Novel parenteral formulations of cannabidiol

Abstract

The present invention relates to a parenteral emulsion formulation of cannabidiol comprising synthetic cannabidiol (CBD), an omega-3 component, and other pharmaceutically acceptable excipients. The present invention further relates to a parenteral emulsion formulation comprising synthetic cannabidiol in combination with one or more active agents, an omega-3 component, and other pharmaceutically acceptable excipients. The formulation is used to treat acute and chronic pain, inflammatory diseases, liver diseases, cardiovascular diseases, respiratory diseases, immune diseases, and central nervous system diseases.

Description

[Technical Field]

[0001] The present invention relates to a parenteral emulsion formulation of cannabidiol containing synthetic cannabidiol (CBD), an omega-3 component, and other pharmaceutically acceptable excipients. The present invention further relates to a parenteral emulsion formulation containing synthetic cannabidiol in combination with one or more active agents, an omega-3 component, and other pharmaceutically acceptable excipients. The formulation is used to treat acute and chronic pain, inflammatory diseases, liver diseases, cardiovascular diseases, respiratory diseases, immune diseases, and central nervous system (CNS) diseases. [Background technology]

[0002] Cannabidiol (CBD) is a phytocannabinoid found in the cannabis plant and is one of 113 identified cannabinoids. CBD has a complex pharmacological mechanism, exhibiting antipsychotic, analgesic, anticonvulsant, muscle relaxant, anxiety-reducing, anti-inflammatory, antitumor, cytostatic, and antiangiogenic effects. At low doses, CBD exhibits physiological effects that promote and maintain health, including antioxidant, anti-inflammatory, and neuroprotective effects. CBD is considered more effective as a neuroprotective antioxidant than vitamins C and E and can also be used to treat skin conditions, such as acne.

[0003] In the United States, CBD is available as an oral liquid (100 mg / mL) called Epidiolex™ for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. CBD is highly lipophilic and undergoes extensive first-pass metabolism, resulting in low bioavailability.

[0004] Omega-3 components are highly unsaturated fatty acids found in seafood and are essential for cell and organ function. Of particular importance are omega-3 fatty acids such as docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid, omega-3 ethyl esters, non-phosphate-containing glycerolipids such as omega-3 triglycerides, diacylglycerols, monoacylglycerols, and phospholipids. These are useful in treating a variety of conditions related to the cardiovascular, pulmonary, nervous, immune, and endocrine systems. O3 components are converted into bioactive lipid metabolites in the body to form the endocannabinoid system. These endocannabinoids mimic the functions of cannabinoids. Therefore, CBD, when combined with O3 components, may offer enhanced health benefits.

[0005] U.S. Patent No. 5,849,297 to Chandrashekhar et al. discloses nanolipid carrier systems for cannabidiol for oral administration. These cannabidiol formulations include an active ingredient, a low-phase transition material, a PEGylated lipid, and other excipients dispersed in water or an aqueous medium. These systems have a hydrodynamic diameter (HDD) of less than about 1000 nm in aqueous media.

[0006] US Patent No. 5,999,999 to Garabagi Freydoun et al. discloses a cannabinoid formulation for oral administration, which comprises one or more cannabinoids and a lipid carrier comprising an oil.

[0007] Patent Document 3 by Sinai Alon et al. discloses emulsion compositions containing tetrahydrocannabinol (THC), cannabidiol (CBD) or derivatives thereof, phospholipids, and an oil fraction containing about 50% cannabinoids. These emulsions are intended for topical, oral, or nasal administration and are not suitable for parenteral administration.

[0008] US Patent Publication No. 2005 / 0129994 to Stephen et al. discloses parenteral formulations of cannabinoids containing an isotonicity agent, a surfactant, a bulking agent, a solvent, and one or more stability enhancers. These formulations are spray-dried or freeze-dried and therefore require reconstitution with a suitable diluent prior to administration.

[0009] US Patent No. 5,929,999 to Jackson et al. discloses a parenteral formulation comprising at least one cannabinoid from natural or synthetic sources, at least one surfactant, at least two antioxidants, at least one chelating agent, and a buffering agent.

[0010] Patent Document 6 to Christopher et al. discloses an inhalation and injection emulsion formulation of cannabinoids prepared using at least one co-solvent (ethanol) in the range of 0.5% w / v to 50% w / v and at least one surfactant.

[0011] U.S. Patent No. 6,277,999 to Alexander et al. discloses formulations of natural or synthetic cannabidiol, alone or in combination with antiepileptic drugs, prepared using various nanolipid carrier systems, which require robust and time-consuming techniques for formulation.

[0012] Patent Document 8 to Bolton et al. discloses a method for treating heart-related diseases using cannabidiol. These parenteral formulations are prepared using various solvents, including fatty acids, triglycerides, ethanol, and lipids. Specific exemplified formulations are not included. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2022 / 038528 [Patent Document 2] U.S. Patent Application Publication No. 2021 / 0186870 [Patent Document 3] International Publication No. 2016 / 147186 [Patent Document 4] U.S. Patent No. 1,122,9612 [Patent Document 5] US Patent Application Publication No. 2022 / 193004 [Patent Document 6] International Publication No. 2019 / 140325 [Patent Document 7] International Publication No. 2019 / 094625 [Patent Document 8] International Publication No. 2021 / 077211 Summary of the Invention [Problem to be solved by the invention]

[0014] Most of the CBD used in the art and in commercial preparations is naturally derived, and often contains high concentrations of THC and other undesirable plant-related substances.THC causes many undesirable effects, and patients may experience euphoria and anxiolytic effects and heightened perception.High doses of THC are associated with anxiety, panic and disorientation. [Means for solving the problem]

[0015] The present invention provides a parenteral emulsion formulation of CBD containing less than 1% THC. The emulsion formulation may further contain one or more active agents and may be used to treat acute and chronic pain, inflammation, central nervous system and immune disorders.

[0016] One aspect of the present invention is to provide a parenteral emulsion formulation of synthetic cannabidiol having less than 1.0% tetrahydrocannabinol (THC).

[0017] Another aspect of the present invention is to provide a parenteral emulsion formulation of synthetic cannabidiol having less than 0.5% tetrahydrocannabinol (THC).

[0018] Yet another aspect of the present invention is to provide a parenteral emulsion formulation comprising synthetic cannabidiol, an omega-3 component, and other pharmaceutically acceptable excipients.

[0019] Yet another aspect of the present invention is to provide a parenteral emulsion formulation comprising synthetic cannabidiol, an omega-3 fatty acid or an omega-3 fatty acid ethyl ester or an omega-3 triglyceride, and other pharmaceutically acceptable excipients.

[0020] Another aspect of the present invention is to provide a parenteral emulsion formulation comprising synthetic cannabidiol and an omega-3 fatty acid, or an omega-3 fatty acid ethyl ester, or an omega-3 triglyceride, wherein the concentration of CBD ranges from about 0.05 mg / ml to about 250 mg / ml, and the concentration of the omega-3 component ranges from about 1 mg / ml to about 500 mg / ml.

[0021] Yet another aspect of the present invention is to provide a parenteral emulsion formulation comprising synthetic cannabidiol in combination with other active ingredients, omega-3 components and other pharmaceutically acceptable excipients. DETAILED DESCRIPTION OF THE INVENTION

[0022] The term "CBD" as used herein refers to synthetic cannabidiol or a derivative of synthetic cannabidiol. The CBD content in the formulation may range from about 0.005% w / v to 25% w / v.

[0023] The term "parenteral administration" refers to administration by subcutaneous, intramuscular, intraarticular, intravenous, intrathecal or intra-articular injection or infiltrative injection.

[0024] In the context of the present invention, "O3 components or omega-3 components" refers to (i) highly unsaturated fatty acids (omega-3 fatty acids) contained in seafood, or (ii) omega-3 ethyl esters present in fish oil, or (iii) omega-3 triglycerides, or (iv) α-lipoic acid and derivatives of α-lipoic acid. The formulations of the present invention preferably contain one or more omega-3 components, including docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA). When a formulation contains two or more O3 components, the ratios thereof may vary.

[0025] The present invention provides a parenteral emulsion formulation of cannabidiol, comprising synthetic CBD, an omega-3 component in the form of an omega-3 fatty acid or an omega-3 ethyl ester or an omega-3 triglyceride, and other pharmaceutically acceptable excipients, wherein the composition contains less than 1% THC. Preferably, the formulation has less than 0.5% THC, more preferably less than 0.3% THC. Most preferably, the formulation contains no THC below the detection limit as determined by standard analytical techniques.

[0026] The parenteral emulsion formulation comprises an oil phase and an aqueous phase. The oil or lipid phase comprises cannabidiol dispersed / dissolved in an oil or lipid vehicle. The oil phase may optionally comprise a polymer, co-solvent, surfactant, and stabilizer. The aqueous phase comprises one or more aqueous vehicles and optionally co-solvents, surfactants, stabilizers, buffers, and isotonicity agents. The oil phase ranges from about 5% to about 40% w / v and the aqueous phase ranges from about 25% to about 95% w / v of the total formulation.

[0027] The emulsion formulation preferably has a D of less than 550 nm 90 and globules having a hydrodynamic diameter (HDD) of less than 250 nm. 90The globule size ranges from about 75 nm to 450 nm, and the HDD ranges from about 50 nm to 300 nm. It is advantageous to have a formulation with such globule sizes as they minimize irritation and discomfort to the patient.

[0028] The concentration of cannabidiol ranges from about 0.05 mg / ml to about 250 mg / ml or about 0.005% to 25% (w / v) in the formulation, with CBD comprising about 2% to 60% w / v in the oil phase.

[0029] The oil phase in the emulsion formulation comprises one or more omega-3 components selected from the group comprising omega-3 fatty acids (FA), such as docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA), or omega-3 ethyl esters or omega-3 triglycerides.The concentration of omega-3 FA or ethyl esters in the formulation can range from about 0.1 w / v% to about 50 w / v%.The content of omega-3 components can vary from about 1 mg / ml to about 500 mg / ml.

[0030] The oil phase may further comprise one or more of medium chain triglycerides USP / NF (Labrafac Lipophile WL 1349), medium chain triglyceride oil, sunflower oil, triacetin, coconut oil, grape seed oil, oleic acid, decanoic acid, free fatty acids and derivatives of free fatty acids, and triglycerides of free fatty acids, vegetable / plant and animal derived oils, phospholipid derivatives of fatty acids.

[0031] The aqueous phase comprises one or more pharmaceutically acceptable excipients selected from the group including cosolvents, buffers, surfactants, stabilizers, preservatives, chelating agents, tonicity modifiers, etc. The aqueous phase may comprise about 25% to 95% w / v of the total weight of the formulation.

[0032] The pharmaceutical formulations of the present invention may further comprise inactive ingredients selected from the group comprising polymers, solvents, co-solvents, buffers, surfactants, stabilizers, preservatives, chelating agents and tonicity modifiers.

[0033] The co-solvent may range from about 0 to 25% (w / v) and may be selected from, but not limited to, ethanol, N-methyl-2-pyrrolidone (NMP), tert-butyl alcohol (TBA), glycerol, propylene glycol, polyethylene glycol, Transcutol HP, Gelucire™ 50 / 13 (stearoyl polyoxylglyceride), and the like.

[0034] The buffer or pH adjuster described in the present invention is selected from L-histidine, L-arginine, Tris base, meglumine, glycine, sodium succinate, diethanolamine, aspartic acid, glutamic acid, alanine, sodium acetate, sodium ascorbate, sodium citrate, citric acid, succinic acid, triethanolamine, boric acid, sodium hydroxide, sodium bicarbonate, etc.

[0035] Stabilizers may range from about 0.5 to 5% (w / v) and are selected from, but are not limited to, antioxidants such as vitamin E acetate, ascorbyl palmitate, ascorbic acid, monothioglycerol (MTG), citric acid, tartaric acid, etc., and chelating agents such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), disodium EDTA, etc.

[0036] The tonicity or isotonic agent may range from about 0.5 to 10% (w / v) and may be selected from, but not limited to, dextrose, mannitol, glycerol, and sodium chloride.

[0037] The surfactant may range from about 0.5 to 15% (w / v) and may include, but is not limited to, amphiphilic surfactants, lipophilic surfactants, such as alpha-lecithin, cholesterol oleate, and the like; phospholipids, such as soybean lecithin, egg lecithin (LIPOID E 80 S / Egg Lip 80 W), hydrogenated soybean lecithin, and alpha-lecithin; modified phospholipid derivatives, such as dimyristoylphosphatidylcholine (DMPC), 1,2-dipalmitoyl-rac-glycero-3-phosphocholine (DPPC), dimyristoylphosphatidylethanolamine (DMPE), 1,2-bis(diphenylphosphino)ethane (DPPE), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), 1,2-distearoyl-sn-glycerol (DPPG), and the like. di-3-phosphorylethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), hydrophilic surfactants such as poloxamer-188, sodium oleate, sodium cholate, ethylene oxide / propylene oxide copolymers such as poloxamer 182, poloxamer 407 and poloxamine 908, poloxamer-188, non-ionic surfactants such as polysorbate 20, polysorbate 60, polysorbate 80 (Tween 80), Span-20, Span-60 and Span-80, Cremophor EL, the anionic bile salts sodium cholate, sodium glycocholate, sodium taurocholate, sodium taurodeoxycholate, and sucrose esters of fatty acids (e.g., sucrose laurate, sucrose oleate, sucrose palmitate, sucrose stearate, etc.), Kolliphor RH40, PEGylated lipids such as N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, MPEG-2000-DSPE, Na-salt (Lipoid PE 18:0 / 18:0-PEG 2000) (PEG-PE), etc.

[0038] In one embodiment, the parenteral emulsion formulation comprises (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in the oil phase, and (ii) an omega-3 component selected from an omega-3 fatty acid, an omega-3 ethyl ester, and an omega-3 triglyceride; and (b) an aqueous phase and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0039] The formulations of the present invention are used to treat a variety of disorders, including acute and chronic pain, neuralgia, inflammatory disorders, liver disorders, cardiovascular disorders, respiratory disorders, immune disorders, and central nervous system disorders such as anxiety, depression, and epilepsy.

[0040] The parenteral emulsion formulation contains less than 1% THC, preferably less than 0.5% THC, and more preferably less than 0.3% THC. Most preferably, the formulation contains no detectable THC as determined by standard analytical techniques.

[0041] The formulations of the present invention retained at least 90% of the CBD after storage at room temperature for more than 12 months.

[0042] The formulations of the present invention have a pH in the range of 2.5 to 9.75.

[0043] The formulations of the present invention were tested for stability, with details as follows:

[0044] [Table 1]

[0045] In another embodiment, the parenteral emulsion formulation comprises (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in an oil phase, (ii) an omega-3 component selected from an omega-3 fatty acid, an omega-3 ethyl ester, and an omega-3 triglyceride, and (iii) one or more surfactants; and (b) an aqueous phase and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0046] Yet another embodiment relates to a parenteral emulsion formulation of cannabidiol comprising: (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in the oil phase, (ii) an omega-3 ethyl ester, (iii) egg lecithin, and (iv) a PEGylated lipid; and (b) an aqueous phase and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0047] Parenteral formulations can be highly advantageous in the treatment of acute and chronic diseases, diseases where local action is desired, diseases where immediate therapeutic effect is required, or diseases where undesirable side effects exist with other administration routes.The formulations can be useful in the treatment of various diseases, such as acute and chronic pain, inflammatory diseases, immune diseases, and central nervous system diseases.The formulations do not have any adverse psychological effects on patients, nor do they cause any psychological disorders.

[0048] The present invention may also be configured to be administered in combination with at least one pharmaceutically active agent. Such active agents may be selected from the group including nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, antifibrotic agents, antiepileptics, anxiolytics, antidepressants, antipsychotics, opioid antagonists, psychoactive drugs, analgesics, immunosuppressants, antiinsomniacs, neuroprotective agents, leukotriene receptor antagonists (LTRAs), lipid-modulating agents, HMG-CoA reductase inhibitors, etc. The dosage of each active agent will depend on the condition being treated.

[0049] The formulation of the present invention further comprises a drug selected from any class of the BCS classification, and this nomenclature is well understood by those skilled in the art.The formulation of the present invention comprises Class 1 drugs such as pregabalin, melatonin, ketorolac tromethamine, tramadol, tapentadol, Class 2 drugs such as duloxetine, naproxen, atorvastatin, rosuvastatin, montelukast, brexpiprazole, lurasidone, prochlorperazine edisylate, bilastine, Class 3 drugs such as gabapentin, acetaminophen, tofacitinib, cetirizine, naloxone, morphine, and Class 4 drugs such as naltrexone, allopregnanolone.

[0050] In one embodiment, the parenteral emulsion formulation comprises (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in the oil phase, and (ii) an omega-3 ethyl ester; and (b) an aqueous phase comprising gabapentin; and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0051] In another embodiment, the parenteral emulsion formulation comprises: (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in an oil phase, (ii) duloxetine or a salt of duloxetine also dispersed or dissolved in the oil phase, and (iii) an omega-3 ethyl ester; and (b) an aqueous phase and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0052] In another embodiment, the parenteral emulsion formulation comprises (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in the oil phase, and (ii) an omega-3 ethyl ester; and (b) an aqueous phase comprising acetaminophen; and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0053] In yet another embodiment, the parenteral emulsion formulation comprises: (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in the oil phase, (ii) allopregnanolone also dispersed or dissolved in the oil phase, and (iii) an omega-3 ethyl ester; and (b) an aqueous phase and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0054] In yet another embodiment, the parenteral emulsion formulation comprises: (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in the oil phase, (ii) brexpiprazole also dispersed or dissolved in the oil phase, and (iii) an omega-3 ethyl ester; and (b) an aqueous phase and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0055] In one embodiment, the parenteral emulsion formulation comprises (a) an oil phase comprising (i) cannabidiol dispersed or dissolved in the oil phase, and (ii) an omega-3 ethyl ester; and (b) an aqueous phase comprising pregabalin; and suitable pharmaceutically acceptable excipients in the oil and aqueous phases.

[0056] Samples were analyzed using a high-performance liquid chromatography (HPLC) method using a reversed-phase Inertsil C18 analytical column (150 x 4.6 mm i.d., 5 μm particle size) with mobile phase A being 0.1% orthophosphoric acid and mobile phase B being acetonitrile-water-acetic acid (80:20:1, v / v). An ultraviolet detector operating at 220 nm was used, and the chromatographic run time was 75 minutes.

[0057] The following examples are not intended to limit the scope of the present invention but are for illustrative purposes only.

[0058] [Example 1] [Table 2]

[0059] Manufacturing Procedure: 1. The required amount of omega-3 ethyl ester was added to a manufacturing vessel containing a surfactant selected from egg lecithin, PEG-PE, and sodium caprylate, and dissolved by heating on a water bath at 55°C (50°C to 60°C).

[0060] 2. A weighed amount of cannabidiol was added to the above mixture and dissolved by heating on a water bath at 45°C (40°C to 50°C) to obtain an oil phase.

[0061] 3. An aqueous phase was prepared by dissolving the required amount of a tonicity agent, such as glycerol or sodium chloride, and the required amount of a buffer selected from sodium bicarbonate, sodium hydroxide, sodium citrate, and citric acid in 90% Milli-Q water and stirring at 400 rpm on a magnetic stirrer, maintaining the temperature at 55°C (50°C to 60°C).

[0062] 4. The oil phase was added into the water phase and homogenized at 8500 rpm for 15 minutes by maintaining the product temperature at 45°C (40°C to 50°C), then the volume was adjusted to the required level, followed by homogenization at 8500 rpm for 15 minutes to form a coarse emulsion.

[0063] 5. The obtained crude emulsion was subjected to high pressure homogenization in three passes at different pressures, namely, pass 1 at 10,000 psi, pass 2 at 18,000 psi and pass 3 at 18,000 psi, followed by subsequent cooling of the product to room temperature to obtain an emulsion.

[0064] The physical parameters of the emulsions, particle size distribution and zeta potential (ZP) were determined.

[0065] [Table 3]

[0066] [Table 4]

[0067] Additionally, Examples 2-8 below are prepared using the manufacturing procedure of Example 1.

[0068] [Example 2] [Table 5]

[0069] [Table 6]

[0070] [Table 7]

[0071] [Example 3] [Table 8]

[0072] [Table 9]

[0073] [Table 10]

[0074] [Example 4] [Table 11]

[0075] [Example 5] [Table 12]

[0076] [Example 6] [Table 13]

[0077] [Example 7] [Table 14]

[0078] [Example 8] [Table 15]

[0079] [Example 9] [Table 16]

[0080] Manufacturing Procedure: 1. A weighed amount of omega-3 acid ethyl ester was added to a manufacturing vessel containing egg lecithin and PEG-PE and dissolved by heating on a water bath at 55°C (50°C to 60°C).

[0081] 2. A weighed amount of cannabidiol was added to the above mixture and dissolved by heating on a water bath at 45°C (40°C to 50°C) to obtain an oil phase.

[0082] 3. The aqueous phase was prepared by dissolving the required amount of drug, e.g., pregabalin, gabapentin, acetaminophen, along with glycerol and sodium bicarbonate in 90% Milli-Q water and stirring at 400 rpm on a magnetic stirrer, maintaining the temperature at 55°C (50°C to 60°C).

[0083] 4. The oil phase was added into the water phase and homogenized at 8500 rpm for 15 minutes by maintaining the product temperature at 45°C (40°C to 50°C), then the volume was adjusted to the required level, followed by homogenization at 8500 rpm for 15 minutes to form a coarse emulsion.

[0084] 5. The obtained crude emulsion was subjected to high pressure homogenization in three passes at different pressures, namely, pass 1 at 10,000 psi, pass 2 at 18,000 psi and pass 3 at 18,000 psi, followed by subsequent cooling of the product to room temperature to obtain an emulsion.

[0085] The physical parameters of the emulsions, particle size distribution and zeta potential (ZP) were determined.

[0086] [Table 17]

[0087] [Table 18]

[0088] [Example 10] [Table 19]

[0089] Manufacturing Procedure: 1. A weighed amount of omega-3 acid ethyl ester was added to a manufacturing vessel containing egg lecithin and PEG-PE and dissolved by heating on a water bath at 55°C (50°C to 60°C).

[0090] 2. Weighed amounts of cannabidiol and drugs, such as duloxetine, allopregnanolone, and brexpiprazole, were added to the above mixture and dissolved by heating on a water bath at 45°C (40°C to 50°C) to obtain an oil phase.

[0091] 3. The aqueous phase was prepared by dissolving the required amount of glycerol and sodium bicarbonate in 90% Milli-Q water and stirring at 400 rpm on a magnetic stirrer, maintaining the temperature at 55°C (50°C to 60°C).

[0092] 4. The oil phase was added into the aqueous phase and homogenized at 8500 rpm for 15 minutes by maintaining the product temperature at 45°C (40°C to 50°C), then the volume was adjusted to the required level, followed by homogenization at 8500 rpm for 15 minutes to form a coarse emulsion.

[0093] 5. The obtained crude emulsion was subjected to high pressure homogenization in three passes at different pressures, namely, pass 1 at 10,000 psi, pass 2 at 18,000 psi and pass 3 at 18,000 psi, followed by subsequent cooling of the product to room temperature to obtain an emulsion.

[0094] The physical parameters of the emulsions, particle size distribution and zeta potential (ZP) were determined.

[0095] [Table 20]

[0096] [Table 21]

[0097] [Example 11] [Table 22]

[0098] Manufacturing Procedure: 1. A weighed amount of the omega-3 component was added to a manufacturing vessel containing egg lecithin and PEG-PE and dissolved by heating on a water bath at 55°C (50°C to 60°C).

[0099] 2. A weighed amount of cannabidiol was added to the above mixture along with the required amount of decanoic acid and dissolved by heating on a water bath at 45°C (40°C to 50°C) to obtain an oil phase.

[0100] 3. The aqueous phase was prepared by dissolving the required amount of glycerol and sodium bicarbonate in 90% Milli-Q water and stirring at 400 rpm on a magnetic stirrer, maintaining the temperature at 55°C (50°C to 60°C).

[0101] 4. While homogenizing at 8500 rpm for 15 minutes by maintaining the product temperature at 45°C (40°C to 50°C), the oil phase was added into the water phase, then the volume was adjusted to the required level, followed by homogenizing at 8500 rpm for 15 minutes to form a coarse emulsion.

[0102] 5. The obtained crude emulsion was subjected to high pressure homogenization in three passes at different pressures, namely, pass 1 at 10,000 psi, pass 2 at 18,000 psi and pass 3 at 18,000 psi, followed by subsequent cooling of the product to room temperature to obtain an emulsion.

[0103] [Example 12] [Table 23]

[0104] The above formulation (Example 12) is prepared using the manufacturing procedure of Example 1.

Claims

1. 1. A parenteral emulsion formulation of cannabidiol, comprising: (a) i. cannabidiol dispersed or dissolved in an oil phase; and ii. an omega-3 component selected from omega-3 fatty acids, omega-3 fatty acid ethyl esters, and omega-3 triglycerides; an oil phase comprising (b) an aqueous phase; and (c) other pharmaceutically acceptable excipients; and 1. A formulation comprising:

2. 2. The formulation of claim 1, wherein the THC content is 1% by weight or less based on the weight of the entire formulation.

3. 2. The formulation according to claim 1, wherein the THC content is 0.5% by weight or less based on the weight of the entire formulation.

4. D ９０ 2. The formulation of claim 1, wherein the .DELTA.H is less than 550 nm and the hydrodynamic diameter (HDD) is less than 250 nm.

5. 5. The formulation of claim 1, wherein the CBD ranges from about 0.005 mg / ml to about 250 mg / ml.

6. 6. The formulation of claim 1, wherein the omega-3 component ranges from about 1 mg / ml to about 500 mg / ml.

7. 7. The formulation of claim 1, wherein the aqueous phase is in the range of about 25% w / v to about 95% w / v of the total formulation.

8. 8. A formulation according to any one of claims 1 to 7, wherein the oil phase ranges from about 5% w / v to about 40% w / v of the total formulation.

9. 1. A parenteral emulsion formulation of cannabidiol, comprising: (a) i. cannabidiol dispersed or dissolved in an oil phase; and ii. an omega-3 component selected from omega-3 fatty acids, omega-3 fatty acid ethyl esters, and omega-3 triglycerides; an oil phase comprising (b) an aqueous phase; and with other pharmaceutically acceptable excipients Including, A formulation having a THC content of 1% by weight or less based on the weight of the total formulation.

10. 10. The formulation of claim 9, wherein the CBD content is 90% or greater after 12 months.

11. 1. A parenteral emulsion formulation of cannabidiol, comprising: (a) a formulation comprising (i) an oil phase comprising cannabidiol dispersed or dissolved therein, (ii) an omega-3 ethyl ester, (iii) egg lecithin, and (iv) a PEGylated lipid; and (b) an aqueous phase and other pharmaceutically acceptable excipients.

12. 12. The formulation of claim 1 or 11, wherein the pharmaceutically acceptable excipient is selected from a surfactant, a buffer, a stabilizer, and a tonicity agent.

13. 13. The formulation of claim 12, wherein the buffer is selected from the group comprising L-histidine, L-arginine, Tris base, meglumine, glycine, sodium succinate, diethanolamine, aspartic acid, glutamic acid, alanine, sodium acetate, sodium ascorbate, sodium citrate, citric acid, succinic acid, triethanolamine, boric acid, sodium hydroxide and sodium bicarbonate.

14. 13. The formulation of claim 12, wherein the stabilizer is selected from the group comprising vitamin E acetate, ascorbyl palmitate, ascorbic acid, monothioglycerol (MTG), citric acid, tartaric acid, and the like, chelating agents such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and disodium EDTA.

15. 13. The formulation of claim 12, wherein the tonicity agent is selected from the group comprising dextrose, mannitol, glycerol, and sodium chloride.

16. 1. A parenteral emulsion formulation of cannabidiol and one or more active ingredients, comprising: (a) i. cannabidiol dispersed or dissolved in an oil phase; and ii. an omega-3 component selected from omega-3 fatty acids, omega-3 fatty acid ethyl esters, and omega-3 triglycerides; an oil phase comprising (b) an aqueous phase; and further comprising one or more active ingredients and other pharmaceutically acceptable excipients.

17. 17. The formulation of claim 16, wherein the active ingredient is selected from the group comprising nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, antifibrotic agents, antiepileptics, anxiolytics, antidepressants, antipsychotics, opioid antagonists, psychoactive drugs, analgesics, immunosuppressants, antiinsomniacs, neuroprotective drugs, leukotriene receptor antagonists (LTRAs), lipid regulating agents and HMG-CoA reductase inhibitors.

18. 1. A parenteral emulsion formulation of cannabidiol and one or more active ingredients, comprising: (a) i. cannabidiol and one or more active ingredients dispersed or dissolved in an oil phase; and ii. an omega-3 component selected from omega-3 fatty acids, omega-3 fatty acid ethyl esters, and omega-3 triglycerides; an oil phase comprising (b) an aqueous phase; and with other pharmaceutically acceptable excipients 10. A parenteral emulsion formulation comprising:

19. 19. The parenteral emulsion formulation of claim 18, wherein the active ingredient is selected from allopregnanolone / brexanolone, duloxetine, and brexpiprazole.

20. 1. A parenteral emulsion formulation of cannabidiol and one or more active ingredients, comprising: (a) i. cannabidiol and allopregnanolone / brexanolone dispersed or dissolved in an oil phase, and ii. an omega-3 component selected from omega-3 fatty acids, omega-3 fatty acid ethyl esters, and omega-3 triglycerides; an oil phase comprising (b) an aqueous phase; and with other pharmaceutically acceptable excipients 1. A formulation comprising:

21. 21. A method of treating anxiety or depression using the formulation of claim 20.

22. 1. A parenteral emulsion formulation of cannabidiol and one or more active ingredients, comprising: (a) i. cannabidiol dispersed or dissolved in an oil phase; and ii. an omega-3 component selected from omega-3 fatty acids, omega-3 fatty acid ethyl esters, and omega-3 triglycerides; an oil phase comprising (b) one or more active ingredients selected from pregabalin, acetaminophen, and gabapentin dissolved or dispersed in an aqueous phase; with other pharmaceutically acceptable excipients 1. A formulation comprising:

23. 23. A method of treating pain or inflammation or nerve pain using the formulation of claim 22.

Images