition according to claim 10, wherein the solid cannabinoid composition contains 0 to 1% by weight of oil, and the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

12. The solid cannabinoid composition according to any one of claims 1 to 11, wherein the solid cannabinoid composition contains triglycerides and one or more cannabinoids in a weight ratio of triglycerides to one or more cannabinoids in the range of 0 to 1.

13. The solid cannabinoid composition according to claim 12, wherein the solid cannabinoid composition contains oil and one or more cannabinoids in a weight ratio of oil to one or more cannabinoids in the range of 0 to 1, and the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters and combinations thereof.

14. A solid cannabinoid composition according to any one of claims 1 to 13, wherein when dispersed in distilled water at a concentration of 10 to 200 mg / mL at a temperature of 37°C, an aqueous solution having an osmolality in the range of 100 to 800 mOsm / L is produced.

15. a. 0.1 to 10 mg / mL of one or more types of cannabinoids; b. One or more nonionic surfactants having an HLB value of 10 to 25; c. One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; d. At least 85% by weight of water; A method for preparing a solid cannabinoid composition according to any one of claims 1 to 14, comprising freeze-drying an aqueous solution containing the following: A method comprising the presence of one or more nonionic surfactants and one or more cannabinoids in the aqueous solution in a weight ratio of 3:1 to 30:1, and the presence of one or more carbohydrates and one or more cannabinoids in the aqueous solution in a weight ratio of 3:1 to 300:

1.

16. A vial or syringe containing a solid cannabinoid composition according to any one of claims 1 to 14 in an amount that provides 0.2 to 100 mg of cannabinoids.

17. (a) 0.1 to 10 mg / mL of one or more cannabinoids; (b) One or more nonionic surfactants having an HLB value of 10 to 25; (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; (d) at least 85% by weight of water; A sterile aqueous solution used in medical treatment, which includes, A sterile aqueous solution in which one or more types of nonionic surfactants and one or more types of cannabinoids are present in the sterile aqueous solution in a weight ratio of 3:1 to 30:1, and one or more types of carbohydrates and one or more types of cannabinoids are present in the sterile aqueous solution in a weight ratio of 3:1 to 300:

1.

18. The sterile aqueous solution used in medical treatment according to claim 17, wherein the one or more cannabinoids are selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, cannabinol, 11-hydroxytetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, delta-11-tetrahydrocannabinol, and tetrahydrocannabivarin, levonantradol, and nabilone, preferably selected from tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabidiol, and cannabinol, and most preferably selected from cannabidiol and tetrahydrocannabinol.

19. The sterile aqueous solution used in medical treatment according to claim 17 or 18, wherein the one or more nonionic surfactants have an HLB value in the range of 11 to 18, preferably in the range of 12 to 16.

20. A sterile aqueous solution used in medical treatment according to any one of claims 17 to 19, wherein the one or more nonionic surfactants are fatty acid esters of polyethylene glycol.

21. The one or more nonionic surfactants are esters of glycerol polyethylene glycol and C １２ -C ２０ hydroxy fatty acids, esters of polyethylene glycol and C １２ -C ２０ hydroxy fatty acids, esters of polyethylene glycol sorbitol and C １２ -C ２０ fatty acids, and combinations thereof, a sterile aqueous solution for use in the medical treatment according to any one of claims 17 to 20.

22. A sterile aqueous solution used in medical treatment according to any one of claims 17 to 21, wherein the one or more carbohydrates are selected from mannitol, sucrose, trehalose, and stachyose.

23. The sterile aqueous solution used in medical treatment according to claim 22, wherein the one or more carbohydrates are mannitol.

24. A sterile aqueous solution for use in medical treatment according to any one of claims 17 to 23, containing 0 to 10 mg / L of triglycerides.

25. A sterile aqueous solution for use in medical treatment according to claim 24, wherein the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

26. A sterile aqueous solution for use in medical treatment according to any one of claims 17 to 25, containing triglycerides and one or more cannabinoids in a weight ratio of triglycerides to one or more cannabinoids in the range of 0 to 1.

27. A sterile aqueous solution for use in medical treatment according to claim 26, comprising oil and one or more cannabinoids in a weight ratio of oil to one or more cannabinoids in the range of 0 to 1, wherein the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

28. A sterile aqueous solution for use in medical treatment according to any one of claims 17 to 27, which is prepared by combining the solid cannabinoid composition according to any one of claims 1 to 14 with a sterile solution containing at least 90% by weight of water.

29. A sterile aqueous solution used in a medical treatment according to any one of claims 17 to 28, wherein the medical treatment includes parenteral administration, preferably intravenous administration, of the sterile aqueous solution.

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