Solid cannabinoid compositions for parenteral use

Abstract

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

Description

Technical Field

[0001] This invention relates to a solid cannabinoid composition for parenteral use. The solid pharmaceutical composition of this invention can be suitably combined with a sterile aqueous liquid to produce a liquid suitable for parenteral administration.

[0002] The solid cannabinoid composition of the present invention is very stable and dissolves extremely quickly in aqueous liquids, thus enabling rapid preparation of liquids suitable for parenteral administration.

[0003] The cannabinoid compositions of the present invention can be suitably used to treat newborns at risk of epilepsy and brain injury, especially for the treatment of hypoxic-ischemic encephalopathy (HIE). Background Technology

[0004] Cannabinoids are highly hydrophobic substances with poor water solubility. For example, cannabidiol 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, to prepare parenteral aqueous solutions containing sufficiently therapeutically effective cannabinoids, it is necessary to improve the solubility of the cannabinoids.

[0005] Cannabinoids have limited stability, notably due to oxidation, especially when used in aqueous formulations.

[0006] Hypothermia ulcera (HIE) is caused by insufficient oxygen and / or blood flow from the placenta to the newborn. Currently, there are no approved drugs or pharmacological therapies for HIE, and the standard of care is therapeutic hypothermia, which is beneficial only to a select group of newborns. Each year, more than two million newborns worldwide die from HIE or develop permanent disabilities as a result.

[0007] Preclinical studies have provided strong evidence for 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 regulation of excitotoxicity, inflammation, and oxidative stress—major components of the pathophysiology of HIE. CBD protects neurons and glial cells and plays a significant role in maintaining normal myelination. Therefore, CBD is a valuable tool for HIE management because it is safe and effective. It is administered post-hoc via a parenteral route, providing a wide therapeutic window.

[0008] WO 2018 / 002636 describes preparations containing aqueous extragastric cannabinoids, which include:

[0009] (i) Cannabinoids;

[0010] (ii) Isotonic agents;

[0011] (iii) Surfactants; and

[0012] (iv) One or more stability enhancers.

[0013] WO 2022 / 174352 relates to a monophasic injectable cannabinoid formulation for parenteral administration. The formulation contains at least one cannabinoid completely dissolved in a co-solvent system. The co-solvent system contains (i) an effective amount of at least one triglyceride; (ii) an effective amount of at least one C6 to C6... 22 (iii) fatty acids; about 1% to about 3% w / v at least one phosphatidylglycerol and / or its salt; and (iv) (optionally) an effective amount of at least one antioxidant (or preservative) to improve shelf life. These formulations are free of water and ethanol.

[0014] WO 2022 / 017911 relates to the use of cannabidiol (CBD) for the treatment of epilepsy associated with a rare epilepsy syndrome related to brain injury. The CBD formulation contains greater than 95% (w / w) CBD and between 0.01% and 0.15% (w / w) tetrahydrocannabinol (THC). No injectable form is mentioned.

[0015] US 2019 / 015383 describes a water-soluble cannabinoid composition comprising:

[0016] • A purified mixture of cannabinoids;

[0017] • At least one carrier oil; and

[0018] • At least one water-soluble agent selected from complex carbohydrates, polyols, polysaccharides, oligosaccharides, or combinations thereof;

[0019] The composition is soluble in water at a temperature less than or equal to about 20°C; and

[0020] The composition is in the form of aggregated particles.

[0021] US 2023 / 030491 describes liquid emulsion formulations that contain:

[0022] i) One or more cannabinoids and / or cannabinoid extracts;

[0023] ii) one or more surfactants; and

[0024] iii) One or more oils,

[0025] The weight ratio of one or more surfactants to one or more cannabinoids and / or cannabinoid extracts is from about 1:1 to about 20:1, and the weight ratio of one or more oils to one or more cannabinoids and / or cannabinoid extracts is from about 1:1 to about 10:1. Summary of the Invention

[0026] The inventors have developed a solid cannabinoid composition that is highly stable and suitable for use in preparing a parenteral liquid by simply mixing the solid composition with an aqueous liquid (such as a sterile isotonic liquid) for a short period of time.

[0027] The solid cannabinoid composition according to the present invention comprises:

[0028] (i) 0.3-10 wt.% of one or more cannabinoids;

[0029] (ii) 4-69 wt.% of one or more nonionic surfactants with an HLB value of at least 10, preferably 10-25;

[0030] (iii) at least 20 wt.% of one or more carbohydrates selected from mannitol, sucrose, trehalose and stachyose;

[0031] (iv) 0-5 wt.% water;

[0032] The combination of one or more nonionic surfactants and one or more carbohydrates accounts for at least 70 wt. of the composition.

[0033] The solid cannabinoid compositions of the present invention can be suitably prepared by freeze-drying an aqueous liquid comprising one or more cannabinoids at appropriate concentrations, one or more nonionic surfactants having an HLB of 10 to 25, and one or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose. The resulting solid cannabinoid compositions are highly porous and comprise a substantially amorphous and glassy carbohydrate matrix. While the inventors do not wish to be bound by theory, it is believed that this characteristic combination and the presence of nonionic surfactants having an HLB in the range of 10 to 25 contribute to the high stability and rapid aqueous dissolution of the solid cannabinoid compositions of the present invention.

[0034] A second aspect of the invention relates to a method for preparing the solid cannabinoid composition of the invention, the method comprising freeze-drying an aqueous liquid comprising:

[0035] a. One or more cannabinoids at a concentration of 0.3-10 mg / mL;

[0036] b. One or more nonionic surfactants with an HLB value of at least 10, preferably 10-25;

[0037] c. One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and

[0038] d. At least 85 wt.% water;

[0039] One or more nonionic surfactants and one or more cannabinoids are present in an aqueous liquid in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in an aqueous liquid in a weight ratio of 3:1 to 300:1.

[0040] A third aspect of the invention relates to a vial or syringe containing a solid cannabinoid composition according to any one of the preceding claims, providing 0.2-100 mg of cannabinoids.

[0041] A fourth aspect of the present invention relates to a sterile aqueous liquid for medical treatment, said liquid comprising:

[0042] (a) One or more cannabinoids at a concentration of 0.1-10 mg / mL;

[0043] (b) One or more nonionic surfactants with an HLB value of at least 10, preferably 10-25;

[0044] (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and

[0045] (d) At least 85 wt.% water;

[0046] One or more nonionic surfactants and one or more cannabinoids are present in a sterile aqueous liquid in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in a sterile aqueous liquid in a weight ratio of 3:1 to 300:1. Detailed Implementation

[0047] A first aspect of the present invention relates to a solid cannabinoid composition comprising:

[0048] (i) 0.3-10 wt.% of one or more cannabinoids;

[0049] (ii) 4-69 wt.% of one or more nonionic surfactants with an HLB value of 10-25;

[0050] (iii) at least 20 wt.% of one or more carbohydrates selected from mannitol, sucrose, trehalose and stachyose;

[0051] (iv) 0-5 wt.% water;

[0052] The combination of one or more nonionic surfactants and one or more carbohydrates accounts for at least 70 wt. of the composition.

[0053] As used in this article, the term "freeze-drying" refers to a method in which the material is dried by cooling it to a temperature below its triple point (the temperature at which the solid, liquid, and gas phases of the material can coexist) and then sublimating it under reduced pressure.

[0054] As used herein, the term "parenteral" refers to a mode of administration in which the active pharmaceutical ingredient is delivered via a route other than enteral administration. Examples of parenteral administration include intravenous, intraperitoneal, intramuscular, and subcutaneous administration.

[0055] Solid cannabinoid compositions are preferably prepared by freeze drying.

[0056] The solid cannabinoid composition is preferably provided in the form of microcapsules, powder, or granules. Most preferably, the composition is provided in the form of microcapsules. The microcapsules preferably have a weight in the range of 50-1,200 mg, more preferably in the range of 100-1,000 mg.

[0057] Solid cannabinoid compositions provided in pellet form preferably have a density of 30 to 300 mg / mL, more preferably 40 to 200 mg / mL.

[0058] Solid cannabinoid compositions provided in powder or granule form preferably have a density of 10-200 mg / mL, more preferably 20 to 160 mg / mL.

[0059] The solid cannabinoid composition of the present invention preferably contains 0.4-8 wt.%, more preferably 0.6-6 wt.%, and most preferably 0.8-4 wt.% of one or more cannabinoids.

[0060] The cannabinoids used in this invention can be isolated from natural materials (e.g., cannabis plant materials) or obtained via synthetic routes. One or more cannabinoids in the solid compositions of this invention are preferably selected from tetrahydrocannabinol, Δ-9-tetrahydrocannabinol, Δ-8-tetrahydrocannabinol, cannabidiol, cannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-Δ-9-tetrahydrocannabinol, Δ-11-tetrahydrocannabinol, and tetrahydrocannabivarin, levonantradol, and nabilone. More preferably, one or more cannabinoids are selected from tetrahydrocannabinol, Δ-9-tetrahydrocannabinol, Δ-8-tetrahydrocannabinol, cannabidiol, and cannabinol. Even more preferably, one or more cannabinoids are selected from cannabidiol and tetrahydrocannabinol. Most preferably, the solid cannabinoid compositions of this invention comprise cannabidiol.

[0061] The solid cannabinoid composition preferably contains 5-40 wt.%, more preferably 6-30 wt.%, and most preferably 8-24 wt.% of one or more nonionic surfactants.

[0062] The one or more nonionic surfactants used in this invention preferably have an HLB content 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.

[0063] According to a preferred embodiment, one or more nonionic surfactants are fatty acid esters of polyethylene glycol, more preferably selected from glycerol polyethylene glycol and C... 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol and C 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol sorbitol and C 12 -C 20 Fatty acid esters and their combinations of fatty acid esters in polyethylene glycol.

[0064] In an advantageous embodiment, one or more surfactants are glycerol polyethylene glycol and C 12 -C 20 Hydroxy fatty acids, more preferably C 16 -C 18 Esters of hydroxy fatty acids. 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.

[0065] In another advantageous embodiment, one or more surfactants are polyethylene glycol and C 12 -C 20 Hydroxy fatty acids, more preferably C16 -C 18 Esters of hydroxy fatty acids. Most preferably, the nonionic surfactant is an ester of polyethylene glycol and 12-hydroxystearic acid. Kolliphor® HS 15 is a commercially available example of such a surfactant.

[0066] According to another advantageous embodiment, one or more surfactants are polyethylene glycol sorbitol and C 12 -C 20 Fatty acids, more preferably C 16 -C 18 Fatty acid esters. Most preferably, the nonionic surfactant is an ester of polyethylene glycol sorbitol and oleic acid. Polysorbate 80 is an example of such a surfactant.

[0067] The solid cannabinoid composition preferably contains at least 30 wt.%, more preferably 40-95 wt.%, even more preferably 60-93 wt.%, and most preferably 75-92 wt.% of one or more carbohydrates.

[0068] One or more carbohydrates are preferably selected from mannitol and sucrose. Most preferably, mannitol is used as the carbohydrate.

[0069] According to a particularly preferred embodiment, the solid cannabinoid composition contains at least 80 wt.% of one or more amorphous carbohydrates.

[0070] The combination of one or more nonionic surfactants and one or more carbohydrates accounts for at least 80 wt.%, more preferably at least 85 wt.%, of the solid cannabinoid composition.

[0071] Preferably, the combination of one or more cannabinoids, one or more nonionic surfactants and one or more carbohydrates accounts for at least 75 wt.%, more preferably at least 85 wt.%, and most preferably at least 90 wt.% of the solid cannabinoid composition.

[0072] 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 in a weight ratio of 4:1 to 25:1, and even more preferably in a weight ratio of 5:1 to 20:1.

[0073] 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.

[0074] As described by Werk et al. (An Impedance-Based Method to Determine Reconstitution Time for Freeze-Dried Pharmaceuticals), J. of Pharm.Sc. (2015) 104:2948-2955), using 300 mg of solid cannabinoid composition and 5 mL of water for injection at 20°C, the solid cannabinoid composition of the present invention preferably has a reconstitution time of less than 180 seconds, more preferably less than 120 seconds, and most preferably less than 60 seconds.

[0075] In addition to rapid dissolution, the solid cannabinoid composition of the present invention preferably forms a clear solution. Therefore, medical personnel can easily determine whether the solid composition is sufficiently dissolved and ready for parenteral administration.

[0076] According to a preferred embodiment, 300 mg of the solid cannabinoid composition of the present invention is reconstituted with 5 mL of water for injection at 20°C to produce a clear solution. The reconstituted composition is considered clear if its clarity is the same as that of water R, or if the opalescence of the reconstituted composition does not exceed the opalescence of reference suspension I as per Table 2.2.1-2 of Chapter 2.2.1 of the European Pharmacopoeia.

[0077] In addition to one or more cannabinoids, the solid cannabinoid composition preferably does not contain significant amounts of lipophilic components, because the presence of such components in the composition may lead to the formation of a cloudy or turbid emulsion when the solid composition is reconstituted in an aqueous liquid for parenteral use.

[0078] Therefore, in preferred embodiments, the solid cannabinoid composition contains 0-1 wt.% triglycerides, more preferably 0-0.5 wt.% triglycerides, even more preferably 0-0.3 wt.% triglycerides, and most preferably 0-0.1 wt.% triglycerides.

[0079] Preferably, the solid cannabinoid composition contains 0-1 wt.% oil, more preferably 0-0.5 wt.% oil, even more preferably 0-0.3 wt.% oil, and most preferably 0-0.1 wt.% oil, said oil being selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

[0080] The solid cannabinoid composition of the present invention preferably contains triglycerides and one or more cannabinoids, wherein the weight ratio of triglycerides to one or more cannabinoids is 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.

[0081] The oil and one or more cannabinoids are preferably present in the solid cannabinoid composition, wherein the weight ratio of oil to one or more cannabinoids is 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.

[0082] The water content of the solid cannabinoid composition is preferably in the range of 0-3 wt.%, more preferably in the range of 0-2.5 wt.%, and most preferably in the range of 0-2 wt.%.

[0083] In addition to cannabinoids, nonionic surfactants, carbohydrates, and water, the solid cannabinoid compositions of the present invention may suitably contain other ingredients. Examples of such ingredients include salts, polymers (such as polyvinylpyrrolidone), antioxidants (such as ascorbic acid), and isotonic agents (such as glycerin).

[0084] According to a particularly preferred embodiment, when the solid cannabinoid composition is dispersed in distilled water at a concentration of 10 to 200 mg / mL, an aqueous liquid with an osmotic pressure in the range of 100 to 800 mOsm / L, more preferably in the range of 150 to 500 mOsm / L, and most preferably in the range of 200 to 400 mOsm / L is produced.

[0085] According to a second aspect of the present invention, a method for preparing the solid cannabinoid composition of the present invention is provided. The method includes freeze-drying an aqueous liquid comprising:

[0086] (a) One or more cannabinoids at a concentration of 0.1-10 mg / mL;

[0087] (b) One or more nonionic surfactants with an HLB value of 10-25;

[0088] (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and

[0089] (d) At least 85 wt.% water;

[0090] One or more nonionic surfactants and one or more cannabinoids are present in an aqueous liquid in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in an aqueous liquid in a weight ratio of 3:1 to 300:1.

[0091] One or more nonionic surfactants and one or more cannabinoids are preferably present in an aqueous liquid in a weight ratio of 4:1 to 25:1, more preferably in a weight ratio of 5:1 to 20:1.

[0092] Preferably, one or more carbohydrates and one or more cannabinoids are present in an aqueous liquid 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.

[0093] Preferably, the freeze-dried aqueous liquid in the method of the present invention contains 0.2-8 mg / mL of one or more cannabinoids, more preferably 0.4-4 mg / mL of one or more cannabinoids.

[0094] Freeze-drying of aqueous liquids includes the following three consecutive stages: (1) freezing; (2) primary drying (sublimation); and (3) secondary drying (absorption).

[0095] Freeze-drying of aqueous liquids may include additional process steps, such as one or more annealing steps.

[0096] In the first drying stage, the pressure is reduced and heat is added to the material to cause water to sublimate. Most of the water in the material is removed in this stage. In the second drying stage, ion-bound water molecules are removed. By raising the temperature above that of the first drying stage, the bonds between the material and water molecules break. Once the freeze-drying process is complete, the vacuum is broken.

[0097] After freeze-drying, the solid cannabinoid composition is preferably introduced into a vial or syringe. According to a particularly preferred embodiment, the solid cannabinoid composition is introduced and sealed into the vial or syringe under reduced pressure. The inventors have found that this embodiment provides an important advantage in effectively minimizing foaming when the solid cannabinoid composition is combined with an aqueous solvent. In a preferred embodiment, the solid cannabinoid composition is introduced and sealed into the vial or syringe under a pressure of less than 10 kPa, more preferably less than 5 kPa, and most preferably 0-1 kPa.

[0098] A third aspect of the invention relates to a vial or syringe comprising a solid cannabinoid composition of the invention providing 0.2-100 mg, more preferably 0.5-40 mg, even more preferably 1-20 mg of cannabinoid, and most preferably 2-10 mg of cannabinoid.

[0099] In a preferred embodiment, the syringe comprises two chambers, a first chamber containing a solid cannabinoid composition and a second chamber containing a sterile isotonic aqueous solvent. Preferably, the syringe is configured to allow the contents of the two chambers to mix to produce an aqueous cannabinoid solution and to allow the aqueous cannabinoid solution to be expelled from the syringe, for example, by pushing the syringe plunger.

[0100] As explained above, the chamber of the vial or syringe containing the solid cannabinoid composition is preferably under reduced pressure. Preferably, the reduced pressure is at most 50 kPa, more preferably at most 30 kPa, and most preferably from 0.0001 to 10 kPa.

[0101] A fourth aspect of the present invention relates to a sterile aqueous liquid for medical treatment, said liquid comprising:

[0102] (a) One or more cannabinoids at a concentration of 0.1-10 mg / mL;

[0103] (b) One or more nonionic surfactants with an HLB value of 10-25;

[0104] (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and

[0105] (d) At least 85 wt.% water;

[0106] One or more nonionic surfactants and one or more cannabinoids are present in a sterile aqueous liquid in a weight ratio of 3:1 to 30:1, and one or more carbohydrates and one or more cannabinoids are present in a sterile aqueous liquid in a weight ratio of 3:1 to 300:1.

[0107] According to a particularly preferred embodiment, a sterile aqueous liquid can be obtained by dispersing the solid cannabinoid composition of the present invention into water for injection.

[0108] Preferably, the sterile aqueous solution used in the treatment contains 0.2-8 mg / mL of one or more cannabinoids, more preferably 0.4-4 mg / mL of one or more cannabinoids.

[0109] The one or more cannabinoids in the sterile aqueous liquid are preferably selected from tetrahydrocannabinol (THC), Δ-9-tetrahydrocannabinol (Δ-8-THC), cannabidiol (CBD), cannabinol (CBD), 11-hydroxy-tetrahydrocannabinol (THC), 11-hydroxy-Δ-9-tetrahydrocannabinol (Δ-11-THC), tetrahydrocannabidiol (THC), zonanchodole, and cannabinol. More preferably, the one or more cannabinoids are selected from THC, Δ-9-tetrahydrocannabinol (THC), Δ-8-tetrahydrocannabinol (THC), cannabidiol, and cannabinol. Even more preferably, the one or more cannabinoids are selected from cannabidiol and THC. Most preferably, the cannabinoid is cannabidiol.

[0110] The one or more nonionic surfactants used preferably have an HLB content 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.

[0111] One or more nonionic surfactants in sterile aqueous liquids are preferably fatty acid esters of polyethylene glycol, more preferably selected from glycerol polyethylene glycol and C 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol and C 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol sorbitol and C 12 -C 20 Fatty acid esters and their combinations of fatty acid esters in polyethylene glycol.

[0112] In an advantageous embodiment, one or more surfactants are glycerol polyethylene glycol and C 12 -C 20 Esters of hydroxy fatty acids. 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.

[0113] In another advantageous embodiment, one or more surfactants are polyethylene glycol and C 12 -C 20 Esters of hydroxy fatty acids. 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.

[0114] According to another advantageous embodiment, one or more surfactants are polyethylene glycol sorbitol and C 12 -C 20 Fatty acid esters. Most preferably, the nonionic surfactant is an ester of polyethylene glycol sorbitol and oleic acid. Polysorbate 80 is an example of such a surfactant.

[0115] Preferably, one or more carbohydrates are selected from mannitol, sucrose, and combinations thereof. Most preferably, the carbohydrate used is mannitol.

[0116] One or more nonionic surfactants and one or more cannabinoids are preferably present in a sterile aqueous liquid in a weight ratio of 4:1 to 25:1, more preferably in a weight ratio of 5:1 to 20:1.

[0117] Preferably, one or more carbohydrates and one or more cannabinoids are present in a sterile aqueous liquid 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.

[0118] The sterile aqueous liquid preferably contains 0-10 mg / L of triglycerides, more preferably 0-6 mg / L of triglycerides, even more preferably 0-3 mg / L of triglycerides, and most preferably 0-1 mg / L of triglycerides.

[0119] The oil is preferably contained in a sterile aqueous liquid at a concentration of 0-10 mg / L, more preferably 0-6 mg / L, even more preferably 0-3 mg / L, and most preferably 0-1 mg / L, said oil being selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

[0120] The sterile aqueous liquid preferably contains triglycerides and one or more cannabinoids, wherein the weight ratio of triglycerides to one or more cannabinoids is 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.

[0121] The oil and one or more cannabinoids are preferably contained in a sterile aqueous liquid, wherein the weight ratio of oil to one or more cannabinoids is 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.

[0122] According to a particularly preferred embodiment, the aqueous liquid has a pH of 2-11, more preferably 4-9, and most preferably 6.5-8.0.

[0123] According to a particularly preferred embodiment, the aforementioned aqueous liquid has an osmotic pressure 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.

[0124] According to a particularly preferred embodiment, a sterile aqueous liquid is prepared by combining the solid cannabinoid composition of the present invention with a sterile liquid. Preferably, the sterile liquid used to prepare the sterile aqueous liquid contains at least 90 wt.% water, more preferably at least 95 wt.% water.

[0125] According to a particularly preferred embodiment, the medical treatment includes parenteral administration, more preferably intravenous, intraperitoneal, intramuscular or subcutaneous administration, and most preferably intravenous administration of sterile aqueous liquid.

[0126] The medical treatment of the present invention preferably includes administering a sterile aqueous solution to a newborn. Preferably, the sterile aqueous solution is administered to the newborn to provide a dose of cannabinoids of 1-15 mg, more preferably 2-10 mg.

[0127] In a particularly preferred embodiment, the medical treatment of the present invention is the treatment of newborns at risk of epilepsy and brain injury, especially hypoxic-ischemic encephalopathy (HIE).

[0128] The invention is further illustrated by the following non-limiting examples. Example

[0129] Example 1

[0130] Prepare an aqueous solution containing cannabidiol based on the formulation shown in Table 1.

[0131] Table 1

[0132]

[0133] 1 Ester of glycerol polyethylene glycol and ricinoleic acid (HLB 12-14)

[0134] First, dissolve cannabidiol in a surfactant and first dissolve mannitol in demineralized water, then mix the two solutions using a magnetic stirrer.

[0135] Five ml aliquots of cannabidiol solution were placed into transparent glass vials with rolled necks (8R: diameter = 22 mm, height = 45 mm), then frozen and lyophilized.

[0136] Freeze-drying was performed in a freeze dryer (Drawell Analytical, DW-10N series) using a vacuum pump (2XZ-2 rotary vane vacuum pump (A4218)).

[0137] The freeze-drying operation settings are as follows:

[0138] • Cold trap temperature -60°C,

[0139] • Pressure 1.0-3.0 Pa,

[0140] • Duration + / - 24 hours.

[0141] The glass vials containing the freeze-dried microparticles are sealed by using a screw cap that includes a septum.

[0142] The dissolution rate (reconstruction time) of the lyophilized cannabidiol microspheres was evaluated within the vial by introducing 5 mL of demineralized water at 20°C through a septum into a clear glass vial using a syringe, gently shaking the vial manually, and determining the time elapsed until a clear solution was formed. The results are summarized in Table 2.

[0143] Table 2

[0144]

[0145] The advantage of cannabinoid microcapsules 2 is that they can be easily diluted with water for injection to produce an isotonic intravenous solution, which can be appropriately administered to newborns by injection to provide a dose of cannabinoids of 2-10 mg.

[0146] Example 2

[0147] Repeat Example 1, starting with formulation number 3, except that mannitol was replaced with sucrose. This time, it took slightly more than 2 minutes to achieve complete dissolution of the microspheres.

[0148] Example 3

[0149] Example 1 was repeated starting with formulation number 3, except that the vials were freeze-dried at 2 Pa and sealed. Dissolution tests yielded similar dissolution times to Example 1, but significantly less foaming was observed during shaking.

[0150] Example 4

[0151] Prepare an aqueous solution containing cannabidiol based on the formulation shown in Table 3.

[0152] Table 3

[0153]

[0154] 1 Ester of glycerol polyethylene glycol and ricinoleic acid (HLB 12-14)

[0155] 2 Esters of polyethylene glycol and 12-hydroxystearic acid (HLB 14-16)

[0156] 3 Ester of polyethylene glycol sorbitol and oleic acid (HLB 15)

[0157] First, cannabidiol was dissolved in a surfactant, and mannitol was first dissolved in demineralized water. The two solutions were then mixed using a magnetic stirrer. All the cannabidiol solutions thus obtained were completely clear, indicating that after lyophilization, the lyophilized material will form a clear solution after reconstruction with water.

[0158] Example 5

[0159] Prepare an aqueous solution containing cannabidiol based on the formulation shown in Table 4.

[0160] Table 4

[0161]

[0162] 1 Ester of glycerol polyethylene glycol and ricinoleic acid (HLB 12-14)

[0163] First, dissolve cannabidiol in a surfactant and then dissolve each carbohydrate in demineralized water. Then, mix the two solutions using a magnetic stirrer.

[0164] The cannabidiol solution obtained in this way was filled into a transparent glass tubular injection vial with a rolled neck (8R: diameter = 22 mm, height = 45 mm), and then frozen and lyophilized.

[0165] Freeze-drying was performed in a freeze dryer (Drawell Analytical, DW-10N series) using a vacuum pump (2XZ-2 rotary vane vacuum pump (A4218)).

[0166] The freeze-drying operation settings are as follows:

[0167] • Cold trap temperature -60°C,

[0168] • Pressure 1.0-3.0 Pa,

[0169] • Duration + / - 24 hours.

[0170] Glass vials containing lyophilized microparticles are sealed by using screw caps with septa.

[0171] The dissolution rate of the lyophilized cannabidiol microspheres was evaluated in a clear glass vial by introducing 5 mL of demineralized water at 20°C through a septum using a syringe, gently shaking the vial manually, and determining the time elapsed until a clear solution formed or until no further dissolution occurred. The appearance of the lyophilized product and the reconstituted liquid was also evaluated. The results obtained for the lyophilized cannabidiol solution in Table 4 are summarized in Table 5.

[0172] Table 5

[0173]

[0174] Under these conditions, cake collapse and / or remelting occur, resulting in freeze-dried products that cannot be reliably reconstituted.

[0175] Example 6

[0176] Prepare an aqueous solution containing cannabidiol based on the formulation shown in Table 6.

[0177] Table 6

[0178]

[0179] 1 Ester of glycerol polyethylene glycol and ricinoleic acid (HLB 12-14)

[0180] First, dissolve cannabidiol in an emulsifier and first dissolve trehalose in demineralized water, then mix the two solutions using a magnetic stirrer.

[0181] The dissolution rate, appearance of the lyophilized cannabidiol microspheres, lyophilized product, and reconstituted liquid were evaluated in the same manner as in Example 5. The results are summarized in Table 7.

[0182] Table 7

[0183]

[0184] Example 7

[0185] Prepare an aqueous solution containing cannabidiol based on the formulation shown in Table 8.

[0186] Table 8

[0187]

[0188] 1 Ester of glycerol polyethylene glycol and ricinoleic acid (HLB 12-14)

[0189] First, dissolve cannabidiol in an emulsifier and first dissolve stachyose in demineralized water, then mix the two solutions using a magnetic stirrer.

[0190] The dissolution rate, appearance of the lyophilized cannabidiol microspheres, lyophilized product, and reconstituted liquid were evaluated in the same manner as in Example 5. The results are summarized in Table 9.

[0191] Table 9

[0192]

[0193] Example 8

[0194] Prepare an aqueous solution containing tetrahydrocannabinol based on the formulation shown in Table 10.

[0195] Table 10

[0196]

[0197] 1 Ester of glycerol polyethylene glycol and ricinoleic acid (HLB 12-14)

[0198] 2 Esters of polyethylene glycol and 12-hydroxystearic acid (HLB 14-16)

[0199] 3 Ester of polyethylene glycol sorbitol and oleic acid (HLB 15)

[0200] First, dissolve tetrahydrocannabinol in an emulsifier, and then dissolve mannitol in demineralized water. Finally, mix the two solutions using a magnetic stirrer.

[0201] All the tetrahydrocannabinol solutions obtained in this way were completely clear, indicating that after freeze-drying, the dried material will form a clear solution after being reconstituted with water.

[0202] Example 9

[0203] The tetrahydrocannabinol solution 2 of Example 7 was freeze-dried in the same manner as described in Example 5.

[0204] The dissolution rate of the lyophilized product and the appearance of the lyophilized product and the reconstituted liquid were evaluated in the same manner as in Example 5. It was found that the lyophilized product formed a clear solution within 23 seconds.

[0205] Comparison Example A

[0206] The mixture of SNEDD, water, and sorbitol from Example 11 of US 2023 / 0030491 was reproduced. The resulting aqueous liquid was cloudy, indicating that the dried material would also form a cloudy liquid upon reconstruction with water after freeze-drying.

[0207] Comparison Example B

[0208] Prepare an aqueous solution containing cannabidiol based on the formulation shown in Table 11.

[0209] Table 11

[0210]

[0211] 1 Block copolymer of ethylene oxide and propylene oxide (HLB 29)

[0212] All cannabidiol preparations obtained were cloudy dispersions.

Claims

1. A solid cannabinoid composition comprising: (i) 0.3-10 wt.% of one or more cannabinoids; (ii) 4-69 wt.% of one or more nonionic surfactants with an HLB value of 10-25; (iii) at least 20 wt.% of one or more carbohydrates selected from mannitol, sucrose, trehalose and stachyose; (iv) 0-5 wt.% water; The combination of said one or more nonionic surfactants and said one or more carbohydrates accounts for at least 70 wt.% 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, Δ-9-tetrahydrocannabinol, Δ-8-tetrahydrocannabinol, cannabidiol, cannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-Δ-9-tetrahydrocannabinol, Δ-11-tetrahydrocannabinol and tetrahydrocannabidiol, zonanchodolurea and cannabinol, preferably selected from tetrahydrocannabinol, Δ-9-tetrahydrocannabinol, Δ-8-tetrahydrocannabinol, cannabidiol and cannabinol, and most preferably selected from cannabidiol and tetrahydrocannabinol.

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

5. The solid cannabinoid composition according to any one of the preceding claims, wherein, The composition contains at least 4 wt.% of a nonionic surfactant with 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 the preceding claims, wherein, The one or more nonionic surfactants are fatty acid esters of polyethylene glycol.

7. The solid cannabinoid composition according to claim 6, wherein, The fatty acid ester of the polyethylene glycol is selected from glycerol polyethylene glycol and C. 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol and C 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol sorbitol and C 12 -C 20 Fatty acid esters and their combinations.

8. The solid cannabinoid composition according to any one of the preceding claims, 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 mentioned are mannitol.

10. The solid cannabinoid composition according to any one of the preceding claims, wherein, The solid cannabinoid composition contains 0-1 wt.% triglycerides.

11. The solid cannabinoid composition according to claim 10, wherein, The solid cannabinoid composition contains 0-1 wt.% oil, which 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 the preceding claims, wherein, The solid cannabinoid composition contains triglycerides and one or more cannabinoids, with the weight ratio of triglycerides to one or more cannabinoids ranging from 0 to 1.

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

14. The solid cannabinoid composition according to any one of the preceding claims, wherein, When the composition is dispersed in distilled water at a concentration of 10 to 200 mg / mL at a temperature of 37°C, it produces an aqueous liquid with an osmotic pressure in the range of 100 to 800 mOsm / L.

15. A method for preparing a solid cannabinoid composition according to any one of claims 1-14, the method comprising freeze-drying an aqueous liquid, the aqueous liquid comprising: a. One or more cannabinoids at a concentration of 0.1-10 mg / mL; b. One or more nonionic surfactants with an HLB value of 10-25; c. One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and d. At least 85 wt.% water; The one or more nonionic surfactants and the one or more cannabinoids are present in the aqueous liquid in a weight ratio of 3:1 to 30:1, and the one or more carbohydrates and the one or more cannabinoids are present in the aqueous liquid 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 1-14, providing 0.2-100 mg of cannabinoid.

17. A sterile aqueous liquid for medical treatment, said liquid comprising: (a) One or more cannabinoids at a concentration of 0.1-10 mg / mL; (b) One or more nonionic surfactants with an HLB value of 10-25; (c) One or more carbohydrates selected from mannitol, sucrose, trehalose, and stachyose; and (d) At least 85 wt.% water; The one or more nonionic surfactants and the one or more cannabinoids are present in the sterile aqueous liquid in a weight ratio of 3:1 to 30:1, and the one or more carbohydrates and the one or more cannabinoids are present in the sterile aqueous liquid in a weight ratio of 3:1 to 300:

1.

18. The sterile aqueous liquid for medical treatment according to claim 17, wherein, The one or more cannabinoids are selected from tetrahydrocannabinol, Δ-9-tetrahydrocannabinol, Δ-8-tetrahydrocannabinol, cannabidiol, cannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-Δ-9-tetrahydrocannabinol, Δ-11-tetrahydrocannabinol and tetrahydrocannabidiol, zonanchodolurea and cannabinol, preferably selected from tetrahydrocannabinol, Δ-9-tetrahydrocannabinol, Δ-8-tetrahydrocannabinol, cannabidiol and cannabinol, and most preferably selected from cannabidiol and tetrahydrocannabinol.

19. The sterile aqueous liquid for 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. The sterile aqueous liquid for medical treatment according to any one of claims 17-19, wherein, The one or more nonionic surfactants are fatty acid esters of polyethylene glycol.

21. The sterile aqueous liquid for medical treatment according to any one of claims 17-20, wherein, The one or more nonionic surfactants are selected from glycerol, polyethylene glycol, and C. 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol and C 12 -C 20 Esters of hydroxy fatty acids, polyethylene glycol sorbitol and C 12 -C 20 Fatty acid esters and their combinations.

22. The sterile aqueous liquid for medical treatment according to any one of claims 17-21, wherein, The one or more carbohydrates are selected from mannitol, sucrose, trehalose and stachyose.

23. The sterile aqueous liquid for medical treatment according to claim 22, wherein, The one or more carbohydrates mentioned are mannitol.

24. The sterile aqueous liquid for medical treatment according to any one of claims 17-23, wherein, The sterile aqueous liquid contains 0-10 mg / L of triglycerides.

25. The sterile aqueous liquid for medical treatment according to claim 24, wherein, The sterile aqueous liquid contains 0-10 mg / L of oil, wherein the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, propylene glycol monoesters, propylene glycol diesters, and combinations thereof.

26. The sterile aqueous liquid for medical treatment according to any one of claims 17-25, wherein, The sterile aqueous liquid contains triglycerides and one or more cannabinoids, with the weight ratio of triglycerides to one or more cannabinoids ranging from 0 to 1.

27. The sterile aqueous liquid for medical treatment according to claim 26, wherein, The sterile aqueous liquid contains oil and one or more cannabinoids, wherein the weight ratio of oil to one or more cannabinoids is in the range of 0 to 1, and the oil is selected from fatty acids, monoglycerides, diglycerides, triglycerides, monopropylene glycol esters, propylene glycol diesters, and combinations thereof.

28. The sterile aqueous liquid for medical treatment according to any one of claims 17-27, wherein, The sterile aqueous liquid is prepared by combining a solid cannabinoid composition according to any one of claims 1-14 with a sterile liquid containing at least 90 wt.% water.

29. The sterile aqueous liquid for medical treatment according to any one of claims 17-28, wherein, The medical treatment includes parenteral administration, preferably intravenous administration, of the sterile aqueous liquid.

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