Stable cannabinoid formulations

Abstract

To provide substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of their use.SOLUTION: A method of treating Prader-Willi syndrome comprising administering an effective amount of an oral pharmaceutical formulation comprising: cannabidiol; and a vehicle selected from the group consisting of a lipid, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400 and a combination thereof. Optionally, the cannabidiol is greater than 98% pure.SELECTED DRAWING: Figure 10

Description

[Technical Field]

[0001] This application claims priority to U.S. patent application Ser. No. 15 / 499,178, filed April 27, 2017, U.S. patent application Ser. No. 15 / 253,010, filed August 31, 2016, U.S. patent application Ser. No. 15 / 166,476, filed May 27, 2016, U.S. patent application Ser. No. 14 / 815,936, filed July 31, 2015, U.S. patent application Ser. No. 14 / 724,351, filed May 28, 2015, and U.S. provisional patent application Ser. Nos. 62 / 004,495, filed May 29, 2014, and 62 / 154,660, filed April 29, 2015, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention is generally directed to substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of use thereof. [Background technology]

[0003] Cannabinoids are chemicals produced by cannabis flowers that mimic endogenous compounds in humans.

[0004] Cannabinoids include cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, anandamide, nabilone, and acids and analogs thereof. It is now possible to synthesize many cannabinoids in the laboratory, thereby eliminating the need to grow cannabis for the extraction of the compounds.

[0005] One cannabinoid, cannabidiol, (-)-trans-2-p-mentha-1,8-dien-3-yl-5-pentylresorcinol, is non-psychoactive and has shown promise in treating a number of diseases and disorders. Synthetic cannabidiol has the same structure as naturally occurring cannabidiol.

[0006] [ka]

[0007] Commercially available cannabidiol is typically contaminated with delta-9-tetrahydrocannabinol. The presence of delta-9-tetrahydrocannabinol can be problematic because delta-9-tetrahydrocannabinol is regulated by the U.S. Drug Enforcement Administration as a Schedule I substance. The higher the Schedule I number, the easier it is for patients to access cannabidiol treatment. Furthermore, delta-9-tetrahydrocannabinol is a hallucinogen, and patients receiving cannabidiol wish to avoid this undesirable side effect of delta-9-tetrahydrocannabinol contamination. Therefore, there is a need for substantially pure synthetically synthesized cannabidiol that does not contain delta-9-tetrahydrocannabinol.

[0008] Cannabinoids, including cannabidiol, may be suitable for treating diseases or disorders or symptoms of diseases or disorders such as Dravet syndrome, Lennox-Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile convulsions, West syndrome, refractory infantile spasms, infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early stage psychosis, Alzheimer's disease, autism, and the treatment of withdrawal symptoms from opioids, cocaine, heroin, amphetamines, and nicotine. Summary of the Invention [Problem to be solved by the invention]

[0009] Therefore, there is a need for new stable cannabinoid formulations. Additionally, there is a need for substantially pure cannabidiol. [Means for solving the problem]

[0010] (Summary of the Invention) In one aspect, the present invention provides a method of treating Prader-Willi syndrome, comprising: Cannabidiol; A vehicle consisting of a lipid or selected from the group consisting of water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof. The present invention relates to a method for treating a rheumatoid arthritis, comprising administering an effective amount of an oral pharmaceutical formulation comprising:

[0011] In another embodiment, the cannabidiol has a purity of greater than 98%.

[0012] In another embodiment, the vehicle is a medium chain glyceride, preferably caprylic / capric triglyceride.

[0013] In another embodiment, the vehicle is sesame oil.

[0014] In another embodiment, the oral pharmaceutical formulation of the present invention further comprises an antioxidant or preservative selected from the group consisting of alpha-tocopherol, ascorbyl palmitate, methylparaben, propylparaben, and combinations thereof.

[0015] In another embodiment, the oral pharmaceutical formulation of the present invention comprises: about 8% to about 31% w / w cannabidiol; and A vehicle consisting of about 60% to about 90% w / w lipid or a combination of about 40% to about 60% w / w ethanol, about 1% to about 5% w / w polyethylene glycol, about 5% to about 10% w / w propylene glycol, and about 20% to about 40% w / w water. Includes:

[0016] In another embodiment, the oral pharmaceutical formulation of the present invention comprises cannabidiol in a concentration of about 10% w / w and caprylic / capric triglyceride in a concentration of about 89% w / w.

[0017] In another embodiment, the oral pharmaceutical formulation of the present invention comprises cannabidiol in a concentration of about 31% w / w and caprylic / capric triglyceride in a concentration of about 68% w / w.

[0018] In another embodiment, the oral pharmaceutical formulation of the present invention comprises cannabidiol in a concentration of about 11% w / w and the vehicle is sesame oil in a concentration of about 80% w / w.

[0019] In another embodiment, the oral pharmaceutical formulation of the present invention comprises cannabidiol at a concentration of about 8.8% w / w, and a combination of ethanol at a concentration of about 50% w / w, polyethylene glycol at a concentration of about 3% w / w, propylene glycol at a concentration of about 7.5% w / w, and water at a concentration of about 30% w / w.

[0020] In another embodiment, the effective amount of the oral pharmaceutical formulation of the present invention is from about 0.5 to about 100 milligrams per kilogram per day, or from about 10 to about 40 milligrams per kilogram per day.

[0021] In another aspect, the present invention provides a method of treating one or more symptoms of Prader-Willi syndrome, comprising: Cannabidiol; A vehicle consisting of a lipid or selected from the group consisting of water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof. The present invention relates to a method for treating a rheumatoid arthritis, comprising administering an effective amount of an oral pharmaceutical formulation comprising:

[0022] In a preferred embodiment, the one or more symptoms of Prader-Willi syndrome is binge eating.

[0023] In another aspect, the present invention provides a method of treating infantile spasms, comprising: Cannabidiol; and a vehicle selected from the group consisting of lipids, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof; to a patient in need thereof.

[0024] In a preferred embodiment, vigabatrin or adrenocorticotropic hormone is administered to the patient prior to administration of the oral pharmaceutical formulation of the present invention.

[0025] In another aspect, the present invention provides a method of treating childhood absence epilepsy, comprising: Substantially pure cannabidiol and / or synthetic cannabidiol, preferably having a purity greater than 98%; and a vehicle selected from the group consisting of lipids, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof; The present invention relates to a method for treating a rheumatoid arthritis, comprising administering an effective amount of an oral pharmaceutical formulation comprising: [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 shows results from the study detailed in Example 7 and illustrates the benefits of administering a substantially pure synthetically synthesized cannabidiol formulation for the treatment of neuropathic pain. [Figure 2] FIG. 1 shows results from the study detailed in Example 8 and illustrates the benefits of administering a substantially pure synthetically synthesized cannabidiol formulation over a THC formulation for the treatment of neuropathic pain. [Figure 3-1] FIG. 10 shows further results from the study detailed in Example 8, illustrating the dose-dependent benefit of administering a substantially pure synthetically synthesized cannabidiol formulation over a THC formulation for the treatment of neuropathic pain. [Figure 3-2]FIG. 10 shows further results from the study detailed in Example 8, illustrating the dose-dependent benefit of administering a substantially pure synthetically synthesized cannabidiol formulation over a THC formulation for the treatment of neuropathic pain. [Figure 3-3] FIG. 10 shows further results from the study detailed in Example 8, illustrating the dose-dependent benefit of administering a substantially pure synthetically synthesized cannabidiol formulation over a THC formulation for the treatment of neuropathic pain. [Figure 4] FIG. 10 shows further results from the study detailed in Example 8, illustrating the synergistic results of administering a substantially pure synthetically synthesized cannabidiol and THC formulation for the treatment of neuropathic pain. [Figure 5] FIG. 1 shows results from the study detailed in Example 9 and illustrates the benefits of administering a higher ratio of substantially pure synthetically synthesized cannabidiol to a THC formulation for the treatment of neuropathic pain. [Figure 6] FIG. 1 shows results from the study detailed in Example 10 and illustrates the benefits of administering a substantially pure synthetically synthesized cannabidiol formulation for the treatment of neuropathic pain. [Figure 7] FIG. 1 shows results from the study detailed in Example 14 and illustrates the benefits of administering a substantially pure synthetically synthesized cannabidiol formulation for the treatment of glioblastoma multiforme. [Figure 8] FIG. 1 shows results from the study detailed in Example 15 and illustrates the benefits of administering a substantially pure synthetically synthesized cannabidiol formulation for the treatment of glioblastoma multiforme. [Figure 9]

[0023] Figure 1 shows results from the study detailed in Example 17 and illustrates the benefits of administering an oral cannabidiol solution to subjects in a fed condition. Panel A shows the mean cannabidiol concentration over time. Panel B shows the natural logarithm of the mean cannabidiol concentration over time. [Figure 10]1 shows results from the study detailed in Example 17 and illustrates the benefits of administering an oral cannabidiol solution to subjects in a fed condition. Panel A shows the mean 7-OH-cannabidiol concentration over time. Panel B shows the natural logarithm of the mean 7-OH-cannabidiol concentration over time. DETAILED DESCRIPTION OF THE INVENTION

[0027] As shown above, applicants have created stable formulations with and without alcohol (see Examples 1 and 3). The alcohol-free formulations are particularly suitable for administration to children. Furthermore, the alcohol-free formulations are particularly suitable for patients recovering from drug and alcohol addiction.

[0028] Additionally, Applicants have created stable lipid formulations (see Example 5). These formulations were unexpectedly stable during storage (see Example 6).

[0029] Moreover, applicants have unexpectedly discovered that substantially pure cannabidiol formulations are particularly suitable for the treatment of neuropathic pain (see Examples 7-10 and Figures 1-6), epilepsy (see Examples 11-13), glioblastoma multiforme (see Examples 14 and 15 and Figures 7 and 8), treatment-resistant seizure disorders (see Example 16), and Prader-Willi syndrome (see Example 19). <Alcohol-free formulation>

[0030] In one embodiment, the present invention is directed to a stable pharmaceutical formulation for oral administration comprising about 0.1 to about 50% cannabinoid, about 0.1 to about 40% polyethylene glycol, about 0.1 to about 50% propylene glycol, and about 0.1 to about 20% water, wherein the formulation does not contain alcohol and the formulation has a pH of about 5 to about 8.

[0031] In a preferred embodiment, the formulation contains about 1 to about 40% cannabinoid, and in more preferred embodiments, the formulation contains about 5 to about 35%, about 20 to about 35%, or about 30 to 35% cannabinoid.

[0032] In yet another embodiment, the formulation contains a cannabinoid selected from the group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, anandamide, nabilone, acids, analogs and synthetic derivatives thereof. In a preferred embodiment, the cannabinoid is cannabidiol.

[0033] In a preferred embodiment, the formulation contains about 1 to about 40% cannabidiol, and in more preferred embodiments, the formulation contains about 5 to about 35%, about 20 to about 35%, or about 30 to 35% cannabidiol.

[0034] In yet another embodiment, the formulation contains substantially pure synthetically synthesized cannabidiol having a purity greater than 98%. In a more preferred embodiment, the cannabidiol has a purity greater than 99%. In an even more preferred embodiment, the cannabidiol has a purity greater than 99.5%. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.

[0035] In another embodiment, the formulation contains about 0.001 to about 1% antioxidant. In a preferred embodiment, the formulation contains about 0.01 to about 1% antioxidant. In a more preferred embodiment, the formulation contains about 0.02 to about 0.5% antioxidant.

[0036] Suitable antioxidants include butylated hydroxyl toluene ("BHT"), butylated hydroxyl anisole ("BHA"), alpha-tocopherol (vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethylenediaminotetraacetic acid, cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, monothioglycerol tert-butylhydroquinone ("TBHQ"), and combinations thereof. In a preferred embodiment, the formulation contains alpha-tocopherol (vitamin E), ascorbic acid, sodium ascorbate, ascorbyl palmitate, or combinations thereof.

[0037] In another embodiment, the formulation contains about 1 to about 40% polyethylene glycol. In a preferred embodiment, the formulation contains about 1 to about 35%, about 5 to about 35%, about 20 to about 30%, or about 25 to about 30% polyethylene glycol.

[0038] Suitable polyethylene glycols include low molecular weight polyethylene glycols having an average molecular weight between 200 and 10,000. One preferred polyethylene glycol that can be used is polyethylene glycol 400.

[0039] In another embodiment, the formulation contains about 1 to about 40% polyethylene glycol 400. In a preferred embodiment, the formulation contains about 1 to about 35%, about 5 to about 35%, about 20 to about 30%, or about 25 to about 30% polyethylene glycol 400.

[0040] In another embodiment, the formulation contains about 1 to about 50% propylene glycol. In a preferred embodiment, the formulation contains about 1 to about 40%, about 5 to about 35%, about 20 to about 35%, or about 30 to about 35% propylene glycol.

[0041] In further embodiments, the formulations contain water. The formulations can contain 0% water. If the formulations contain water, they contain about 1 to about 15% water, about 1 to about 10% water, or about 4 to about 8% water.

[0042] The pH of the formulation can be modified using any pharmaceutically acceptable means. Preferably, the pH of the formulation is about 5 to about 8. In a more preferred embodiment, the pH of the formulation is about 6 to about 7. In a most preferred embodiment, the pH of the formulation is about 6.2 to about 6.7.

[0043] The formulations of the present invention may also contain sweeteners, sweetness enhancers, preservatives, pH modifiers, and flavoring agents.

[0044] Suitable sweeteners include, but are not limited to, sucralose, sucrose, aspartame, saccharin, dextrose, mannitol, xylitol, and combinations thereof.

[0045] If the preparation contains a sweetener, the preparation preferably contains from about 0.001 to about 1% of the sweetener.

[0046] If the formulation contains a sweetener enhancer, the formulation preferably contains from about 0.001 to about 1% of the sweetener enhancer.

[0047] Suitable sweetness enhancers include, but are not limited to, crude and purified ammonium salt forms of glycyrrhizic acid. Magnasweet® products (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation) use crude and purified ammonium salt forms of glycyrrhizic acid. Glycyrrhizic acid is also available as a pure derivative in sodium and potassium salt forms.

[0048] Suitable pH modifiers include, but are not limited to, hydrochloric acid, ascorbic acid, citric acid, sodium citrate, fumaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, and combinations thereof.

[0049] Suitable preservatives include, but are not limited to, methylparaben, propylparaben, benzyl alcohol, benzoic acid, sodium benzoate, sorbic acid, and combinations thereof.

[0050] Suitable flavoring agents include, but are not limited to, raspberry, peppermint oil, grape flavor, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, lemon oil, lemon mint flavor, fruit punch flavor, and combinations thereof. In a preferred embodiment, the formulation contains strawberry flavor.

[0051] If the formulation contains a flavoring agent, the formulation preferably contains from about 0.001 to about 1% of the flavoring agent. In a more preferred embodiment, the formulation contains from about 0.005 to about 0.5% of the flavoring agent.

[0052] The formulations are suitable for oral, buccal, sublingual, inhalation, or intravenous / intramuscular administration. Preferably, the formulation is an orally administered liquid. More preferably, the formulation is an orally administered simple solution.

[0053] <Preparations containing alcohol> In another embodiment, the present invention is directed to a stable pharmaceutical formulation for oral administration comprising about 0.1 to about 40% cannabinoid, about 0.1 to about 25% polyethylene glycol, about 0.1 to about 40% propylene glycol, optionally about 0.1 to about 50% water, and about 0.1 to about 70% alcohol, wherein the formulation has a pH of about 5 to about 8.

[0054] In preferred embodiments, the formulation contains about 1 to about 35% cannabinoid. In more preferred embodiments, the formulation contains about 1 to about 15%, about 5 to about 12%, or about 7 to about 11% cannabinoid. Alternatively, the formulation may contain about 20 to about 35% or about 30 to about 35% cannabinoid.

[0055] In yet another embodiment, the formulation contains a cannabinoid selected from the group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, anandamide, nabilone, acids, analogs and synthetic derivatives thereof. In a preferred embodiment, the cannabinoid is cannabidiol.

[0056] In preferred embodiments, the formulation contains about 1 to about 35% cannabidiol. In more preferred embodiments, the formulation contains about 1 to about 15%, about 5 to about 12%, or about 7 to about 11% cannabidiol. Alternatively, the formulation may contain about 20 to about 35% or about 30 to about 35% cannabidiol.

[0057] In yet another embodiment, the formulation contains substantially pure synthetically synthesized cannabidiol having a purity greater than 98%. In a more preferred embodiment, the cannabidiol has a purity greater than 99%. In an even more preferred embodiment, the cannabidiol has a purity greater than 99.5%. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.

[0058] In another embodiment, the formulation contains about 0.001 to about 1% antioxidant. In a preferred embodiment, the formulation contains about 0.01 to about 1% antioxidant. In a more preferred embodiment, the formulation contains about 0.02 to about 0.5% antioxidant.

[0059] Suitable antioxidants include butylated hydroxyl toluene ("BHT"), butylated hydroxyl anisole ("BHA"), alpha-tocopherol (vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethylenediaminotetraacetic acid, cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, tert-butylhydroquinone ("TBHQ"), and combinations thereof. In a preferred embodiment, the formulation contains alpha-tocopherol (vitamin E), ascorbyl palmitate, or a combination thereof.

[0060] In another embodiment, the formulation contains about 1 to about 20% propylene glycol. In a preferred embodiment, the formulation contains about 1 to about 15% or about 5 to about 10% propylene glycol.

[0061] In alternative embodiments, the formulation contains about 20 to about 50% propylene glycol. In preferred embodiments, the formulation contains about 30 to about 40% or about 35 to about 40% propylene glycol.

[0062] In another embodiment, the formulation contains about 1 to about 20% polyethylene glycol. In a preferred embodiment, the formulation contains about 1 to about 10% or about 1 to about 5% polyethylene glycol.

[0063] In an alternative embodiment, the formulation contains about 10 to about 30% polyethylene glycol. In an alternative preferred embodiment, the formulation contains about 15 to about 25% polyethylene glycol.

[0064] Suitable polyethylene glycols include low molecular weight polyethylene glycols having an average molecular weight between 200 and 10,000. One preferred polyethylene glycol that can be used is polyethylene glycol 400.

[0065] In another embodiment, the formulation contains about 1 to about 20% polyethylene glycol 400. In a preferred embodiment, the formulation contains about 1 to about 10% or about 1 to about 5% polyethylene glycol 400.

[0066] In an alternative embodiment, the formulation contains about 1 to about 5% polyethylene glycol 400. In an alternative preferred embodiment, the formulation contains about 15 to about 25% polyethylene glycol 400.

[0067] In further embodiments, the formulation contains water. The formulation can contain 0% water. If the formulation contains water, it can contain about 1 to about 40% water, about 5 to about 40% water, about 10 to about 35% water, or about 25 to about 35% water.

[0068] In yet another embodiment, the formulation contains about 1 to about 65% alcohol. In preferred embodiments, the formulation contains about 10 to about 65%, about 15 to about 60%, or about 30 to 55% alcohol.

[0069] In alternative embodiments, the formulation contains from about 1 to about 20% alcohol. In alternative preferred embodiments, the formulation contains from about 1 to about 10% or from about 3 to about 7% alcohol.

[0070] The pH of the formulation can be modified using any pharmaceutically acceptable means. Preferably, the pH of the formulation is about 6 to about 7. In a more preferred embodiment, the pH of the formulation is about 6.2 to about 6.7.

[0071] The formulations of the present invention may also contain sweeteners, sweetness enhancers, pH modifiers, preservatives and flavoring agents.

[0072] Suitable sweeteners include, but are not limited to, sucralose, sucrose, aspartame, saccharin, dextrose, mannitol, xylitol, and combinations thereof.

[0073] If the preparation contains a sweetener, the preparation preferably contains from about 0.001 to about 1% of the sweetener.

[0074] Suitable sweetness enhancers include, but are not limited to, crude and purified ammonium salt forms of glycyrrhizic acid. Magnasweet® products (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation) use crude and purified ammonium salt forms of glycyrrhizic acid. Glycyrrhizic acid is also available as a pure derivative in sodium and potassium salt forms.

[0075] If the formulation contains a sweetener enhancer, the formulation preferably contains from about 0.001 to about 1% of the sweetener enhancer.

[0076] Suitable pH modifiers include, but are not limited to, hydrochloric acid, ascorbic acid, citric acid, sodium citrate, fumaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, and combinations thereof.

[0077] Suitable preservatives include, but are not limited to, methylparaben, propylparaben, benzyl alcohol, benzoic acid, sodium benzoate, sorbic acid, and combinations thereof.

[0078] Suitable flavoring agents include, but are not limited to, raspberry, peppermint oil, grape flavor, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, lemon oil, lemon mint flavor, fruit punch flavor, and combinations thereof. In a preferred embodiment, the formulation contains fruit punch flavor, raspberry flavor, grape flavor, or lemon mint flavor.

[0079] If the formulation contains a flavoring agent, the formulation preferably contains from about 0.001 to about 1% of the flavoring agent. In a more preferred embodiment, the formulation contains from about 0.005 to about 0.5% of the flavoring agent.

[0080] The formulations are suitable for oral, buccal, sublingual, inhalation, or intravenous / intramuscular administration. Preferably, the formulation is an orally administered liquid. More preferably, the formulation is an orally administered simple solution.

[0081] <Preparation containing lipids> In another embodiment, the present invention is directed to a stable pharmaceutical formulation for oral administration comprising about 0.1 to about 40% cannabinoid and about 10 to about 95% lipid.

[0082] In a preferred embodiment, the lipids are selected from the group consisting of sesame oil, olive oil, corn oil, sunflower oil, safflower oil, linseed oil, almond oil, peanut oil, walnut oil, cashew oil, castor oil, coconut oil, palm oil, soybean oil, rapeseed oil, vegetable oil, rice bran oil, fatty acids such as caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, oleic acid, stearic acid, nonadecylic acid, The lipid is selected from the group consisting of medium-chain glycerides, such as linoleic acid, arachidic acid, and arachidonic acid, decanoyl glycerides, octanoyl glycerides, caprylic / capric triglycerides, caprylic / capric / linoleic triglycerides, oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, polyglyceryl-3 dioleate, glyceryl monolinoleate, glyceryl monocaprylate, oleic acid, and combinations thereof. In a more preferred embodiment, the lipid is a medium-chain triglyceride in which the fatty acid has an aliphatic tail of 6 to 12 carbon atoms. In a most preferred embodiment, the lipid is caprylic / capric triglyceride.

[0083] Suitable commercial sources for lipids include Miglyol® 812N (caprylic / capric triglyceride) (fatty acid ester) (Miglyol is available from and is a registered trademark of Cremer Oleo GmbH & Co.), which contains a proprietary mixture of decanoyl and octanoyl glycerides, and Miglyol® 840 (caprylic / capric / linoleic triglyceride), which contains a proprietary mixture of propylene glycol dicaprylate / dicaprate and is otherwise known as decanoate / octanoate / propane-1,2-diol.

[0084] In yet another embodiment, the formulation contains a cannabinoid selected from the group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, anandamide, nabilone, acids, analogs and synthetic derivatives thereof. In a preferred embodiment, the cannabinoid is cannabidiol.

[0085] In yet another embodiment, the formulation contains substantially pure synthetically synthesized cannabidiol having a purity greater than 98%. In a more preferred embodiment, the cannabidiol has a purity greater than 99%. In an even more preferred embodiment, the cannabidiol has a purity greater than 99.5%. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.

[0086] In a preferred embodiment, the formulation contains about 1 to about 35% cannabidiol. In a more preferred embodiment, the formulation contains about 10 to about 32% cannabidiol. In a most preferred embodiment, the formulation contains about 31.09% cannabidiol.

[0087] In a preferred embodiment, the formulation contains about 20 to about 90% lipid. In a more preferred embodiment, the formulation contains about 50 to about 90% lipid. In a most preferred embodiment, the formulation contains about 50 to about 74% lipid.

[0088] In yet another embodiment, the formulation contains alcohol. The formulation can contain 0% alcohol. If the formulation contains alcohol, it can contain about 0.1 to about 20% alcohol. In a preferred embodiment, the formulation contains about 1 to about 15% alcohol. In a more preferred embodiment, the formulation contains about 1 to about 10% alcohol.

[0089] In another embodiment, the formulation contains an antioxidant. The formulation may contain 0% antioxidant. If the formulation contains an antioxidant, it may contain about 0.01 to about 1% antioxidant. In a preferred embodiment, the formulation contains about 0.02 to about 0.5% antioxidant.

[0090] Suitable antioxidants include butylated hydroxyl toluene, butylated hydroxyl anisole, alpha-tocopherol (vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethylenediaminotetraacetic acid, cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, TBHQ, and combinations thereof. In a preferred embodiment, the formulation contains alpha-tocopherol (vitamin E), ascorbyl palmitate, or a combination thereof.

[0091] Suitable sweeteners include, but are not limited to, sucralose, sucrose, aspartame, saccharin, dextrose, mannitol, xylitol, and combinations thereof. In a preferred embodiment, the sweetener is saccharin.

[0092] If the formulation contains a sweetener, the formulation preferably contains about 0.01 to about 2% sweetener. In a more preferred embodiment, the formulation contains about 0.01 to about 0.8% sweetener. In a most preferred embodiment, the formulation contains about 0.02 to about 0.05% sweetener.

[0093] Suitable sweetness enhancers include, but are not limited to, crude and purified ammonium salt forms of glycyrrhizic acid. Magnasweet® products (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation) use crude and purified ammonium salt forms of glycyrrhizic acid. Glycyrrhizic acid is also available as a pure derivative in sodium and potassium salt forms.

[0094] If the formulation contains a sweetener enhancer, the formulation preferably contains from about 0.001 to about 1% of the sweetener enhancer.

[0095] Suitable pH modifiers include, but are not limited to, hydrochloric acid, ascorbic acid, citric acid, sodium citrate, fumaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, and combinations thereof.

[0096] Suitable preservatives include, but are not limited to, methylparaben, propylparaben, benzyl alcohol, benzoic acid, sodium benzoate, sorbic acid, and combinations thereof.

[0097] Suitable flavoring agents include, but are not limited to, raspberry, peppermint oil, grape flavor, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, lemon oil, lemon mint flavor, fruit punch flavor, and combinations thereof. In a preferred embodiment, the flavoring agent is strawberry flavor.

[0098] If the formulation contains a flavoring agent, the formulation preferably contains from about 0.01 to about 1% of the flavoring agent. In a more preferred embodiment, the formulation contains from about 0.005 to about 0.5% of the flavoring agent.

[0099] The formulations may be suitable for oral, buccal, sublingual, inhalation or intravenous / intramuscular administration. Preferably, the formulation is a liquid that is administered orally.

[0100] Exemplary Uses of Formulations of the Invention (Alcohol-Containing, Alcohol-Free, and Lipid) and Synthetically Synthesized Substantially Pure Cannabidiol The formulations of the present invention are particularly suitable for treating many diseases or disorders or symptoms of diseases and disorders. Additionally, synthetically synthesized and substantially pure cannabidiol is more effective and suitable for treating diseases or symptoms of these diseases.

[0101] The formulations of the present invention can be administered to a patient in a fed state. As used herein, "fed state" refers to a patient who has consumed food prior to administration of the formulations of the present invention and whose food has been removed from the gastrointestinal tract prior to administration.

[0102] Diseases and disorders or symptoms of these diseases or disorders that can be treated or prevented by the formulations of the present invention include, but are not limited to, Prader-Willi syndrome, obesity, graft versus host disease, giardia / hypothalamic hamartoma, neonatal seizures, movement disorders including dystonia, central pain syndromes including, but not limited to, complex regional pain syndrome, phantom limb pain, multiple sclerosis, traumatic brain injury, radiation therapy, acute and chronic graft versus host disease, T-cell autoimmune disorders, colitis, Dravet syndrome, Lennox-Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, intractable epilepsy, childhood absence epilepsy, schizophrenia, These conditions include juvenile convulsions, West syndrome, infantile spasms, intractable infantile spasms, tuberous sclerosis, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's disease, autism, acne, Parkinson's disease, social anxiety disorder, depression, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic damage to the heart, ischemic damage to the brain, chronic pain syndromes, and rheumatoid arthritis, and patients experience adverse emotional reactions, nausea, and addiction disorders related to drugs of abuse such as opioid, heroin, cocaine, and amphetamine dependence, as well as acute and long-term treatment of addiction and relapse associated with drugs of abuse.

[0103] As first described in U.S. Patent Application No. 62 / 004,495, Applicant has unexpectedly created a new synthetic route to create cannabidiol. This new process eliminates the need to grow cannabis to extract cannabidiol. Applicant's cannabidiol has high purity levels and is substantially free of Scheduled Drug I, including delta-9-tetrahydrocannabinol.

[0104] Applicants have chemically synthesized cannabidiol by combining p-menthadienol and olivetol in toluene or dichloromethane or hexane with p-toluenesulfonic acid catalyst to produce cannabidiol (see diagram below).

[0105] [ka]

[0106] In certain embodiments, the present invention is directed to a method for treating Prader-Willi syndrome, comprising administering a formulation of the present invention to a patient in need thereof.

[0107] In another embodiment, the present invention is directed to a method for treating one or more symptoms of Prader-Willi syndrome, comprising administering a formulation of the present invention to a patient in need thereof.

[0108] In a preferred embodiment, the one or more symptoms of Prader-Willi syndrome is bulimia.

[0109] In another embodiment, the present invention is directed to a method for treating Prader-Willi syndrome, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0110] In another embodiment, the present invention is directed to a method for treating infantile spasms, comprising administering a formulation of the present invention to a patient in need thereof.

[0111] In another embodiment, the present invention is directed to a method of treating childhood absence epilepsy, comprising administering a formulation of the present invention to a patient in need thereof.

[0112] In another embodiment, the present invention is directed to a method for treating obesity comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0113] In certain embodiments, the present invention is directed to a method for treating graft-versus-host disease, comprising administering a formulation of the present invention to a patient in need thereof.

[0114] In another embodiment, the present invention is directed to a method for treating graft versus host disease comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0115] In certain embodiments, the present invention is directed to a method for preventing or treating acute and chronic graft-versus-host disease, comprising administering a formulation of the present invention to a patient in need thereof.

[0116] In another embodiment, the present invention is directed to a method for preventing or treating acute and chronic graft-versus-host disease, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0117] In one embodiment, the present invention is directed to a method for treating giddiness / hypothalamic hamartoma, comprising administering a formulation of the present invention to a patient in need thereof.

[0118] In another embodiment, the present invention is directed to a method for treating giddiness / hypothalamic hamartoma, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0119] In certain embodiments, the present invention is directed to a method for treating neonatal seizures, comprising administering a formulation of the present invention to a patient in need thereof.

[0120] In another embodiment, the present invention is directed to a method for treating neonatal seizures, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0121] In another embodiment, the present invention is directed to a method for treating a movement disorder comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof, preferably wherein the movement disorder is dystonia.

[0122] In certain embodiments, the present invention is directed to a method for treating a movement disorder, comprising administering a formulation of the present invention to a patient in need thereof, preferably wherein the movement disorder is dystonia.

[0123] In another embodiment, the present invention is directed to a method for treating a central pain syndrome comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof, preferably wherein the central pain syndrome is complex regional pain syndrome.

[0124] In certain embodiments, the present invention is directed to a method for treating a central pain syndrome, comprising administering a formulation of the present invention to a patient in need thereof, preferably wherein the central pain syndrome is complex regional pain syndrome.

[0125] In certain embodiments, the present invention is directed to a method for treating phantom limb pain, comprising administering a formulation of the present invention to a patient in need thereof.

[0126] In another embodiment, the present invention is directed to a method for treating phantom limb pain, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0127] In certain embodiments, the present invention is directed to a method for providing neuroprotection after stroke, comprising administering a formulation of the present invention to a patient in need thereof.

[0128] In another embodiment, the present invention is directed to a method for providing neuroprotection following a stroke, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0129] In certain embodiments, the present invention is directed to a method for treating traumatic brain injury, comprising administering a formulation of the present invention to a patient in need thereof.

[0130] In another embodiment, the present invention is directed to a method for treating traumatic brain injury comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0131] In certain embodiments, the present invention is directed to a method for treating brain damage caused by radiation therapy, comprising administering a formulation of the present invention to a patient in need thereof.

[0132] In another embodiment, the present invention is directed to a method for treating brain damage caused by radiation therapy, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0133] In certain embodiments, the present invention is directed to a method for providing enhanced neurological repair following traumatic brain injury, concussion, cerebral infarction, brain irradiation, or encephalomyelitis, comprising administering a formulation of the present invention to a patient in need thereof.

[0134] In another embodiment, the present invention is directed to a method for providing enhanced neurological repair following traumatic brain injury, concussion, cerebral infarction, brain irradiation, or encephalomyelitis, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0135] In certain embodiments, the present invention is directed to a method for providing recovery from myocardial infarction, comprising administering a formulation of the present invention to a patient in need thereof.

[0136] In another embodiment, the present invention is directed to a method for providing recovery from myocardial infarction comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0137] In one embodiment, the present invention is directed to a method for providing recovery from radiation damage, preferably radiation damage to the lungs, intestines, kidneys, and heart, comprising administering to a patient in need thereof a formulation of the present invention.

[0138] In another embodiment, the present invention is directed to a method for providing recovery from radiation damage, preferably radiation damage to the lungs, intestines, kidneys and heart, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0139] In certain embodiments, the present invention is directed to a method for treating brain tumors, comprising administering a formulation of the present invention to a patient in need thereof.

[0140] In another embodiment, the present invention is directed to a method for treating brain tumors comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0141] In one embodiment, the present invention is directed to a method for treating a T-cell autoimmune disorder, comprising administering a formulation of the present invention to a patient in need thereof.

[0142] In another embodiment, the present invention is directed to a method for treating a T-cell autoimmune disorder comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0143] In certain embodiments, the present invention is directed to a method for treating colitis, comprising administering a formulation of the present invention to a patient in need thereof.

[0144] In another embodiment, the present invention is directed to a method for treating colitis comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0145] In certain embodiments, the present invention is directed to a method for treating glioma, comprising administering a formulation of the present invention to a patient in need thereof.

[0146] In another embodiment, the present invention is directed to a method for treating glioma comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0147] In certain embodiments, the present invention is directed to a method for treating glioblastoma multiforme, comprising administering a formulation of the present invention to a patient in need thereof.

[0148] In another embodiment, the present invention is directed to a method for treating glioblastoma multiforme comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0149] In certain embodiments, the present invention is directed to a method for treating Dravet Syndrome, comprising administering a formulation of the present invention to a patient in need thereof.

[0150] In another embodiment, the present invention is directed to a method for treating Dravet Syndrome, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0151] In yet another embodiment, the present invention is directed to a method for treating Lennox-Gastaut syndrome, comprising administering a formulation of the present invention to a patient in need thereof.

[0152] In another embodiment, the present invention is directed to a method for treating Lennox-Gastaut syndrome, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0153] In a further embodiment, the present invention is directed to a method for treating myoclonic seizures comprising administering a formulation of the present invention to a patient in need thereof, hi a more preferred embodiment, the alcohol-free formulation contains substantially pure cannabidiol.

[0154] In another embodiment, the present invention is directed to a method for treating myoclonic seizures, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0155] In a further embodiment, the present invention is directed to a method for treating juvenile myoclonic epilepsy, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a young patient in need of treatment.

[0156] In another embodiment, the present invention is directed to a method for treating juvenile myoclonic epilepsy comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0157] In certain embodiments, the present invention is directed to a method for treating intractable epilepsy, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulation of the present invention is administered to a young patient in need of treatment.

[0158] In another embodiment, the present invention is directed to a method for treating intractable epilepsy comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0159] In certain embodiments, the present invention is directed to a method for treating juvenile convulsions, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a young patient in need of treatment.

[0160] In another embodiment, the present invention is directed to a method for treating juvenile convulsions, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0161] In certain embodiments, the present invention is directed to a method for treating West syndrome, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulation of the present invention is administered to a young patient in need of treatment.

[0162] In another embodiment, the present invention is directed to a method for treating West Syndrome comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0163] In certain embodiments, the present invention is directed to a method for treating infantile spasms, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a young patient in need of treatment.

[0164] In another embodiment, the present invention is directed to a method for treating infantile spasms comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0165] In certain embodiments, the present invention is directed to a method for treating refractory infantile spasms, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a young patient in need of treatment.

[0166] In another embodiment, the present invention is directed to a method for treating refractory infantile spasms, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0167] In certain embodiments, the present invention is directed to a method for treating tuberous sclerosis complex, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a young patient in need of treatment.

[0168] In another embodiment, the present invention is directed to a method for treating tuberous sclerosis comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0169] In a further embodiment, the present invention is directed to a method for treating neuropathic pain, comprising administering a formulation of the present invention to a patient in need thereof. In a further embodiment, the neuropathic pain is caused by a neurotoxic chemotherapeutic agent such as paclitaxel, docetaxel, cisplatin, oxaliplatin, carboplatin, vincristine, methotrexate, cytarabine, fluorouracil, ifosfamide, cyclophosphamide, procarbazine, etoposide, carmustine, and lomustine. In yet another embodiment, the neuropathic pain is caused by paclitaxel, and the patient is receiving paclitaxel due to a diagnosis of breast cancer, cervical cancer, endometrial cancer, and / or ovarian cancer. In a further embodiment, the breast cancer, cervical cancer, endometrial cancer, and / or ovarian cancer is platinum-resistant. In another embodiment, the breast cancer, cervical cancer, endometrial cancer, and / or ovarian cancer is recurrent.

[0170] In another embodiment, the present invention is directed to a method for treating neuropathic pain, comprising administering synthetically synthesized, substantially pure cannabidiol to a patient in need thereof. In a further embodiment, the neuropathic pain is caused by a neurotoxic chemotherapeutic agent such as paclitaxel, docetaxel, cisplatin, oxaliplatin, carboplatin, vincristine, methotrexate, cytarabine, fluorouracil, ifosfamide, cyclophosphamide, procarbazine, etoposide, carmustine, and lomustine. In yet another embodiment, the neuropathic pain is caused by paclitaxel, and the patient is receiving paclitaxel due to a diagnosis of breast cancer, cervical cancer, endometrial cancer, and / or ovarian cancer. In a further embodiment, the breast cancer, cervical cancer, endometrial cancer, and / or ovarian cancer is platinum-resistant. In another embodiment, the breast cancer, cervical cancer, endometrial cancer, and / or ovarian cancer is recurrent.

[0171] In a further embodiment, the present invention is directed to a method for using cannabidiol as an analgesic, comprising administering a formulation of the present invention to a patient in need thereof.

[0172] In another embodiment, the present invention is directed to a method for using cannabidiol as an analgesic, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0173] In a further embodiment, the present invention is directed to a method for treating opioid addiction withdrawal symptoms, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a patient in need of treatment.

[0174] In another embodiment, the present invention is directed to a method for treating opioid addiction withdrawal symptoms, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0175] In yet another embodiment, the present invention is directed to a method for treating cocaine addiction withdrawal symptoms, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a patient in need of treatment.

[0176] In another embodiment, the present invention is directed to a method for treating cocaine addiction withdrawal symptoms, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0177] In a further embodiment, the present invention is directed to a method for treating heroin addiction withdrawal symptoms, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a patient in need of treatment.

[0178] In another embodiment, the present invention is directed to a method for treating heroin addiction withdrawal symptoms, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0179] In a further embodiment, the present invention is directed to a method for treating nicotine addiction withdrawal symptoms, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a patient in need of treatment.

[0180] In another embodiment, the present invention is directed to a method for treating nicotine addiction withdrawal symptoms, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0181] In a further embodiment, the present invention is directed to a method for treating amphetamine addiction withdrawal symptoms, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a patient in need of treatment.

[0182] In another embodiment, the present invention is directed to a method for treating amphetamine addiction withdrawal symptoms, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0183] In another embodiment, the present invention is directed to a method for treating drug addiction, wherein the treatment is selected from acute and long-term.

[0184] In another embodiment, the present invention is directed to a method for treating relapse associated with substance abuse.

[0185] In certain embodiments, the present invention is directed to a method for treating acne, comprising administering a formulation of the present invention to a patient in need thereof.

[0186] In another embodiment, the present invention is directed to a method for treating acne comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0187] In certain embodiments, the present invention is directed to a method for treating Parkinson's disease, comprising administering a formulation of the present invention to a patient in need thereof.

[0188] In another embodiment, the present invention is directed to a method for treating Parkinson's disease comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0189] In certain embodiments, the present invention is directed to a method for treating schizophrenia, comprising administering a formulation of the present invention to a patient in need thereof.

[0190] In another embodiment, the present invention is directed to a method for treating schizophrenia comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0191] In certain embodiments, the present invention is directed to a method for treating social anxiety disorder, comprising administering a formulation of the present invention to a patient in need thereof.

[0192] In another embodiment, the present invention is directed to a method for treating social anxiety disorder, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0193] In a further embodiment, the present invention is directed to a method for treating depression, comprising administering a formulation of the present invention to a patient in need thereof.

[0194] In another embodiment, the present invention is directed to a method for treating depression comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0195] In a further embodiment, the present invention is directed to a method for treating a patient experiencing adverse emotional stimuli, comprising administering a formulation of the present invention to a patient in need thereof.

[0196] In another embodiment, the present invention is directed to a method for treating a patient experiencing adverse emotional stimuli, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0197] In certain embodiments, the present invention is directed to a method for treating nausea, comprising administering a formulation of the present invention to a patient in need thereof.

[0198] In another embodiment, the present invention is directed to a method for treating nausea comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0199] In certain embodiments, the present invention is directed to a method for treating multiple sclerosis, comprising administering a formulation of the present invention to a patient in need thereof.

[0200] In another embodiment, the present invention is directed to a method for treating multiple sclerosis, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0201] In certain embodiments, the present invention is directed to a method for treating the symptoms of cannabis use disorder, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a patient in need of treatment.

[0202] In another embodiment, the present invention is directed to a method for treating symptoms of cannabis use disorder, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0203] In another embodiment, the present invention is directed to a method for treating early psychotic symptoms, comprising administering a formulation of the present invention to a patient in need thereof.

[0204] In another embodiment, the present invention is directed to a method for treating symptoms of early psychosis, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0205] In another embodiment, the present invention is directed to a method for treating the symptoms of Alzheimer's disease, comprising administering a formulation of the present invention to a patient in need thereof.

[0206] In another embodiment, the present invention is directed to a method for treating the symptoms of Alzheimer's disease, comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0207] In yet another embodiment, the present invention is directed to a method for treating symptoms of post-traumatic stress disorder ("PTSD"), comprising administering to a patient in need thereof a formulation of the present invention.

[0208] In another embodiment, the present invention is directed to a method for treating symptoms of post-traumatic stress disorder (PTSD), comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0209] In certain embodiments, the present invention is directed to a method for treating symptoms of anxiety, comprising administering a formulation of the present invention to a patient in need thereof.

[0210] In another embodiment, the present invention is directed to a method for treating anxiety comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0211] In a further embodiment, the present invention is directed to a method for treating symptoms of autism, comprising administering a formulation of the present invention to a patient in need thereof. In a preferred embodiment, an alcohol-free formulation of the present invention is administered to a patient in need of treatment.

[0212] In another embodiment, the present invention is directed to a method for treating symptoms of autism comprising administering synthetically synthesized substantially pure cannabidiol to a patient in need thereof.

[0213] <Definition> As used herein, "patient" refers to a single patient and not a patient population.

[0214] As used herein, "synthetic" refers to the chemical synthesis of cannabidiol and not to cannabidiol extracted from cannabis plant material.

[0215] As used herein, "substantially pure" refers to a preparation having a chromatographic purity of cannabidiol of greater than 98%, preferably greater than 98.5%, more preferably greater than 99.0%, and most preferably greater than 99.5%.

[0216] As used herein, "substantially free of delta-9-tetrahydrocannabinol" refers to a preparation of cannabidiol having less than 0.3% delta-9-tetrahydrocannabinol as determined by HPLC. Preferably, the preparation contains less than 0.25% delta-9-tetrahydrocannabinol, more preferably 0.2%, and most preferably less than 0.1% delta-9-tetrahydrocannabinol.

[0217] As used herein, all numerical values relating to amounts, weights, etc., where each particular value is defined as "about," are plus or minus 10%. For example, the phrase "about 10% w / w" is to be understood as "9% w / w to 11% w / w." Thus, amounts within 10% of the claimed value are encompassed by the scope of the claim.

[0218] As used herein, "liquid" refers to a flowable, fluid pharmaceutical formulation. This type of formulation is not a powder or solid.

[0219] All weights herein refer to % w / w or percent weight of the total formulation.

[0220] As used herein, the term "effective amount" refers to the amount needed to treat a patient in need thereof.

[0221] As used herein, the term "pharmaceutically acceptable" refers to ingredients that are not biologically or otherwise undesirable in an oral dosage form.

[0222] As used herein, "qs" means a sufficient quantity of that component to reach a desired volume or concentration.

[0223] The disclosed embodiments are merely illustrative embodiments of the inventive concepts disclosed herein and are not to be considered limiting unless otherwise stated in the claims.

[0224] The following examples are intended to illustrate the present invention and to teach one of ordinary skill in the art how to use the formulations of the present invention. They are not intended to be limiting in any way.

[0225] All claims, aspects and embodiments of the invention, and specific examples thereof, are intended to encompass their equivalents. [Example]

[0226] [Example 1. Alcohol-free preparation] The formulations in Table 1 below were prepared as follows: All solvents were purged with nitrogen before use in manufacturing. Vitamin E, methylparaben, and propylparaben were dissolved in propylene glycol. Polyethylene glycol 400 (PEG400) and flavoring agents were added to the propylene glycol solution and mixed thoroughly. An aqueous phase was prepared by dissolving sucralose and sodium ascorbate in water. These solutions were then combined, and the pH was adjusted using a pH modifier. The cannabinoid was added to the excipient solution and mixed until dissolved.

[0227] Synthetically synthesized substantially pure cannabidiol was used as the cannabinoid.

[0228] Strawberry flavor was used as the flavoring agent.

[0229] [Table 1]

[0230] Example 2. Stability of alcohol-free formulations The formulations listed in Table 1 were subjected to stability testing at 55°C ± 2°C, 40°C ± 2°C, and 25°C ± 2°C under 75% ± 5% relative humidity, and 60% ± 5% relative humidity. The stability of the formulations was analyzed by assessing their potency (assay value) and impurity levels at specific time points. High-performance liquid chromatography with ultraviolet detection was used to detect the assay and impurities. Assays were performed at 228 nm and expressed as % of the initial concentration. For all impurities, analyses were performed at 228 nm and expressed as % area. The amount of a particular impurity, along with the amount of total impurities, is listed in Tables 2-13 as a percentage of the area of each formulation. The relative retention time (RRT) is shown for each impurity.

[0231] [Table 2] TIFF2025118786000006.tif65170

[0232] [Table 3]

[0233] [Table 4]

[0234] [Table 5]

[0235] [Table 6]

[0236] [Table 7]

[0237] [Table 8]

[0238] [Table 9]

[0239] [Table 10]

[0240] [Table 11]

[0241] [Table 12]

[0242] [Table 13]

[0243] The control formulation (#AF1) showed a significant increase in the level of total impurities and a decrease in assay values. Adjusting the pH of formulation (#AF2) to a range of about 6 to about 7 increased the stability of the formulation compared to the control formulation. This illustrates the important role that pH plays in the stability of cannabinoid formulations. Applicant determined that the pH should be about 6 to about 7 for optimal stability. The addition of antioxidants, along with pH adjustment, further increased the stability of cannabinoid formulations. For example, formulations #AF3 and #AF4, which contain antioxidant(s) and a pH modifier, showed excellent stability for 4 weeks regardless of temperature and humidity conditions.

[0244] Example 3: Alcohol preparation The formulations in Tables 14 and 15 below were prepared as follows. All solvents were purged with nitrogen before use. Vitamin E, ascorbyl palmitate, methylparaben, propylparaben, and sucralose were dissolved in ethanol. Propylene glycol, polyethylene glycol 400, glycerol, flavoring agents, and water were added to the solution and mixed thoroughly. The pH of the solution was then adjusted, if applicable, using a pH modifier. The cannabinoid was added to the excipient solution and mixed until completely dissolved.

[0245] Synthetically synthesized, substantially pure cannabidiol was used as the cannabinoid, and strawberry flavor was used as the flavoring agent.

[0246] [Table 14]

[0247] [Table 15]

[0248] Example 4: Stability of formulations using alcohol The formulations listed in Tables 14 and 15 were subjected to stability testing at 25°C ± 2°C under 60% ± 5% relative humidity and 40°C ± 2°C under 75% ± 5% relative humidity. The stability of the formulations was analyzed by assessing their potency (assay value) and impurity levels at specific time points. High-performance liquid chromatography with ultraviolet detection was used to detect the assay and impurities. Assays were performed at 228 nm and expressed as % of the initial concentration. For all impurities, analyses were performed at 228 nm and expressed as % area. The amount of a particular impurity, along with the amount of total impurities, is listed in Tables 16-22 as a percentage of the area of each formulation. The relative retention time (RRT) is shown for each impurity.

[0249] [Table 16] TIFF2025118786000021.tif88170

[0250]

Table 17

[0251] Table 18

[0252]

Table 19

[0253] Table 20 TIFF2025118786000027.tif31170

[0254] Table 21

[0255] Table 22

[0256] Table 23

[0257] The control formulation (#A5) showed a significant increase in the level of total impurities and a decrease in the assay value. The addition of antioxidants, vitamin E and ascorbyl palmitate (see #A6), significantly increased the stability of the formulation. These results illustrate the important role of antioxidants in stabilizing cannabinoid formulations. The antioxidant vitamin E and ascorbic acid (or its salts) exhibit excellent synergy, as ascorbic acid (or its salts) strongly inhibits vitamin E deficiency by regenerating vitamin E. The addition of a pH modifier to adjust the pH to a range of 6-7, along with the antioxidant, resulted in exceptionally stable formulations (#A7 and #A8). Stability testing data demonstrate the importance of a pH range of approximately 6 to approximately 7. Formulations #A9 and #A10 also showed good stability after 4 weeks.

[0258] Example 5. Lipid formulation The formulations in Table 24 were created by mixing all solid and liquid excipients in lipid. Cannabidiol was then dissolved. Synthetically synthesized substantially pure cannabidiol was used as the cannabinoid source. Strawberry was used as the flavoring source.

[0259] [Table 24]

[0260] [Table 25] TIFF2025118786000033.tif230170TIFF2025118786000034.tif229169TIFF2025118786000035.tif234167TIFF2025118786000036.tif61161

[0261] Example 6. Stability of lipid-based formulations Formulation #LF1 was subjected to stability testing at 25°C ± 2°C under 60% ± 5% relative humidity and 40°C ± 2°C under 75% ± 5% relative humidity. Formulations #LF10 and #LF11 were subjected to stability testing at 55°C ± 2°C and 40°C ± 2°C under 75% ± 5% relative humidity. Formulations #LF8, #LF9, and #LF12 to #LF15 were subjected to stability testing under all three storage conditions. The stability of the formulations was analyzed by assessing the potency (assay value) and impurity levels at specific time points. High-performance liquid chromatography with an ultraviolet detector was used to detect the assay and impurities. Assays were performed at 228 nm and expressed as % of the initial concentration. For all impurities, analyses were performed at 228 nm and expressed as % area. The amount of specific impurities, along with the amount of total impurities, is listed in Table 25 as a percentage of the area of each formulation. The relative retention time (RRT) is shown for each impurity.

[0262] [Table 26]

[0263] [Table 27]

[0264] [Table 28]

[0265] [Table 29]

[0266] [Table 30]

[0267] [Table 31]

[0268] Table 32

[0269] Table 33

[0270] Table 34

[0271] Table 35

[0272] Table 36

[0273] Table 37

[0274] Table 38

[0275] Table 39

[0276] Table 40

[0277] Table 41

[0278] Table 42

[0279] [Table 43]

[0280] [Table 44]

[0281] [Table 45]

[0282] [Table 46]

[0283] [Table 47]

[0284] [Table 48]

[0285] As can be seen in Table 25 above, formulation #LF1 using sesame oil showed good stability after 3 months at both storage conditions of 25°C ± 2°C / 60% ± 5% relative humidity and 40°C ± 2°C / 75% ± 5% relative humidity. Furthermore, formulation #LF8 using olive oil showed good stability after 4 weeks at storage conditions of 55°C ± 2°C, and after 3 months at 25°C ± 2°C / 60% ± 5% relative humidity and 40°C ± 2°C / 75% ± 5% relative humidity.

[0286] Formulations #LF9-#LF15 each contain caprylic / capric triglyceride and one of alpha-tocopherol (vitamin E), ascorbyl palmitate, or a combination thereof as antioxidants. Formulations #LF13-#LF15 each additionally contain ethanol. Formulations #LF9-#LF15 each demonstrated good stability after 4 weeks at storage conditions of 55°C ± 2°C, 40°C ± 2°C / 75% ± 5% relative humidity, and 25°C ± 2°C / 60% ± 5% relative humidity. #LF9-#LF12 surprisingly demonstrate the ability of alpha-tocopherol (vitamin E) to achieve less than 0.5% total impurities after 4 weeks at 40°C ± 2°C / 75% ± 5% relative humidity. #LF13-#LF15 demonstrate the ability of ascorbyl palmitate in formulations containing 1%-5% ethanol to surprisingly achieve less than 0.2% total impurities after 4 weeks at all three storage conditions. #LF14 demonstrates that the addition of alpha-tocopherol (vitamin E) does not improve stability, surprising from the use of ascorbyl palmitate.

[0287] Example 7. Paclitaxel-induced neuropathic pain study Paclitaxel is an antineoplastic agent active against several types of cancer, including ovarian, breast, lung, and head and neck cancer. Paclitaxel works by promoting microtubule assembly, resulting in neuropathy as a toxic side effect. Peripheral sensory neuropathy is the most commonly reported neurotoxic side effect of paclitaxel and limits treatment with high and cumulative doses of paclitaxel when given alone or in combination with other neurotoxic antineoplastic agents, such as cisplatin. Currently, there are no highly effective treatments for this type of pain. Therefore, there is a need for highly effective treatments to alleviate the symptoms of paclitaxel-induced neuropathy.

[0288] A mouse study was conducted to determine the effects of cannabidiol, delta-9-tetrahydrocannabinol, and a cannabidiol plus delta-9-tetrahydrocannabinol combination to reduce neuropathic pain caused by chemotherapy-induced peripheral neuropathy. The cannabidiol administered to the mice was substantially pure synthetically synthesized cannabidiol having a purity greater than 98%.

[0289] A detailed description of Figure 1 is as follows: The Y-axis represents threshold sensitivity to mechanical stimuli, expressed as a percent of baseline sensitivity. The X-axis represents the dose of drug in milligrams per kilogram ("mg / kg") administered intraperitoneally ("IP"). The dotted line represents the withdrawal threshold level to mechanical stimuli for saline controls, while the dashed line represents paclitaxel-treated animals. Points along the dashed line indicate neuropathic pain, while points along the dotted line represent protection from neuropathic pain. Data shown are mean + SEM sensitivity measured 21 days after treatment. * p<0.05 from saline control as determined by one-way ANOVA.

[0290] Particular doses of drugs that produce similar overt behavioral effects when added together should produce an additive effect level.

[0291] example: 1) If 1.25mg / kg cannabidiol produces a 100% reduction in pain effect and 1.25mg / kg delta-9-tetrahydrocannabinol produces a 0% effect, then these doses added together should be completely effective (as does 2.5mg / kg cannabidiol + 2.5mg / kg delta-9-tetrahydrocannabinol).

[0292] 2) If 0.625 mg / kg cannabidiol and 0.625 delta-9-tetrahydrocannabinol produce a 0% effect, then these doses in combination should be ineffective.

[0293] Applicant has found that cannabidiol, when administered alone, provides the most effective levels for reducing chemotherapy-induced neuropathic pain compared to delta-9-tetrahydrocannabinol (as illustrated in Figure 1). The presence of delta-9-tetrahydrocannabinol can inhibit the ability of cannabidiol to reduce neuropathic pain, depending on its concentration. The ability of delta-9-tetrahydrocannabinol to block the pain-reducing activity of cannabidiol is, in turn, dependent on the concentration of cannabidiol. This study illustrates that substantially pure cannabidiol preparations are highly desirable.

[0294] Example 8. Additional Paclitaxel-Induced Neuropathic Pain Studies method Paclitaxel was administered on days 1, 3, 5, and 7 following baseline mechanical sensitivity assessment, with cannabinoids administered 15 minutes before each paclitaxel injection. Mechanical sensitivity was then assessed again on days 9, 14, and 21. For mechanical sensitivity testing, mice were placed on the wire mesh surface inside individual clear Plexiglas chambers, and the plantar surface of their hind paws was contacted with von Frey filaments of increasing thickness (0.16 to 2.0 grams of force) until they withdrew their paws from the stimulus. von Frey hairs are a series of fine calibrated filaments that are pressed against the plantar surface of the mouse's paw in a curved "C" shape for 6 seconds. The final sample size for each treatment group was eight animals. A two-way ANOVA was used to determine significant effects of CBD and THC treatment.

[0295] Single-drug dose-effect curves are presented as a percentage of baseline mechanical sensitivity levels to normalize the data. Dose equivalence analysis was used to determine significant synergistic effects of CBD + THC compared to the predicted added value derived from single-drug dose-response curves. To obtain predicted and observed effect levels, data were converted to the percent maximal possible effect (MPE) of cannabinoids to reverse paclitaxel-induced mechanical sensitivity. To determine this value for each animal, the mean sensitivity score of the paclitaxel control group on a given test day was set to zero, and the animal's baseline score before treatment was set to 100. For example, if an animal had a mechanical sensitivity score of 1.0 at baseline and a score of 0.75 on day 9, and the paclitaxel group showed an average score of 0.5 on day 9, the animal's percent MPE score was 50%. A %MPE score of 0% indicates that the animal was at least as sensitive as the paclitaxel control group. A %MPE score of 100% indicates that the animal was as sensitive or less sensitive on the test day than at baseline. This conversion of the data is necessary to determine effective dose levels (ED50, ED25, etc.).

[0296] result Pretreatment with CBD or THC significantly attenuated paclitaxel-induced mechanical sensitivity, with P<0.0001 for each drug. See Figure 2. CBD produced this effect with greater potency, in that the minimum effective dose for CBD was 1.25 mg / kg IP, while the minimum effective dose for THC was 2.5 mg / kg IP. Two-way ANOVA also revealed significant differences between the CBD and THC dose-response curves, with the 1.25 mg / kg dose of CBD producing a significantly higher % baseline score compared to the 1.25 mg / kg dose of THC. Both drugs appeared to be efficacious.

[0297] Over a wider range of doses, it became clear that both CBD and THC did not produce a monotonic dose effect, but instead followed an inverted U- or N-shaped function. For both CBD and THC at each time point, the curves inverted between 5.0 mg / kg and 10 mg / kg, but the treatment regained efficacy at higher doses. See Figure 3, top-middle and middle-middle panels. In the combination group, the data appeared more U-shaped, although it was unclear whether the increase reappeared at larger dose combinations. See Figure 3, bottom-middle panel.

[0298] Dose equivalence analysis was used to predict the combined effects of CBD and THC on the ascending limb of these dose-response curves based on their effects alone. The individual dose-effect equations were: E = 78.47 D for CBD; 2.5 / D 2.5 +0.497, and E=80D for THC 3 / D 3+3.44. In the dose equivalence analysis, for each CBD dose, an effect-equivalent dose of THC is identified. This dose is added to the actual THC dose in each combination, resulting in the predicted effective dose of the combination. For example, to predict the additive effect of 0.31 mg / kg CBD and 0.31 mg / kg THC, the determined dose-effect formula for CBD is used to identify a dose of THC that is equally effective as 0.31 mg / kg CBD. 0.31 mg / kg CBD produces a %MPE of 8.3%. From this, the determined dose-effect formula for THC is used to calculate the dose of THC to produce a %MPE of 8.3. The dose of THC required to achieve the %MPE is 0.7 mg / kg, which represents a dose that is equally effective to 0.31 mg / kg CBD. Adding 0.7 mg / kg to 0.31 mg / kg results in an effect level of 1.01 mg / kg THC, equivalent to the predicted effect level of 0.31 mg / kg CBD + 0.31 mg / kg THC. This predicted effect level is determined to be 13.68% MPE. When the actual combination experiment was performed, 0.31 mg / kg CBD + 0.31 mg / kg THC (labeled as the 0.625 mg / kg combination on the graph) actually had an ED78 (78% of the maximum possible effect; Figure 2, bottom panel). Applying a modified t-test statistic, the predicted combination dose-response curve was determined to be statistically significantly different from the observed dose-response curve, demonstrating the synergistic effect of the CBD + THC combination. See Figure 4.

[0299] Example 9. Additional Paclitaxel-Induced Neuropathic Pain Studies method The study was designed to test the efficacy of CBD+THC combinations that deviated from a 1:1 dose ratio. Six additional combinations were tested: 4:1, 3:1, 2:1, 1:2, 1:3, and 1:4. Four doses of each treatment combination were tested in mice treated with paclitaxel. The final sample size for each treatment group was eight animals.

[0300] result A 4:1 combination of CBD to THC produced an effect similar to CBD alone, while 2:1 and 3:1 ratios of CBD to THC were more potent than CBD alone. See Figure 5. A two-way ANOVA revealed an overall effect of treatment and dose (p<0.05), but no significant interaction. Combinations higher in THC than CBD produced an effect similar to THC alone, with a significant effect of dose (p<0.05), but no main effect of treatment and no significant interaction.

[0301] Example 10. Oxaliplatin- or vincristine-induced neuropathic pain study method The study was designed to test the efficacy of CBD in preventing oxaliplatin- or vincristine-induced peripheral neuropathy. Two doses of CBD and vehicle were tested against each of these first-line chemotherapy agents. Oxaliplatin was administered once at a dose of 6 mg / kg. CBD was administered 15 minutes before a single oxaliplatin injection. Vincristine was administered once daily at a dose of 0.1 mg / kg for 7 days. CBD was administered 15 minutes before each vincristine injection. The final sample size for each treatment group was 8 animals.

[0302] result Pretreatment with CBD attenuated oxaliplatin-induced mechanosensitivity but not vincristine-induced mechanosensitivity (see Figure 6). Two-way ANOVA for oxaliplatin revealed a significant time effect and a significant treatment effect (p<0.05), but no significant interaction. Two-way ANOVA for vincristine revealed a significant time effect (p<0.05), but no main treatment effect or interaction.

[0303] Example 11. Anticonvulsant drug study The study was conducted according to the standard model for anticonvulsant drug screening, including a maximal electroshock test ("MES"), a minimal clonic seizure ("6 Hz") test, and a toxicity assessment ("TOX"), as follows. Data are reported as the number of animals protected (N) out of the number of animals tested (F), see Tables 26-29 below. The study was repeated once. The cannabidiol administered to mice and rats was substantially pure synthetically synthesized cannabidiol with a purity greater than 98%. Cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 ratio of ethanol:polyethoxylated castor oil:phosphate buffered saline ("PBS").

[0304] The maximal electroshock test is a model for generalized tonic-clonic seizures and provides an indication of a compound's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active. These seizures are highly reproducible and electrophysiologically consistent with human seizures. For all tests based on maximal electroshock convulsions, a 60 Hz alternating current (50 mA in mice, 150 mA in rats) was delivered for 0.2 seconds through a corneal electrode primed with an electrolyte solution containing an anesthetic (0.5% tetracaine HCl). Following doses of 10 mg / kg, 30 mg / kg, and 100 mg / kg of cannabidiol administered by intraperitoneal injection at a volume of 0.01 mL / g, mice were tested at various intervals. Animals were considered "protected" from maximal electroshock-induced seizures upon the disappearance of the hindlimb tonic extensor component of the seizure.

[0305] The minimal motor impairment test was used to determine undesirable side effects or toxicity of the compounds. During this test, animals were monitored for obvious signs of impaired neurological or muscular function. The rotarod procedure was used to reveal minimal muscular or neurological impairment. Control mice were placed on a rotating rod at a speed of 6 rpm, and the animals were able to maintain their balance for an extended period of time. An animal was considered toxic if it fell from the rotating rod three times within a 60-second period. In addition to minimal motor impairment, animals may exhibit circular or zigzag gait, abnormal body posture and splaying, tremors, hyperactivity, lack of exploratory behavior, lethargy, stupor, catalepsy, loss of the placing response, and changes in muscle tone.

[0306] The third test was the minimal clonic seizure (6 Hz) test. Like the maximal electroshock test, the minimal clonic seizure (6 Hz) test is used to determine the efficacy of compounds against electrically induced seizures, but uses a lower frequency (6 Hz) and longer duration stimulation (3 seconds). Mice were pre-administered with cannabidiol via intraperitoneal injection. Individual mice (four per time point) were challenged for varying periods with sufficient current delivered via corneal electrodes to elicit psychomotor seizures (32 mA for 3 seconds) in 97% of animals. Untreated mice exhibit a minimal clonic phase followed by seizures characterized by stereotyped, automatic behaviors originally described as similar to the aura observed in human patients with partial seizures. Animals that do not exhibit this behavior are considered protected.

[0307] [Table 49]

[0308] [Table 50]

[0309] [Table 51]

[0310] [Table 52]

[0311] As can be seen in Tables 49-52 above, Applicants have found that cannabidiol protects mice and rats from epilepsy.

[0312] Example 1: 2.6 Hz Psychomotor Seizure Test This study was conducted to determine the ability of synthetically synthesized, substantially pure cannabidiol to block psychomotor seizures induced by long-frequency (6 Hz) stimulation, a research model for treatment-resistant partial seizures.

[0313] Adult male CF1 mice (weight 18-25 g) were pretreated intraperitoneally with a dose of 100 mg / kg cannabidiol. The cannabidiol administered to the mice was substantially pure synthetically synthesized cannabidiol with a purity greater than 98%. Cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 ratio of ethanol:polyethoxylated castor oil:PBS.

[0314] Each treatment group (n = 4 mice / group) was tested for anticonvulsant effects at one of five time points (1 / 4 hour, 1 / 2 hour, 1 hour, 2 hours, and 4 hours) following treatment with cannabidiol. Following pretreatment, each mouse received one drop of 0.5% tetracaine hydrochloride applied to each eye. The mice were then challenged with a 3-second low-frequency (6 Hz) stimulus delivered via corneal electrodes. The low-frequency, prolonged stimulus was initially delivered at an intensity of 32 mA. The animals were manually restrained, immediately released following the stimulus, and observed for seizure activity. If the test compound was effective in the 32 mA screen, an additional assay was performed in which the stimulus current was increased to 44 mA using the same protocol described above. Additionally, a dose-response curve could be generated for the time to peak effect (TPE) at a particular stimulus intensity.

[0315] Typically, 6 Hz stimulation produces seizures characterized by a minimal clonic phase followed by stereotypic motility, including vibrissa twitching and tail lifting. Animals not exhibiting these behaviors were considered protected. Data were analyzed by the Mann-Whitney U test, with p<0.05 determined to be statistically significant.

[0316] For each time group, results are expressed as the total number of animals protected out of the number of animals tested over time (i.e., 2 / 4 represents 2 protected out of 4 mice tested).

[0317] [Table 53]

[0318] [Table 54]

[0319] [Table 55]

[0320] [Table 56]

[0321] As can be seen in Tables 53-56, cannabidiol in both vehicles exhibited comparable median effective doses to suppress seizures in 50% of animals (ED50) in the 100 mg / kg range. Cannabidiol dissolved in methylcellulose vehicle had an ED50 of 103.75 mg / kg (95% confidence interval of 53.89 mg / kg to 163.84 mg / kg), while it exhibited an ED50 of 121.52 mg / kg (95% confidence interval of 87.83 mg / kg to 152.96 mg / kg) when dissolved in a 1:1:18 ethanol:polyethoxylated castor oil:PBS vehicle. Based on the toxicity data for cannabidiol in methylcellulose vehicle, the median toxic dose at which toxicity was observed in 50% of animals ("TD50") was determined to be greater than 500 mg / kg at 0.5 hours post-dose. Diarrhea at 24 hours and one death were reported at 24 hours at the highest dose tested, 500 mg / kg.

[0322] The TD50 was determined to be 262.37 mg / kg (95% confidence interval of 232.64 to 301.78) for cannabidiol dissolved in a 1:1:18 ethanol:polyethoxylated castor oil:PBS vehicle. Mortality was reported at 24 hours at 300 mg / kg and at 6 and 24 hours at 500 mg / kg using a 1:1:18 ethanol:polyethoxylated castor oil:PBS vehicle.

[0323] These results further illustrate that cannabidiol is likely to be effective in treating epilepsy and other conditions in humans. Furthermore, synthetically synthesized cannabidiol is likely to be less toxic than plant-derived and less substantially pure cannabidiol.

[0324] Example 13. Maximal electroshock seizures and subcutaneous metrazol The maximal electroshock seizure (MES) and subcutaneous metrazol (scMet) tests are the two most widely used preclinical seizure models for the initial identification and high-throughput screening of investigational antiseizure drugs. These tests are highly effective in identifying new antiseizure drugs that may be useful for the treatment of generalized tonic-clonic and generalized myoclonic seizures in humans. The MES test provides an indication of CBD's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active. The scMet test detects the ability of CBD to raise an animal's chemical convulsive drug-induced seizure threshold, thus protecting it from exhibiting forebrain-clonic seizures.

[0325] For the MES test, a 60 Hz alternating current is delivered for 0.2 seconds via corneal electrodes. A supramaximal seizure is elicited at a current intensity five times that required to produce a threshold tonic extensor seizure, i.e., 50 mA in mice and 150 mA in rats. Electrical stimulation is elicited by applying a corneal electrode to the eye immediately after placing a drop of anesthetic solution, 0.5% tetracaine hydrochloride, in each animal's eye. Animals are manually restrained and immediately released following stimulation, allowing for observation of the entire seizure. Inhibition of the hindlimb tonic extensor component is the endpoint of the MES test.

[0326] A dose of metrazol (85 mg / kg in mice) induces convulsions in 97% of mice (CD97). The CD97 dose of metrazol is injected into a loose skin fold in the midline of the neck. The CD97 dose for metrazol is validated annually in mice. It is administered to mice in a volume of 0.01 ml / g body weight. Animals are then placed in isolation cages to minimize stress and continuously monitored for the presence or absence of seizures for the next 30 minutes. The endpoint is an episode of clonic convulsions of approximately 3 to 5 seconds of forelimb and / or hindlimb, jaw, or vibrissae. Animals that do not exhibit forelimb and / or hindlimb clonus, jaw chewing, or vibrissae twitching are considered protected.

[0327] All quantitative in vivo anti-seizure / behavioral disorder studies are typically performed at a predetermined TPE. Groups of at least eight mice are tested with various doses of cannabidiol until at least two points are established between the limits of 100% protection or minimal toxicity and 0% protection or minimal toxicity. The dose of drug required to produce the desired endpoint in 50% of the animals (ED50 or TD50) in each test, the 95% confidence interval, the slope of the regression line, and the standard error of the mean (SEM) of the slope are then calculated by probit analysis.

[0328] The cannabidiol administered to mice was substantially pure synthetically synthesized cannabidiol with a purity greater than 98%. Cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 ratio of ethanol:polyethoxylated castor oil:PBS. Maximal electroshock (MES) and subcutaneous metrazol ("sc MET") are the most widely used preclinical seizure models for the initial identification and screening of new antiepileptic drugs.

[0329] [Table 57]

[0330] [Table 58]

[0331] [Table 59]

[0332] [Table 60]

[0333] The ED50 in the MES model for cannabidiol dissolved in methylcellulose solvent cannot be calculated due to a U-shaped dose response (1 / 4 protection at 0.5 hours, 1 / 4 protection at 1 hour, 4 / 8 protection at 2 hours, and 2 / 4 protection at 4 hours). However, the ED50 for cannabidiol dissolved in a 1:1:18 ethanol:polyethoxylated castor oil:PBS solvent is 92.21 mg / kg (95% confidence interval of 78.4 mg / kg to 104.63 mg / kg).

[0334] For the MET model, the ED50 was 241.03 mg / kg (95% confidence interval of 182.23 to 311.87) for cannabidiol dissolved in methylcellulose solvent and 198.51 mg / kg (95% confidence interval of 167.76 mg / kg to 232.58 mg / kg) for cannabidiol dissolved in a 1:1:18 ethanol:polyethoxylated castor oil:PBS solvent. Based on the toxicity data for cannabidiol dissolved in methylcellulose solvent, the TD50 was determined to be greater than 500 mg / kg, the highest dose tested.

[0335] Myoclonic jerks were reported at 1 hour at the 200 mg / kg dose and at 2 hours at the 360 mg / kg dose. The TD50 was determined to be 266.76 mg / kg (95% confidence interval of 222.28 mg / kg to 317.42 mg / kg) for cannabidiol dissolved in a 1:1:18 ethanol:polyethoxylated castor oil:PBS vehicle.

[0336] These results further illustrate that cannabidiol is likely to be effective in treating epilepsy and other conditions in humans. Furthermore, synthetically synthesized cannabidiol is likely to be less toxic than plant-derived and less substantially pure cannabidiol.

[0337] Example 14. Glioblastoma multiforme study Studies were conducted to determine the extent to which systemic administration of cannabidiol or cannabidiol plus delta-9-tetrahydrocannabinol (cannabidiol / delta-9-tetrahydrocannabinol 1:1) could inhibit glioblastoma multiforme progression and enhance the activity of the chemotherapeutic drug temozolomide in an orthotopic mouse model of glioblastoma multiforme utilizing U87 cells. The combination of cannabidiol plus delta-9-tetrahydrocannabinol was previously suggested to be the most effective treatment for targeting tumors derived from U87 serum-induced glioblastoma multiforme cells.

[0338] Studies were performed as follows: Human U87 luciferase-labeled cells were grown in Roswell Park Memorial Institute medium with 10% fetal bovine serum, then harvested from the dishes during their exponential growth phase in culture using 0.1% trypsin / ethylenediaminetetraacetic acid and washed twice with serum-free Roswell Park Memorial Institute medium. For the intracranial model, 0.3 × 10 cells were harvested in 4 μl of Roswell Park Memorial Institute medium. 6 Tumors were developed in female athymic nu / nu mice by intracranial injection of U87 cells. This model can be used to determine drug efficacy (in vivo imaging) as well as survival in the same animal groups. Survival studies were performed in accordance with the National Institutes of Health guidelines for experimental neoplasia and our approved IACUC protocol. Animals in all groups were removed from the study if they demonstrated any single sign of significant tumor burden development, including a hunched back, persistent reduction in general activity, or significant loss of body weight. In the limited cases where tumors were able to escape the intracranial cavity, mice were euthanized when the external tumor measured greater than 5 mm as determined by calipers. Additionally, mice with a radiance >500 × 10 6 Mice bearing tumors measuring 1.0 or 2.0 were removed from the study even if no symptoms were observed to ensure that spontaneous seizure-related deaths were not due to the presence of large intracranial tumors.

[0339] Cannabinoids were dissolved in a mixture of 3% ethanol, 3% surfactant, and 94% saline, and temozolomide was dissolved in 30% dimethyl sulfoxide and 70% saline. Synthetically synthesized and substantially pure cannabidiol was used in this study. Treatment began 9 days after tumor cell injection. Initial tumor size was determined by imaging mice the morning before the first injection, and groups were then organized to have equal tumor size distribution before the start of the first injection. Mice were treated with temozolomide once daily for 5 days. Except for the first week of the study, when mice were injected over the weekend, mice were treated with cannabinoids once daily, 5 days a week (Monday through Friday) until the completion of the study. All mice were administered treatment via intraperitoneal injection. There were 12 mice per group, for a total of 72 mice. Treatment rates were as follows: cannabidiol (15 mg / kg); cannabidiol / delta-9-tetrahydrocannabinol (1:1 together at 15 mg / kg); and temozolomide (2 mg / kg intraperitoneal injection).

[0340] Significant differences were determined using one-way ANOVA. Bonferroni-Dunn post hoc analysis was performed when appropriate. Survival between groups was compared using the log-rank Mantel-Cox test. A P value of <0.05 was defined as statistically significant.

[0341] A detailed description of Figure 7 follows: The x-axis represents days after treatment and the y-axis represents survival rate.

[0342] As can be seen in Figure 7, 15 mg / kg of cannabidiol alone or cannabidiol / delta-9-tetrahydrocannabinol (1:1) did not inhibit glioblastoma multiforme progression, but enhanced the antitumor activity of a suboptimal dose of temozolomide, leading to a significant increase in survival. Furthermore, substantially pure synthetically synthesized cannabidiol produced a 20% complete regression of tumors. This effect was not observed following 1:1 cannabidiol:delta-9-tetrahydrocannabinol treatment. It was previously thought that a 1:1 ratio of cannabidiol (extracted from cannabis, not substantially pure):delta-9-tetrahydrocannabinol produced better effects than cannabidiol alone, so it was unexpected that substantially pure synthetically synthesized cannabidiol would have these effects. However, this study again illustrates the superiority of Applicant's substantially pure synthetically synthesized cannabidiol.

[0343] Example 15. Additional Glioblastoma Multiforme Studies Human U251 luciferase-labeled cells were grown in Roswell Park Memorial Institute medium with 10% fetal bovine serum and then harvested from the dishes during their exponential growth phase in culture with 0.1% trypsin / ethylenediaminetetraacetic acid and washed twice with serum-free Roswell Park Memorial Institute medium. For the intracranial model, 0.3 × 10 cells were harvested in 4 μl of Roswell Park Memorial Institute medium. 6Tumors were developed in female athymic nu / nu mice by intracranial injection of U251 cells. This model can be used to determine drug efficacy (in vivo imaging) as well as survival in the same animal groups. Survival studies were conducted in accordance with the National Institutes of Health guidelines for experimental neoplasia and our approved IACUC protocol. Animals in all groups were removed from the study if they demonstrated any single sign of significant tumor burden development, including a hunched back, persistent reduction in general activity, or significant loss of body weight. In the limited cases where tumors were able to escape the intracranial cavity, mice were euthanized when the external tumor measured greater than 5 mm as determined by calipers. Additionally, mice with a radiance >500 × 10 6 Mice bearing tumors measuring 1.5 mg / kg were removed from the study even if no symptoms were observed to ensure that spontaneous seizure-related deaths were not due to the presence of large intracranial tumors. There were 12 mice per group, for a total of 72 mice. Treatment ratios were as follows: cannabidiol (15 mg / kg); temozolomide (1.5 mg / kg intraperitoneal injection); and cannabidiol / temozolomide (10:1, together at 16.5 mg / kg).

[0344] For drug treatment studies, cannabinoids were dissolved in a mixture of 2.5% ethanol, 2.5% TWEEN® 80, and 95% saline, and temozolomide was dissolved in 30% dimethyl sulfoxide and 70% saline. Treatment began 9 days after tumor cell injection. Mice were imaged the morning before the first injection to determine initial tumor size, and then groups were organized to have equal tumor size distribution before the start of the first injection. Mice were treated with temozolomide once daily for 5 days. Except for the first week of the study, when mice were injected over the weekend, mice were treated with cannabinoids once daily, 5 days a week (Monday through Friday) until the completion of the study. All mice were injected intraperitoneally.

[0345] Significant differences were determined using one-way ANOVA. Bonferroni-Dunn post hoc analysis was performed when appropriate. Kaplan-Meier analysis and the log-rank Mantel-Cox test or Gehan-Breslow-Wilcoxon test were used to compare survival between groups. A P value of <0.05 was defined as statistically significant.

[0346] A detailed description of Figure 8 follows: The x-axis represents days after treatment and the y-axis represents survival rate.

[0347] One of the tumors in the vehicle group completely regressed over time, creating an outlier in the study. Tumor regression in vehicle-treated animals is a rare occurrence, but it can occur. During the beginning of the study, the tumor demonstrated a small increase in growth as determined by IVIS imaging and was not removed from the dataset. Data are presented with (Figure 8A) and without (Figure 8B) the outlier for comparison. When the vehicle outlier was included, temozolomide alone did not increase survival (p=0.48, Figure 8A; p<0.05 is considered significant). Cannabidiol alone also did not increase survival. However, the combination of temozolomide plus 15 mg / kg cannabidiol nearly reached significance (p=0.09) for increasing survival using a log-rank Mantel-Cox test; p<0.05 is considered significant. When this same data set was analyzed using the Gehan-Breslow-Wilcoxon test, temozolomide plus cannabinoid treatment produced a significant increase in survival. The Gehan-Breslow-Wilcoxon test, however, is a less rigorous statistical test compared to the log-rank Mantel-Cox test. It should be noted that 2 of 11 mice were still alive in the temozolomide plus cannabinoid group, and in one of the mice, the tumor had completely regressed based on in vivo imaging of the tumor.

[0348] When vehicle outliers were removed from the dataset, treatment with temozolomide significantly increased survival (p<0.5, FIG. 8B). The combination of temozolomide plus 15 mg / kg cannabidiol, however, was highly significant in increasing survival (p=0.005). Thus, cannabidiol enhanced the antitumor activity of temozolomide.

[0349] Example 16. Pharmacokinetic study of multiple doses of cannabidiol oral solution in pediatric subjects with treatment-resistant seizure disorders. Protocol A Phase 1 / 2, open-label, multiple ascending dose study will be conducted to evaluate the effects of multiple doses of cannabidiol oral solution on pediatric subjects experiencing treatment-resistant seizures. The study will determine the pharmacokinetics, safety, tolerability, and preliminary efficacy of three doses of cannabidiol oral solution (10, 20, and 40 milligrams per kilogram per day (“mg / kg / day”)) administered in a sequential manner. Specifically, 20 subjects will be enrolled in each dose cohort as follows: A) Dose cohorts meeting the following criteria: 1. Subject and / or parent(s) / caregiver(s) fully understand the Informed Consent Form (ICF) and authorization form, understand all study procedures, and are able to communicate adequately with the investigator and study coordinator; 2. Provide subject and / or parent(s) / caregiver(s) informed consent and / or authorization (if applicable) in accordance with applicable laws, regulations, and local requirements; 3. Male or female, between 1 and 17 years of age (inclusive) at the time of consent; 4. a. Appropriate trial of ≥ 3 antiepileptic drugs ("AEDs"), and b. Diagnosed with treatment-resistant seizure disorder, as defined by the investigator and as ongoing seizures, despite ≥1 prior adequate treatment course with ≥2 AEDs in combination (i.e., simultaneously); 5. Willingness to remain on an established AED (stable medication for ≥30 days prior to Day 0 and throughout the duration of the study); a. Neither vagus nerve stimulation (VNS) surgery nor the ketogenic diet are considered AEDs for the purposes of this study; 6. Willingness not to initiate a ketogenic diet during the treatment period or, if already on the diet, not to change the diet during the study; 7. Female subjects are eligible for study participation if they: a. are premenarcheal or b. are of childbearing potential with a negative urine pregnancy test at the screening visit and on Day 0. If sexually active, they must agree to meet one of the following requirements: i. Complete sexual abstinence ≥4 weeks prior to administration of the first dose of the investigational product, throughout the treatment period, and 4 weeks after completion or early discontinuation from the investigational product, and agreement to use a double-barrier method if they become sexually active; ii.Use of acceptable contraceptive methods throughout the study and for 4 weeks after completion or early discontinuation from the investigational product. Double barrier methods (i.e., condoms plus spermicide or condoms plus diaphragm) are acceptable contraceptive methods; 8. Sexually active male subjects must be willing to use acceptable contraceptive methods throughout the study and for 4 weeks after completion of study participation or early discontinuation from the investigational product. Acceptable birth control methods are abstinence or double-barrier birth control (i.e., condoms plus spermicide or condoms plus diaphragm); 9. In the investigator's opinion, the parent(s) / caregiver(s) are willing and able to comply with study procedures and visit schedule, including venipuncture, inpatient stay at the study center, medication at the study center (twice daily if needed while outpatient), and follow-up visits (if applicable); 10. Good general health (defined as the absence of any clinically relevant abnormalities as determined by the investigator) based on physical and neurological examination, medical history, and laboratory values (hematology, chemistry, and urinalysis) completed during the screening visit; and 11. Body weight ≥ 9 kg; and B) dose cohorts not meeting the following criteria: 1. Subject or parent(s) / caregiver(s) have routine responsibilities that interfere with attending all study visits for the duration of the study; 2. Currently have a strong cytochrome P450 3. Currently taking any other unauthorized medication; 4. Currently taking felbamate if not taken for <6 months prior to the screening visit; 5. History of any clinically significant unstable medical abnormality, chronic disease, or clinically significant abnormality of the cardiovascular, gastrointestinal, respiratory, hepatic, or renal systems, in the investigator's opinion; 6. Any disorder or history of conditions that may interfere with drug absorption, distribution, metabolism, or excretion (e.g., malabsorption or gastrointestinal surgery); 7. History or presence of an abnormal electrocardiogram ("ECG") that is clinically significant, in the investigator's opinion; 8.For eligible subjects, an affirmative answer to the question regarding active suicidal ideation with some intent to act but no specific plan, or active suicidal ideation with a specific plan and intent as assessed by the Columbia Suicide Severity Rating Scale ("C-SSRS") at the screening visit. Subjects with significant findings for suicidal ideation as assessed by the C-SSRS must be referred to the investigator for follow-up evaluation; 9. History of suicide attempt; 10. History of poor tolerance of venipuncture or inadequate venous access causing difficulty in collecting blood samples; 11. Participation in any research study currently or within 30 days or 5 half-lives (t1 / 2) of the investigational product (whichever is longer) prior to the screening visit; 12. Use of any cannabinoid (cannabidiol, Δ9-tetrahydrocannabinol [Δ9-THC], hemp oil, Realm oil (Realm oil)) within 30 days prior to the screening visit. 13. Known or suspected history of allergic reaction or sensitivity to any substance contained in the investigational product formulation; 14. Known infection with Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV); 15. In the opinion of the investigator, the subject is otherwise unsuitable to participate in this study; and 16. Body weight >90 kg.

[0350] Each subject will be enrolled in only one dose cohort. Two or more subjects between 2 and 12 years of age must be dosed 10 days before dosing any subject <2 years of age. Each of the three planned dose cohorts will contain 20 subjects, for a total of 60 subjects in the study: 1 to <2 years of age: 5 subjects; 2 to <12 years of age: 9 subjects, with at least 3 under 6 years of age; and 12 to ≤17 years of age: 6 subjects, with at least 3 under 16 years of age. Each subject will complete a screening period of up to 28 days and a 10-day treatment period. Subjects will have a follow-up visit on Day 14 and a follow-up phone call on Day 17. The investigational product will be administered once in the morning according to the subject's assigned dose level cohort on Day 1. The evening dose of investigational product will not be administered on Day 1. Thus, subjects receive only a half-daily dose (5 milligrams, 10 milligrams, or 20 milligrams per kilogram ("mg / kg") total) of the investigational product on Day 1. Subjects do not receive a dose until Days 2-3, but remain in the inpatient setting to complete planned assessments. Subjects are dosed twice daily (i.e., a full daily dose of 10 mg / kg / day, 20 mg / kg / day, or 40 mg / kg / day) on Days 4-10 according to their assigned cohort. Doses are administered approximately 12 hours apart. Doses are administered to fasted subjects on days when serial PK samples are collected (i.e., Days 1 and 10). Fasting periods include 1 hour for subjects aged 1-2 years and 2 hours for subjects aged 2-17 years.

[0351] During screening, treatment, and follow-up, subjects are not to receive: (1) medication(s) that are strong CYP3A4 inhibitors or inducers or CYP3A4-sensitive substrates with a narrow therapeutic index; (2) any cannabinoids (cannabidiol, Δ9-THC, hemp oil, realm oil, or marijuana); corticotropin; systemic steroid therapy (excluding inhaled medications for the treatment of asthma); felbamate (if used for <6 months); or (7) any other investigational drug or device. Subjects will remain on established antiepileptic therapy (i.e., an AED on which dosing has been stable for ≥30 days prior to Day 0) throughout the duration of treatment and follow-up.

[0352] Briefly, for subjects 1 to <2 years of age, serial blood sample collections for pharmacokinetic ("PK") analysis will occur at 2, 4, 8, and 12 hours after the Day 1 dose. Serial blood sample collections for PK analysis will also occur pre-dose and 2, 4, 8, and 12 hours after the morning dose on Day 10. For subjects 2 to <6 years of age, serial blood sample collections will occur pre-dose and 1, 2, 3, 4, 8, 12, 16, 24 (Day 2), and 48 hours (Day 3) after the morning dose on Day 1. Blood samples for PK trough values for cannabidiol and its 7-hydroxy ("OH") metabolite will be assessed on Day 8. Collection will occur prior to the morning dose of the investigational product; the investigational product will not be administered on Day 11. Serial blood sampling for PK analysis also occurs pre-dose and 1, 2, 3, 4, 8, 12, and 24 hours after the morning dose on Day 10 (Day 11). For subjects 6 to ≦17 years of age, serial blood sampling for PK analysis occurs pre-dose and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after the morning dose on Day 1 (Day 2), 36 hours (Day 2), 48 hours (Day 3), and 72 hours (Day 4). Blood samples for PK trough values for cannabidiol and its 7-OH metabolite will be assessed on Days 6 (≧12 years of age only), 8, and 9. Collection occurs prior to the morning dose of investigational product; investigational product will not be administered on Day 11. Serial blood sampling for PK analysis will occur, as well, pre-dose and 1, 2, 3, 4, 6, 8, 12, and 24 hours (day 11) after the morning dose on day 10. In addition to the above measurements of cannabidiol and its 7-OH metabolites, clobazam and norclobazam levels will be measured from pre-dose samples on days 1 (baseline), 8, and 10 (pre-dose) for subjects ≥ 2 years of age and currently taking clobazam.

[0353] endpoint Study endpoints include: (1) incidence, type, and severity of adverse events (“AEs”) (i.e., treatment-emergent adverse events [“TEAEs”]) and serious adverse events (“SAEs”) occurring during the treatment period; (2) changes from baseline in vital signs; (3) changes from baseline in ECG findings; (4) changes from baseline in clinical laboratory values (hematology, chemistry, and urinalysis); and (5) plasma PK variables for cannabidiol (parent compound) and its 7-OH metabolite, as appropriate: (a) maximum plasma concentration (C max ) and dose-normalized Cmax (C max / D)(b)C max (t max ) time to decay; (c) half-life (t 1 / 2 (d) Elimination rate; (e) Oral clearance (cannabidiol only); (f) Volume of distribution (cannabidiol only); (g) Area under the plasma concentration-time curve from 0 hours to 12 hours on Day 1 [AUC (0~12) ] and dose-normalized AUC (0~12) [AUC (0~12) / D]; (h) Area under the curve from time 0 to final quantifiable concentration on day 1 [AUC (0-last) ]: (i) Area under the plasma concentration-time curve (AUC) from 0 to infinity on Day 1 for study subjects ≥ 2 years of age (0-inf) ) and dose-normalized AUC (0-inf) [AUC (0-inf) / D]; (j) C on days 1 and 10 max , AUC (0-inf) , AUC (0~12) (k) Metabolite-to-parent ratio; (k) AUC at 10 days (0~12) and AUC (0~12) / D; (l) minimum plasma concentration at day 10 (C min ); (m) Mean plasma concentration at day 10 (C avg );(n) C on day 10 max and AUC (0~12) (o) time linearity; (6) Clinical Global Impression-Improvement ("CGI-I") assessment at Day 11; and (7) change from baseline in Clinical Global Impression-Severity ("CGI-S") assessment at Day 11 from the screening visit.

[0354] safety Subjects will be assessed daily by measurement of vital signs and neurological examination. A physical examination will be completed at the screening visit and on days 0, 11, and 14. A 12-lead ECG will be completed at the screening visit and on days 1, 4, 8, 11, and 14 (if clinically indicated). Hematology, chemistry, and urinalysis will be performed at the screening visit and on days 1, 4, 8, and 11. Hematology, chemistry, and urinalysis will also be performed on day 14 if clinically indicated.

[0355] method PK concentrations and parameters for cannabidiol and its 7-OH metabolites in plasma will be summarized by study day, sampling time (if appropriate), and dose using descriptive statistics and plots where appropriate. These results will be plotted by age and mg / kg dose where appropriate. Exposure relationships with age and body weight will be assessed using regression and / or inferential analysis where appropriate. Dose proportionality of cannabidiol and its 7-OH metabolite exposure will be investigated using graphical methods and statistical power modeling techniques where appropriate. Accumulation of cannabidiol and its 7-OH metabolites will be determined using appropriate analysis of variance models for exposure PK parameters. Time linearity will also be determined. Trough concentration samples collected prior to dosing at scheduled time points will be plotted for steady-state achievement. Additionally, time to steady-state will be determined using stepwise linear trend analysis. Clobazam and norclobazam levels will be measured on Days 1 (baseline), 8, and 10 (pre-dose) from samples collected pre-dose in subjects ≥2 years of age and currently taking clobazam and will be summarized by time point and treatment. All safety assessments will be listed, including AEs, clinical laboratory assessments, vital signs, 12-lead ECG, C-SSRS, and physical and neurological examinations. These will be summarized by age and dose cohort using descriptive statistics, where appropriate. Results of CGI-I, CGI-S, and daily seizure diary assessments will be summarized using descriptive statistics, where appropriate.

[0356] result Preliminary results are shown in Table 61 below. Cohort #1 received a single dose of 5 mg / kg of the alcohol-based formulation followed by 5 mg / kg BID (10 mg / kg / day) for 7 days. Cohort #2 received a single dose of 10 mg / kg of the lipid-based formulation followed by 10 mg / kg BID (20 mg / kg / day) for 7 days. For Cohort #1, the single dose resulted in a mean C of 59.029 ng / mL. max , 3.0 hours average T max and 276.95h * AUC in ng / mL inf For cohort #2, the single dose resulted in a mean C of 110.522 ng / mL. max , average T of 4.45 hours max and 879.273h * AUC in ng / mL inf As demonstrated, the lipid-based formulation achieved nearly double the maximum plasma concentration of the alcohol-based formulation in approximately one and a half hours at twice the dosage and with a single dose.

[0357] With repeated BID dosing, administration of an alcohol-based oral cannabinoid formulation resulted in a mean C of 119.6 ng / mL. max , average T of 2.75 hours max and 581.744h * AUC in ng / mL tau The lipid-based oral cannabinoid formulation resulted in a C of 214.28 ng / mL. max , average T of 2.55 hours max and 1135.345h * AUC in ng / mL tau As demonstrated, the lipid-based formulation achieved maximum plasma concentrations less than twice as fast as the alcohol-based formulation, 12 minutes faster, at twice the dose and administered BID for 7 days.

[0358] [Table 61]

[0359] Example 17. Pharmacokinetic food effect study of a single dose of cannabidiol oral solution in healthy subjects. An open-label, randomized, single-dose, two-period, two-way, crossover food-effect study was conducted in healthy subjects. The study determined the pharmacokinetics and safety of a single dose of 20 mg / kg / day cannabidiol (i.e., Formulation #LF10 from Table 25 above) administered under fasted or fed conditions. Twenty-four (24) subjects were enrolled in the study, each in separate fasted and fed treatment arms, followed by a 7-day washout period. For pharmacokinetic analysis, nominal time and default lambda z selection were used. All values below the quantifiable limit were set to zero, and all subjects were included in the analysis.

[0360] safety Safety was determined using the following parameters: inclusion / exclusion criteria, medical history and demographics, medical history update, ongoing eligibility, physical examination, clinical laboratory tests, 12-lead electrocardiogram (ECG), urine drug and alcohol screen, previous medication history, concomitant medications, sitting blood pressure, pulse, respiratory rate and oral temperature, and adverse event (AE) determination.

[0361] statistical methods Data from 13 subjects from the fasting treatment and 24 subjects from the fed treatment were included in the pharmacokinetic and statistical analyses.

[0362] Blood samples (1 x 6 mL) for cannabidiol and 7-OH-cannabidiol analysis were collected in vacutainer tubes containing K2-EDTA as a preservative at 0 hours (pre-dose), 0.25 hours, 0.5 hours, 0.75 hours, 1.0 hours, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, and 120 hours (20 time points) post-dose during each study period. The following pharmacokinetic parameters were calculated: peak plasma concentrations (C max ), time to peak concentration (T max ), the final quantifiable concentration (C last), time to final quantifiable concentration (T last ), discharge rate constant (λ z ), terminal half-life (T 1 / 2 ), the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-t ), the area under the plasma concentration-time curve from time zero to infinity (AUC inf ), AUC extrap =[(AUC inf -AUC 0-t ) / AUC inf ] * AUC obtained by extrapolation calculated as 100 inf Percentage of (AUC extrap ), CL / F = dose / AUC for dronabinol only inf Apparent oral clearance (CL / F) calculated as λ / (C≡λ) and volume of distribution in the terminal elimination phase (Vd / F) calculated for cannabidiol only as Vd / F = (CL / F) / λZ.

[0363] Results and Conclusions The results of the pharmacokinetic and statistical analyses for the oral cannabinoid solutions of the present invention are presented in Tables 62-67. Tables 62-64 present the pharmacokinetic parameters of cannabidiol comparing administration to subjects under fasted or fed conditions.

[0364] [Table 62]

[0365] [Table 63]

[0366] ln(C max ), ln(AUC 0-t ) and ln(AUC 0-infSubstantial increases in maximum and total cannabidiol exposure based on food were observed following administration of a 20 mg / kg cannabidiol oral solution with food compared to a 20 mg / kg cannabidiol oral solution administered under fasting conditions. max was approximately 31-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-inf were approximately 14-fold and 29-fold higher, respectively, after administration with food compared to administration under fasting conditions. max The median time to reach maximum concentrations of C occurred approximately 6 hours earlier with food (6 hours) compared to that under fasting conditions (12 hours). Inter-subject variability was substantially reduced with food: C max CV and AUC of 138.1 to 55.3% 0-inf CVs of 52.0 to 36.9%.

[0367] [Table 64]

[0368] Administration of the oral cannabinoid solution of the present invention under fed conditions resulted in a measurable difference in AUC of cannabidiol over administration under fasted conditions within 30 minutes. See Figure 9. Additionally, administration of the oral cannabinoid solution of the present invention under fed conditions resulted in a 90-fold greater AUC of cannabidiol over administration under fasted conditions at 6 hours.

[0369] Tables 65-67 show the pharmacokinetic parameters of 7-OH-cannabidiol, the primary and active metabolites of cannabidiol, comparing oral cannabinoid solutions of the present invention under fasted and fed conditions.

[0370] [Table 65]

[0371] [Table 66]

[0372] ln(C max ), ln(AUC 0-t ) and ln(AUC 0-inf Substantial increases in maximum and total 7-OH-cannabidiol exposure based on 7-OH-cannabidiol C were observed following administration of a 20 mg / kg oral cannabidiol solution with food compared to a 20 mg / kg oral cannabidiol solution administered under fasting conditions. max was approximately 13-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-inf Both were approximately 7-fold higher after administration with food compared to administration under fasting conditions. max occurred 2 h earlier under fed conditions.

[0373] [Table 67]

[0374] Administration of the oral cannabinoid solution of the present invention under fed conditions resulted in a measurable difference in AUC for 7-OH-cannabidiol over administration under fasted conditions within 45 minutes. See Figure 10. Additionally, administration of the oral cannabinoid solution of the present invention under fed conditions resulted in a 35-fold greater AUC for 7-OH-cannabidiol over administration under fasted conditions at 6 hours.

[0375] In conclusion, the oral cannabinoid solutions of the present invention have a substantial food effect resulting in higher peak plasma concentrations in a shorter time period and also higher overall plasma concentrations after oral administration following food intake when compared to oral administration following fasting.

[0376] Example 18. Pharmacokinetic food effect study of a single dose of cannabidiol oral solution in healthy subjects.

[0377] method A multi-formulation, open-label, randomized, single-dose, four-treatment, four-period, four-way crossover food-effect study was conducted in healthy subjects. The study determined the pharmacokinetics of a single 10 mg / kg dose of three separate cannabidiol formulations (#LF41 and #LF42 from Table 26 above, and #A11 from Table 15 above) administered under fed conditions and one cannabidiol formulation (#LF42 above) under fasted conditions. Subjects were enrolled in the study and subjected to fasted and fed treatment arms, each at separate times, followed by a 7-day washout period. Nominal time and default lambda z selection were used for pharmacokinetic analysis. All values below the quantifiable limit were set to zero, and all subjects were included in the analysis.

[0378] result i. Fed vs. Fasted Cannabidiol Oral Solution Sesame Oil Formulation #LF42 ln(C max ), ln(AUC 0-t ) and ln(AUC 0-inf Substantial increases in both maximum and total cannabidiol and 7-OH-cannabidiol exposures based on food were observed following administration of Formulation #LF42 at 10 mg / kg with food compared to Formulation #LF42 at 10 mg / kg administered under fasting conditions. Cannabidiol C max was approximately 10.5-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-inf were approximately 7.5-fold and 3.3-fold higher, respectively, after administration with food compared to administration under fasting conditions. max was approximately 4.5-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-infwere approximately 4.3-fold and 3.7-fold higher, respectively, after administration with food compared to administration under fasting conditions. Thus, there is a substantial food effect when administering the lipid formulations of the present invention.

[0379] ii. Cannabidiol Oral Solution Medium Chain Triglyceride (MCT) Formulation #LF41 Fed vs. #LF42 Fasted

[0380] ln(C max ), ln(AUC 0-t ) and ln(AUC 0-inf Substantial increases in both maximum and total cannabidiol and 7-OH-cannabidiol exposures based on food were observed following administration of Formulation #LF41 at 10 mg / kg with food compared to Formulation #LF42 at 10 mg / kg administered under fasting conditions. max was approximately 10.8-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-inf were approximately 6.8-fold and 3.3-fold higher, respectively, after administration with food compared to administration under fasting conditions. max was approximately 4.1-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-inf were approximately 4.0-fold and 3.5-fold higher, respectively, after administration with food compared to administration under fasting conditions. Thus, there is a substantial food effect when administering the medium-chain glyceride formulations of the present invention.

[0381] iii. Cannabidiol oral solution ethanol formulation #A11 fed vs. #LF42 fasted ln(C max ), ln(AUC 0-t ) and ln(AUC 0-infSubstantial increases in both maximum and total cannabidiol and 7-OH-cannabidiol exposures based on food were observed following administration of Formulation #A11 at 10 mg / kg with food compared to Formulation #LF42 at 10 mg / kg administered under fasting conditions. max was approximately 9.5-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-inf were approximately 6.9-fold and 4.0-fold higher, respectively, after administration with food compared to administration under fasting conditions. max was approximately 3.8-fold higher after administration with food compared to administration under fasting conditions. 0-t and AUC 0-inf were approximately 4.6-fold and 4.0-fold higher, respectively, after administration with food compared to administration under fasting conditions. Thus, there is a substantial food effect when administering the hydro-alcoholic formulations of the present invention.

[0382] Example 19: Safety study of CBD in pediatric patients with intractable epilepsy To determine the pharmacokinetics and safety of multiple doses of pharmaceutical cannabidiol oral solution (MCT formulation, 300 mg / mL, administered BID) in pediatric subjects with treatment-resistant seizure disorders, a long-term safety study was conducted in pediatric patients with refractory epilepsy who had previously participated in a Phase 1 / 2 pharmacokinetic study. This was a long-term, open-label, 48-week study in pediatric subjects aged 1 to 17 years with refractory epilepsy. This study is described in detail above in Example 16.

[0383] Fifty-two subjects (9 infants, 26 children, and 17 adolescents) were enrolled and received at least one dose of cannabidiol oral solution in the study. Seven subjects discontinued treatment and study participation early. Eleven subjects completed study treatment, and thirty-four (34) subjects remained in post-study treatment. The study included five subjects (infants) aged 1 to <2 years; nine subjects (children) aged 2 to <12 years, with ≥3 subjects <6 years; and six subjects (adolescents) aged 12 to ≤17 years, with ≥3 subjects <16 years.

[0384] Results and Discussion Preliminary review of data from the long-term safety study showed weight loss. Analysis of the median percent change in body weight showed a dose-dependent decrease in weight change at week 24. Dose-dependence became less pronounced over the course of the study (up to week 48). This may be due to the small number of patients included in the analysis and frequent shifts in medication during the later time periods.

[0385] The mean modal dose (i.e., the dose using the longest duration) was 23.47 mg / kg / day, and the mean number of days on study for all subjects was 220.6. Overall, seven subjects (13.5%) had dose reductions due to adverse events ("AEs"), and three subjects (5.8%) had dose reductions for other reasons. Dose reductions were more frequent among subjects receiving 40 mg / kg / day compared with subjects receiving 10 mg / kg / day (seven subjects [35.0%] and two subjects [14.3%], respectively). Dose reductions due to AEs were more frequent among subjects receiving 40 mg / kg / day compared with subjects receiving 10 mg / kg / day (six subjects [30.0%] and one subject [7.1%], respectively). There were no dose reductions among subjects receiving 20 mg / kg / day and among infants.

[0386] Among children, 6 subjects (11.5%) had dose reductions due to AEs and 2 subjects (3.8%) had dose reductions for other reasons. Dose reductions were more frequent in subjects receiving 40 mg / kg / day compared with 10 mg / kg / day (5 subjects [25.0%] and 2 subjects [14.3%], respectively).

[0387] Among infants, three subjects (33.3%) received 20 mg / kg / day to <40 mg / kg / day, and six subjects (66.7%) received 40 mg / kg / day. Among children, seven subjects (26.9%) received 10 mg / kg / day to <20 mg / kg / day, 10 subjects (38.5%) received 20 mg / kg / day to <40 mg / kg / day, and eight subjects (30.8%) received 40 mg / kg / day. Among adolescents, three subjects (17.6%) received 10 mg / kg / day to <20 mg / kg / day, eight subjects (47.1%) received 20 mg / kg / day to <40 mg / kg / day, and six subjects (35.3%) received 40 mg / kg / day.

[0388] Among adolescents, one subject (1.9%) had a dose reduction due to an AE and one subject (1.9%) had a dose reduction for other reasons. Both dose reductions occurred in subjects receiving 40 mg / kg / day.

[0389] Overall, 1 subject (1.9%) was taking <10 mg / kg / day, 10 subjects (19.2%) were taking between 10 and <20 mg / kg / day, 20 subjects (38.5%) were taking between 20 and <40 mg / kg / day, and 20 subjects (38.5%) were taking ≥40 mg / kg / day at the time of data cutoff.

[0390] A total of 233 AEs were reported in 44 subjects; the most frequently reported AEs were anemia, diarrhea, constipation, fever, upper respiratory tract infection, seizures, somnolence, and aggression. Overall, 30.0% of subjects at the 40 mg / kg / day dose required dose reduction due to adverse events (AEs). However, many patients increased their dose over the duration of the study, with 21 subjects (40.4%) receiving doses between 20 mg / kg / day and <40 mg / kg / day, and 20 subjects (38.5%) receiving 40 mg / kg / day at the time of data cutoff. Cannabidiol oral solution was safe and well tolerated, even at doses as high as 40 mg / kg / day.

[0391] [Table 68]

[0392] CBD-related weight gain and somnolence were reported in four subjects (7.7%) each. Compared to the mean weight of all subjects at baseline (27.88 kg), mean weight increased (+1.15 kg) at week 24. Mean weight continued to increase throughout the study (+1.74 kg at week 36, +1.94 kg at the final / discontinuation visit, and +2.14 kg at the follow-up visit).

[0393] [Table 69] TIFF2025118786000081.tif28153

[0394] There was a dose-response decrease in weight gain, with the greatest effect seen at a dose of 40 mg / kg / day (Figure 11). These data indicate that cannabidiol oral solution at 300 mg / mL up to a dose of 40 mg / kg / day is safe and generally well tolerated, and data from long-term safety studies indicate that 40 mg / kg / day may be the most efficacious for both seizure control as well as effects on weight gain.

[0395] Prader-Willi syndrome ("PWS") is a multifaceted developmental disorder and the most common genetic syndrome associated with obesity (McAllister and Whittington, 2011; Gunay-Aygun et al., 1997). It is caused by the absence of paternally inherited gene expression in the PWS region on 15q11-q13 (Ledbetter et al., 1981). It manifests with generalized hypotension and developmental delay in early childhood, whereas PWS manifests with uncontrollable appetite, hyperphagia, and excessive weight gain leading to severe obesity (Grechi et al., 2012).

[0396] Clinically, individuals with PWS suffer from a complex pattern of physical, behavioral, endocrine, and intellectual deficits. Endocrine abnormalities lead to hypogonadism and short stature. Growth hormone deficiency, in particular, is reported to occur in 40%–100% of the population (Griggs et al., 2015) and is commonly treated with growth hormone (Butler et al., 2015). Behavioral disorders include compulsive behaviors such as skin picking, hoarding, reworking, and repetitive speech (Griggs et al., 2015).

[0397] The greatest unmet medical need in Prader-Willi syndrome is hyperphagia and related behaviors, leading to morbid obesity and diabetes and the resulting cardiovascular complications. Cannabidiol (CBD) is a low-affinity CB1 antagonist, but it can also modulate CB1 receptor signaling through its inhibition of the metabolism of the endogenous cannabinoid anandamide (Ibeas Bih et al., 2015). Regarding appetite, CBD has been shown to reduce food intake in rats under stress conditions and reduce voluntary intake of a high-sugar diet compared to vehicle-treated controls (Silveira Filho and Tufik, 1981). Additionally, CBD has been shown to reduce daily food consumption without affecting daily water intake (Wierbucka-Ryback and Bojanowska, 2014) and inhibit hyperphagia induced by cannabinoid (CB1) or 5-hydroxytryptamine (5-HT1A) serotonin receptor agonists, suggesting a role for CBD as a regulator of food intake (Scopinho et al., 2011). Thus, cannabidiol (CBD) may have potential to address hyperphagia associated with Prader-Willi syndrome patients.

[0398] Example 20. Study of the efficacy of cannabidiol against infantile spasms using vigabatrin or ACTH as initial treatment. The following studies are ongoing, with results yet to be recorded:

[0399] Protocol A Phase 2, multicenter, randomized, placebo-controlled, parallel-group study will be conducted to determine the efficacy and safety of cannabidiol oral solution as adjunctive treatment in patients with infantile spasms who are receiving either vigabatrin or adrenocorticotropic hormone ("ACTH") as initial treatment.

[0400] The study consists of Part A and Part B. Part A includes five periods: a screening period (14-28 days), a titration period (≥5 days), a treatment period (14 days), a tapering period (approximately 14 ± 3 days) for patients who elect not to enroll in the open-label, long-term safety study, and a follow-up period (30 ± 7 days). The overall maximum study duration is expected to be approximately 101 days. Part B consists of a safety treatment period (48 weeks), a tapering period (2 weeks), and a follow-up period (30 days). The overall study duration is expected to be 64 weeks for those patients who complete the safety period.

[0401] One hundred twenty eligible subjects will be selected from children aged 6 to 36 months with a diagnosis of infantile spasms and will be equally randomized to one of six treatment groups: 1) vigabatrin, 2) vigabatrin plus 20 milligrams per kilogram per day ("mg / kg / day") cannabidiol oral solution, 3) vigabatrin plus 40 mg / kg / day cannabidiol oral solution vigabatrin, 4) ACTH, 5) ACTH plus 20 milligrams per kilogram per day ("mg / kg / day") cannabidiol oral solution, and 6) ACTH plus 40 mg / kg / day cannabidiol oral solution.

[0402] Specifically, 20 subjects will be enrolled in each dose cohort as follows: A) Each dose cohort will fit the following criteria: 1. Parent(s) / caregiver(s) fully understand and sign the informed consent form, understand all study procedures, and be able to communicate adequately with the investigator and study coordinator; 2. Provide patient and / or parent(s) / caregiver(s) informed consent in accordance with applicable laws, regulations, and local requirements; 3. Be 6 months to 36 months of age (inclusive) at the time of consent. 3. Male or female between the ages of 18 and 24; 4. Clinical diagnosis of infantile spasms confirmed by video-EEG analysis obtained during the screening period and read by the investigator (including at least one cluster of electroclinical seizures [≥3 in any 10-minute epoch]); 5. General good health (defined as the absence of any clinically relevant abnormalities as determined by the investigator) based on physical and neurological examination, medical history, and laboratory values completed during the screening visit (Visit 1); and 6. In the opinion of the investigator, parent(s) / caregiver(s) A) the patient(s) are willing and able to comply with the study procedures and visit schedule, and B) each dose cohort does not meet the following criteria: 1) considered by the investigator to be an unsuitable candidate to receive the study drug for any reason (including but not limited to the risks listed as precautions, warnings, and contraindications in the current version of the investigator's booklet for cannabidiol oral solution); 2) known or suspected allergy to cannabidiol oral solution; 3) use of any cannabidiol / cannabis product within 30 days of study entry; 4) the patient is diagnosed or suspected to have tuberous sclerosis complex; 5) the patient has previously received treatment with either vigabatrin, ACTH, or high-dose steroids; 6) previous treatment with felbamate, clobazam, or a ketogenic diet; 7) positive drug screen for THC; or 8) patient currently on any unauthorized medication listed in Appendix 2 (e.g., phenytoin, fluvoxamine, carbamazepine, and St. John's Wort).

[0403] The study will be conducted in the following parts: Part A: Video-electroencephalography ("EEG") will be performed for each treatment group during a screening period and repeated overnight on Day 0 and Day 14. Response to treatment will be scored using the following methodology: 1) Complete Response - complete resolution of seizures and hypsarrhythmia (if present at baseline) confirmed by video-EEG on Day 14; 2) Partial Response - substantial change in background EEG obtained on Day 14 or reduction in seizures on video-EEG; and 3) No Response - no improvement or worsening of seizure / hypsarrhythmia burden on Day 14.

[0404] Part B: After Day 14, willing patients may participate in a long-term safety phase. Treatment visits are scheduled monthly for 3 months and then quarterly thereafter.

[0405] endpoint The primary efficacy endpoint is the percentage of subjects considered to be complete responders at Day 14, defined as complete resolution of video-EEG confirmed seizures and hypsarrhythmia as determined by an independent central reader.

[0406] Secondary efficacy endpoints are: 1) percent of subjects free of infantile spasms at Day 14; 2) percent of subjects free of hypsarrhythmia at Day 14; 3) median reduction in seizure burden comparing video-EEG at screening with repeat video-EEG at Day 14; and 4) parental impression of efficacy and tolerability of study medication (CGIC) at study completion / early discontinuation (Visit 3).

[0407] Exploratory efficacy endpoints were 1) percent seizure-free days on day 14 comparing either vigabatrin or ACTH with CBD versus vigabatrin or ACTH alone, and 2) correlation between plasma drug levels and response.

[0408] Safety endpoints are: 1) incidence of treatment-emergent adverse events ("AEs"); 2) clinical laboratory assessments; 3) vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 4) physical and neurological examination assessments; 5) urinary; 6) THC screen; 7) medical history, and 8) prior and concomitant medications.

[0409] Pharmacokinetic endpoints are trough concentrations (Ctrough) of cannabidiol and metabolite 7-hydroxy-cannabidiol ("7OH-CBD") drawn prior to dosing and 2, 4, and 6 hours after the dose at Visits 2 and 3 to determine exposure-response relationships. Food diaries will be used to record the type of food consumed in conjunction with pharmacokinetic blood draws. method

[0410] Titration period Once patients are approved for the study, they return to the study clinic where a physician prescribes either vigabatrin or ACTH, and the patient is randomized to the appropriate study arm. The following activities are completed: 1. Review of inclusion and exclusion criteria; 2) Obtain a urine sample for urinalysis; 3. Record concomitant medications and procedures; 4. Record vital signs (measurement of blood pressure, pulse rate, respiratory rate, and temperature); 5. Perform a complete physical examination, including height and weight. The weight obtained during this visit is used to calculate dose volume. The dose volume remains constant throughout the titration and treatment period; 6. Obtain blood samples for hematology and chemistry; 7. Perform a brief neurological examination; and 8. Record AEs and serious AEs ("SAEs").

[0411] Screening Period Once the prescription ACTH or vigabatrin is ready to be dispensed, subjects will be admitted to the research center as inpatients on Day 0. The following procedures and assessments must be performed on Day 0 for all subjects prior to IP administration on Day 1: 1. Record concomitant medications and procedures; 2. Perform a brief neurological examination; 3. Record vital signs (measure blood pressure, pulse rate, respiratory rate, and temperature); 4. Record and review a daily seizure diary; 5. Record AEs and SAEs; and 6. Perform a 24-hour video-EEG.

[0412] Treatment duration Patients will be dosed twice daily (i.e., total daily dose of 0 mg / kg / day, 20 mg / kg / day, or 40 mg / kg / day) on days 1 through 14 according to their assigned cohort. Doses will be administered approximately 12 hours apart. Patients will be released from the study center after adjudication and a 6-hour pharmacokinetic blood draw will be completed. The final dose of investigational product will be administered on the evening of day 14. Patients will be admitted for an end of treatment visit on day 14, which will include a 24-hour video-EEG.

[0413] Part B visit The following activities will be completed during each Part B visit, occurring at 1, 2, 3, 6, and 9 months after the end of the treatment period: 1. Record concomitant medications and procedures; 2. Record vital signs (measure blood pressure, pulse rate, respiratory rate, and temperature); 4. Record and review daily seizure and food diaries; 5. Perform a physical examination, including height and weight; 6. Perform a brief neurological examination; and 7. Record AEs and SAEs.

Claims

1. 1. A method of treating Prader-Willi syndrome, comprising: Cannabidiol; and a vehicle selected from the group consisting of lipids, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof; 20. A method comprising administering an effective amount of an oral pharmaceutical formulation comprising:

2. 10. The method of claim 1, wherein the cannabidiol has a purity greater than 98%.

3. 10. The method of claim 1, wherein the vehicle is a medium chain glyceride.

4. 4. The formulation of claim 3, wherein the medium chain glyceride is caprylic / capric triglyceride.

5. The method of claim 4 further comprising alpha-tocopherol.

6. 10. The method of claim 1, wherein the vehicle is sesame oil.

7. 10. The method of claim 1, wherein the vehicle is a combination of ethanol, polyethylene glycol, propylene glycol, and water.

8. 8. The method of claim 7, further comprising alpha-tocopherol and ascorbyl palmitate.

9. The formulation, about 8% to about 31% w / w cannabidiol; and A vehicle consisting of about 60% to about 90% w / w lipid, or a vehicle consisting of a combination of about 40% to about 60% w / w ethanol, about 1% to about 5% w / w polyethylene glycol, about 5% to about 10% w / w propylene glycol, and about 20% to about 40% w / w water.

10. The method of claim 1, wherein w / w indicates weight by weight of the formulation.

10. 10. The method of claim 9, wherein the cannabidiol is at a concentration of about 10% w / w and the vehicle is caprylic / capric triglyceride at a concentration of about 89% w / w.

11. 11. The method of claim 10, wherein the cannabidiol is at a concentration of about 31% w / w and the vehicle is caprylic / capric triglyceride at a concentration of about 68% w / w.

12. 10. The formulation of claim 9, wherein the cannabidiol is at a concentration of about 11% w / w and the vehicle is sesame oil at a concentration of about 80% w / w.

13. 10. The formulation of claim 9, wherein the cannabidiol is at a concentration of about 8.8% w / w and the vehicle is a combination of ethanol at a concentration of about 50% w / w, polyethylene glycol at a concentration of about 3% w / w, propylene glycol at a concentration of about 7.5% w / w and water at a concentration of about 30% w / w.

14. 10. The method of claim 1, wherein the effective amount is from about 0.5 to about 100 milligrams per kilogram per day.

15. 10. The method of claim 1, wherein the effective amount is from about 10 to about 40 milligrams per kilogram per day.

16. 1. A method of treating one or more symptoms of Prader-Willi syndrome, comprising: Cannabidiol; and a vehicle selected from the group consisting of lipids, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof; 20. A method comprising administering an effective amount of an oral pharmaceutical formulation comprising:

17. 17. The method of claim 16, wherein the symptom of Prader-Willi syndrome is binge eating.

18. 1. A method of treating infantile spasms, comprising: Cannabidiol; and a vehicle selected from the group consisting of lipids, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof; to a patient in need thereof.

19. 19. The method of claim 18, wherein vigabatrin or adrenocorticotropic hormone is administered to the patient prior to administration of the oral pharmaceutical formulation.

20. 1. A method of treating childhood absence epilepsy, comprising: Substantially pure cannabidiol; and a vehicle selected from the group consisting of lipids, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof; 20. A method comprising administering an effective amount of an oral pharmaceutical formulation comprising:

21. 20. The method of claim 19, wherein the cannabidiol has a purity greater than 98%.

22. 20. The method of claim 19, wherein the cannabidiol is synthetic cannabidiol.

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