Patent Description:
Cannabinoids are chemicals that are produced by cannabis flowers. Cannabinoids imitate endogenous compounds in humans.

Cannabinoids include cannabinol, cannabidiol, dronabinol (delta-<NUM>-tetrahydrocannabinol), delta-<NUM>-tetrahydrocannabinol, <NUM>-hydroxy-tetrahydrocannabinol, <NUM>-hydroxy-delta9-tetrahydrocannabinol, levonantradol, delta-<NUM>-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, and acids and analogs thereof. It is now possible to synthesize many cannabinoids in a laboratory thereby eliminating the need to grow cannabis for extraction of the compounds.

One cannabinoid, cannabidiol, (-)-trans-<NUM>-p-mentha-<NUM>,<NUM>-dien-<NUM>-yl-<NUM>-pentylresorcinol, is non-psychoactive and has shown promise in treating numerous diseases and disorders. Synthetic cannabidiol has the same structure as naturally occurring cannabidiol.

Commercially available cannabidiol is usually contaminated with delta <NUM>-tetrahydrocannabinol. The presence of delta-<NUM>-tetrahydrocannabinol can be a concern because delta-<NUM>-tetrahydrocannabinol is regulated by the United States Drug Enforcement Administration as a Schedule I Drug. Having a higher Schedule number could result in easier access for patients to cannabidiol treatments. Further, delta-<NUM>-tetrahydrocannabinol is a hallucinogen and patients receiving cannabidiol wish to avoid this undesirable side effect of the delta-<NUM>-tetrahydrocannabinol contaminant. Therefore, there is a need for a substantially pure synthetically synthesized cannabidiol that does not contain delta-<NUM>-tetrahydrocannabinol.

<CIT>, <CIT>, <CIT>, <CIT> and <CIT> suggest substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of their use.

Cannnabinoids, including cannabidiol, may be suitable for the treatment of 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 spasms, West syndrome, refractory infantile spasms, infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's Disease, autism, and withdrawal from opioids, cocaine, heroin, amphetamines, and nicotine.

Accordingly, there is a need for new stable cannabinoid formulations. There is also a need for substantially pure cannabidiol.

The invention is directed to an oral pharmaceutical formulation comprising: cannabidiol; and a vehicle selected from the group consisting of a lipid, water, ethanol, glycerin, propylene glycol, polyethylene glycol <NUM> and a combination thereof, wherein the formulation is for use in a method of treating hyperphagia as a symptom of Prader-Willi syndrome; and wherein the effective amount administered is from <NUM> to <NUM> milligrams cannabidiol per kilogram per day.

In another aspect, the cannabidiol is greater than <NUM>% pure.

In another aspect, the vehicle is a medium chain glyceride, preferably caprylic/capric triglyceride.

In another aspect, the vehicle is sesame oil.

In another aspect, the oral pharmaceutical formulations of the present invention further comprise an antioxidant or preservative selected from the group consisting of alpha-tocopherol, ascorbyl palmitate, methyl paraben, propyl paraben and a combination thereof.

In another aspect, the oral pharmaceutical formulations of the present invention comprise:.

In another aspect, the oral pharmaceutical formulations of the present invention comprise cannabidiol at a concentration of about <NUM>% w/w and caprylic/capric triglyceride at a concentration of about <NUM>% w/w.

In another aspect, the oral pharmaceutical formulations of the present invention comprise cannabidiol is at a concentration of about <NUM>% w/w and the vehicle is sesame oil at a concentration of about <NUM>% w/w.

In another aspect, the oral pharmaceutical formulations of the present invention comprise cannabidiol at a concentration of about <NUM>% w/w, and a combination of ethanol at a concentration of about <NUM>% w/w, polyethylene glycol at a concentration of about <NUM>% w/w, propylene glycol at a concentration of about <NUM>% w/w and water at a concentration of about <NUM>% w/w.

In another aspect, the effective amount is from about <NUM> to about <NUM> milligrams per kilogram per day.

In another aspect (not claimed), the invention is directed to a method of treating infantile spasms comprising administering to a patient in need thereof an effective amount of an oral pharmaceutical formulation comprising:.

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

In another aspect (not claimed), the invention is directed to a method of treating childhood absence epilepsy comprising administering an effective amount of an oral pharmaceutical formulation comprising:.

As indicated above, Applicant created stable formulations with and without alcohol (see Examples <NUM> and <NUM>). The formulations that do not contain alcohol are especially suitable for administration to children. Further, the alcohol-free formulations are especially suitable for patients in recovery from drug and alcohol addiction.

In addition, Applicant created stable lipid formulations (see Example <NUM>). These formulations were also unexpectedly stable during storage (see Example <NUM>).

Further, Applicant unexpectedly found that substantially pure cannabidiol formulations are especially suitable for treatment of neuropathic pain (see Examples <NUM>-<NUM> and <FIG>), epilepsy (see Examples <NUM>-<NUM>), glioblastoma multiforme (see Examples <NUM> and <NUM> and <FIG> and <FIG>), treatment resistant seizure disorder (see Example <NUM>) and Prader-Willi syndrome (see Example <NUM>).

In one embodiment, the present invention is directed to stable pharmaceutical formulation as defined herein, for oral administration as defined herein, comprising from about <NUM> to about <NUM> % of the cannabinoid cannabidiol, from about <NUM> to about <NUM> % of polyethylene glycol <NUM>, from about <NUM> to about <NUM> % of propylene glycol, and from about <NUM> to about <NUM> % of water, wherein the formulation does not contain alcohol and the formulation has a pH of from about <NUM> to about <NUM>.

In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % of the cannabinoid. In more preferred embodiments, the formulations contain from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> % or from about <NUM> to <NUM> % of the cannabinoid.

The formulation of the invention comprises cannabidiol. In yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, dronabinol (delta-<NUM>-tetrahydrocannabinol), delta-<NUM>-tetrahydrocannabinol, <NUM>-hydroxy-tetrahydrocannabinol, <NUM>-hydroxy-delta-<NUM>-tetrahydrocannabinol, levonantradol, delta-<NUM>-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, acids, analogs, and synthetic derivatives thereof.

In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % of a cannabidiol. In more preferred embodiments, the formulations contain from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> % or from about <NUM> to <NUM> % of a cannabidiol.

In yet another embodiment, the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than <NUM> %. In a more preferred embodiment, the cannabidiol is greater than <NUM> % pure. In an even more preferred embodiment, the cannabidiol is greater than <NUM> % pure. In a most preferred embodiment, the cannabidiol formulation contains less than <NUM> % delta-<NUM>-tetrahydrocannabinol.

In another embodiment, the formulations contain from about <NUM> to about <NUM> % of an antioxidant. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % antioxidant. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> % antioxidant.

Suitable antioxidants include butylated hydroxyltoluene ("BHT"), butylated hydroxyl anisole ("BHA"), alpha-tocopherol (Vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethylenediamino tetraacetic 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 formulations contain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorbate, ascobyl palmitate or combinations thereof.

Suitable polyethylene glycols (not claimed) include low molecular weight polyethylene glycols with an average molecular weight of between <NUM> and <NUM>,<NUM>.

In another embodiment, the formulations contain from about <NUM> to about <NUM> % of polyethylene glycol <NUM>. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> %, or from about <NUM> to about <NUM> % polyethylene glycol <NUM>.

In another embodiment, the formulations contain from about <NUM> to about <NUM> % of propylene glycol. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> %, or from about <NUM> to about <NUM> % propylene glycol.

In a further embodiment, the formulations contain water. The formulations can contain <NUM> % water. If the formulations contain water, they can include from about <NUM> to about <NUM> % water, from about <NUM> to about <NUM> % water, or from about <NUM> to about <NUM> % water.

The pH of the formulations may be modified using any pharmaceutically acceptable means. Preferably the pH of the formulation is from about <NUM> to about <NUM>. In a more preferred embodiment, the pH of the formulations is from about <NUM> to about <NUM>. In a most preferred embodiment, the pH of the formulations is from about <NUM> to about <NUM>.

The formulations of the present invention may also contain sweeteners, sweetener enhancers, preservatives, pH modifiers, and flavoring agents.

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

If the formulations contain a sweetener, the formulations preferably contain from about <NUM> to about <NUM> % sweetener.

If the formulations contain a sweetness enhancer, the formulations preferably contain from about <NUM> to about <NUM>% sweetness enhancer.

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

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.

Suitable preservatives include, but are not limited to, methyl paraben, propyl paraben, benzyl alcohol, benzoic acid, sodium benzoate, sorbic acid, and combinations thereof.

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 formulations contain strawberry flavor.

If the formulations contain a flavoring agent, the formulations preferably contain from about <NUM> to about <NUM> % flavoring agent. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> % of the flavoring agent.

The formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration. Preferably, the formulations are liquids administered orally. More preferably, the formulations are simple solutions administered orally.

In another embodiment, the invention is directed to stable pharmaceutical formulation as defined herein, for oral administration as defined here, the formulation comprising from about <NUM> to about <NUM> % of the cannabinoid cannabidiol, from about <NUM> to about <NUM> % of polyethylene glycol <NUM>, from about <NUM> to about <NUM> % of propylene glycol, optionally from about <NUM> to about <NUM> % of water, and from about <NUM> to about <NUM> % of alcohol, wherein the formulation has a pH of from about <NUM> to about <NUM>.

In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % of the cannabinoid cannabidiol. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % the cannabinoid. Alternatively, the formulations may contain from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % the cannabinoid.

In the invention, the cannabinoid is cannabidiol. In yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, dronabinol (delta-<NUM>-tetrahydrocannabinol), delta-<NUM>-tetrahydrocannabinol, <NUM>-hydroxy-tetrahydrocannabinol, <NUM>-hydroxy-delta-<NUM>-tetrahydrocannabinol, levonantradol, delta-<NUM>-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, acids, analogs, and synthetic derivatives thereof.

In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % of a cannabidiol. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % cannabidiol. Alternatively, the formulations may contain from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % cannabidiol.

Suitable antioxidants include butylated hydroxyltoluene ("BHT"), butylated hydroxyl anisole ("BHA"), alpha-tocopherol (Vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethylenediamino tetraacetic 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 formulations contain alpha-tocopherol (Vitamin E), ascorbyl palmitate, or combinations thereof.

In another embodiment, the formulations contain from about <NUM> to about <NUM> % of propylene glycol. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % propylene glycol.

In an alternative embodiment, the formulations contain from about <NUM> to about <NUM> % of propylene glycol. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % propylene glycol.

In another embodiment, the formulations contain from about <NUM> to about <NUM> % of a polyethylene glycol. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % polyethylene glycol.

In an alternative embodiment, the formulations contain from about <NUM> to about <NUM> % of a polyethylene glycol. In a preferred alternative embodiment, the formulations contain from about <NUM> to about <NUM> % polyethylene glycol.

Suitable polyethylene glycols include low molecular weight polyethylene glycols with an average molecular weight of between <NUM> and <NUM>,<NUM>. One preferred polyethylene glycol that can be used is polyethylene glycol <NUM>.

In another embodiment, the formulations contain from about <NUM> to about <NUM> % of polyethylene glycol <NUM>. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % polyethylene glycol <NUM>.

In an alternative embodiment, the formulations contain from about <NUM> to about <NUM> % of polyethylene glycol <NUM>. In a preferred alternative embodiment, the formulations contain from about <NUM> to about <NUM> % polyethylene glycol <NUM>.

In a further embodiment, the formulations contain water. The formulations can contain <NUM> % water. If the formulations contain water, they can include from about <NUM> to about <NUM> % water, from about <NUM> to about <NUM> % water, from about <NUM> to about <NUM> % water or from about <NUM> to about <NUM> % water.

In yet another embodiment, the formulations contain from about <NUM> to about <NUM> % alcohol. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> %, or from about <NUM> to <NUM> % alcohol.

In an alternative embodiment, the formulations contain from about <NUM> to about <NUM> % alcohol. In a preferred alternative embodiment, the formulations contain from about <NUM> to about <NUM> % or from about <NUM> to about <NUM> % alcohol.

The pH of the formulations may be modified using any pharmaceutically acceptable means. Preferably the pH of the formulations is from about <NUM> to about <NUM>. In a more preferred embodiment, the pH of the formulations is from about <NUM> to about <NUM>.

The formulations of the present invention may also contain sweeteners, sweetener enhancers, pH modifiers, preservatives, and flavoring agents.

If the formulations contain a sweetness enhancer, the formulations preferably contain from about <NUM> to about <NUM> % sweetness enhancer.

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 formulations contain fruit punch flavor, raspberry flavor, grape flavor, or lemon mint flavor.

The formulations are liquids administered orally. More preferably, the formulations are simple solutions administered orally.

In another embodiment, the invention is directed to stable pharmaceutical formulation as defined herein for oral administration as defined herein, the formulation comprising from about <NUM> to about <NUM> % of the cannabinoid cannabidiol and from about <NUM> to about <NUM> % of a lipid.

In a preferred embodiment, the lipid is selected from the group consisting of sesame oil, olive oil, corn oil, sunflower oil, safflower oil, flaxseed oil, almond oil, peanut oil, walnut oil, cashew oil, castor oil, coconut oil, palm oil, soybean oil, canola oil, vegetable oil, rice bran oil, ,fatty acids including 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, linoleic acid, arachidic acid and arachidonic acid, medium chain glycerides, decanoyl glycerides, octanoyl glycerides, caprylic/capric triglyceride , caprylic/capric/linoleic triglyceride, oleoyl polyoxyl-<NUM> glycerides, linoleoyl polyoxyl-<NUM> glycerides, polyglyceryl-<NUM> dioleate, glyceryl monolinoleate, glyceryl monocaprylate, oleic acid, and a combination thereof. In a more preferred embodiment, the lipid is a medium-chain triglyceride whose fatty acids have an aliphatic tail of from <NUM> to <NUM> carbon atoms. In a most preferred embodiment, the lipid is caprylic/capric triglyceride.

Suitable commercial sources for the lipid include Miglyol® 812N (caprylic/capric triglyceride) containing a proprietary mixture of decanoyl and octanoyl glycerides (fatty acid esters) (Miglyol is available from and a registered trademark of Cremer Oleo GmbH & Co. ) and Miglyol® <NUM> (caprylic/capric/linoleic triglyceride) containing a proprietary mixture of propylene glycol dicaprylate/dicaprate and otherwise known as decanoic acid/octanoic acid/propane-<NUM>,<NUM>-diol.

In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % of a cannabidiol. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> % cannabidiol. In a most preferred embodiment, the formulations contain about <NUM>% cannabidiol.

In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % of lipids. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> % lipids. In a most preferred embodiment, the formulations contain from about <NUM> to about <NUM> % lipids.

In yet another embodiment, the formulations contain alcohol. The formulations can contain <NUM> % alcohol. If the formulations contain alcohol, they can include from about <NUM> to about <NUM> % alcohol. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % alcohol. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> % alcohol.

In another embodiment, the formulations contain an antioxidant. The formulations can contain <NUM> % antioxidant. If the formulations contain antioxidant, they can include from about <NUM> to about <NUM> % of an antioxidant. In a preferred embodiment, the formulations contain from about <NUM> to about <NUM> % antioxidant.

Suitable antioxidants include butylated hydroxyltoluene, butylated hydroxyl anisole, alpha-tocopherol (Vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethylenediamino tetraacetic 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 formulations contain alpha-tocopherol (Vitamin E), ascorbyl palmitate or combinations thereof.

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.

If the formulations contain a sweetener, the formulations preferably contain from about <NUM> to about <NUM> % sweetener. In a more preferred embodiment, the formulations contain from about <NUM> to about <NUM> % sweetener. In a most preferred embodiment, the formulations contain from about <NUM> to about <NUM> % sweetener.

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.

The formulations of the present invention are for use in a method of treating hyperphagia as a symptom of Prader-Willi syndrome. Further, cannabidiol which is synthetically synthesized and substantially pure will be even more effective and suitable for use in a method of treating hyperphagia as a symptom of Prader-Willi syndrome.

The formulations of the present invention may be administered to a patient in a fed condition. As used herein a "fed condition" refers to a patient that consumes food prior to administration of a formulation of the present invention and from which the food has not been cleared from the gastrointestinal tract prior to the administration.

Disease and disorders or symptoms of these disease or disorders that are described herein (not claimed) include, but are not limited to, obesity, graft versus host disease, gelastic seizures/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, refractory epilepsy, childhood absence epilepsy, schizophrenia, juvenile spasms, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis complex, 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 injury of heart, ischemic injury of brain, chronic pain syndrome, rheumatoid arthritis, patients encountering adverse emotional stimuli, nausea and addiction disorders related to drugs of abuse such as opioid, heroin, cocaine, amphetamine dependence and including acute and long-term treatment of dependence and relapse associated with drugs of abuse.

As first explained in <CIT>, Applicant unexpectedly created a new synthetic pathway for creating cannabidiol. This new process eliminated the need to grow cannabis in order to extract cannabidiol. Applicant's cannabidiol has a high purity level and is substantially free of Schedule I drugs, including delta-<NUM>-tetrahydrocannabinol.

Applicant chemically synthesized cannadbidiol by combining p-menthadienol and olivetol in toluene or dichloromethane or hexane with a p-toluene sulfonic acid catalyst to produce cannabidiol (see diagram below).

The present invention is directed to oral pharmaceutical formulations according to the claims for use in methods of treating hyperphagia as a symptom of Prader-Willi syndrome comprising administering the formulations of the present invention to a patient in need thereof.

As used herein, a "patient" refers to a single patient and not a patient population.

As used herein, "synthetic" refers to the chemical synthesis of cannabidiol does not refer to cannabidiol that is extracted from cannabis plant material.

As used herein, "substantially pure" refers to a preparation having chromatographical purity of cannabidiol of greater than <NUM> %, preferably greater than <NUM> %, more preferably greater than <NUM> %, and most preferably greater than <NUM> %.

As used herein, "substantially free of delta-<NUM>-tetrahydrocannabinol" refers to a preparation of cannabidiol having less than <NUM> % of delta-<NUM>-tetrahydrocannabinol as determined by HPLC. Preferably, the preparation contains less than <NUM> % of delta-<NUM>-tetrahydrocannabinol, more preferably <NUM> %, and most preferably less than <NUM> % of delta-<NUM>-tetrahydrocannabinol.

As used herein, all numerical values relating to amounts, weights, and the like, that are defined as "about" each particular value is plus or minus <NUM> %. For example, the phrase "about <NUM> % w/w" is to be understood as "<NUM> % w/w to <NUM> % w/w. " Therefore, amounts within <NUM> % of the claimed value are encompassed by the scope of the claims.

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

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

As used herein the term "effective amount" refers to the amount necessary to treat a patient in need thereof.

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

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

The disclosed embodiments are simply exemplary embodiments of the inventive concepts disclosed herein and should not be considered as limiting, unless the claims expressly state otherwise.

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 invention. They are not intended to be limiting in any way.

All claims, aspects and embodiments of the invention, and specific examples thereof, are intended to encompass equivalents thereof.

The formulations in Table <NUM> below were prepared as follows. All the solvents are purged with nitrogen before using in manufacturing. Vitamin E, methyl paraben, propyl paraben were dissolved in propylene glycol. Polyethylene glycol <NUM> (PEG400) and a flavoring agent were added to the propylene glycol solution and mixed thoroughly. The water phase was prepared by dissolving sucralose and sodium ascorbate in water. Next, the solutions were combined and pH adjusted using a pH modifier. The cannabinoid was added to the excipient solution and mixed until dissolved.

Synthetically synthesized, substantially pure, cannabidiol was used as the cannabinoid.

Strawberry flavor was used as the flavoring agent.

The formulations listed in Table <NUM> were subjected to stability at <NUM> ± <NUM>, <NUM> ± <NUM> under <NUM> % ± <NUM> % relative humidity, and <NUM> ± <NUM> under <NUM> % ± <NUM> % relative humidity. Stability of the formulations was analyzed at specified time points by evaluating for their potency (assay value) and impurity levels. Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at <NUM> and indicated as a % of initial concentration. For all impurities, analysis was performed at <NUM> and expressed as a % area. Amounts of particular impurities are listed in Tables <NUM> to <NUM> as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.

Control formulation (# AF1) showed significant increase in levels of total impurities and decrease in the assay value. Adjusting the pH of formulation (# AF2) in the range of from about <NUM> to about <NUM> increased the stability of the formulation in comparison to control formulation. This illustrates the critical role that pH plays in cannabinoid formulations' stability. Applicant determined that the pH should be from about <NUM> to about <NUM> for optimal stability. Addition of antioxidants along with pH adjustment further increased the stability of the cannabinoid formulation. For example, formulations # AF3 and # AF4, containing antioxidant(s) and pH modifiers, showed excellent stability for four weeks regardless of temperature and humidity conditions.

The formulations in Tables <NUM> and <NUM> below were prepared as follows. All the solvents were purged with nitrogen before using in manufacturing. Vitamin E, ascorbyl palmitate, methyl paraben, propyl paraben, sucralose were dissolved in ethanol. propylene glycol, polyethylene glycol <NUM>, glycerol, flavoring agent, and water were added to the solution and mixed thoroughly. Then, if applicable, the pH of the solution was adjusted using a pH modifier. The cannabinoid was added to the excipient solution and mixed until completely dissolved.

Synthetically synthesized, substantially pure, cannabidiol was used as the cannabinoid. Strawberry flavor was used as the flavoring agent.

The formulations listed in Table <NUM> and Table <NUM> were subjected to stability at <NUM> ± <NUM> under <NUM>% ± <NUM>% relative humidity and <NUM> ± <NUM> under <NUM> % ± <NUM> % relative humidity. Stability of the formulations was analyzed at specified time points by evaluating for their potency (assay value) and impurity levels. Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at <NUM> and indicated as a % of initial concentration. For all impurities, analysis was performed at <NUM> and expressed as a % area. Amounts of particular impurities are listed in Table <NUM> to <NUM> as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.

Control formulation (# A5) showed significant increase in levels of total impurities and decrease in the assay value. The addition of antioxidants, Vitamin E and ascorbyl palmitate (see # A6) significantly increased the stability of formulation. These results illustrate the critical role of antioxidants in stabilizing cannabinoid formulations. Antioxidants Vitamin E and ascorbic acid (or its salt) show excellent synergism as ascorbic acid (or its salt) strongly inhibits the depletion of Vitamin E by regenerating it. Along with the antioxidants, the addition of pH modifiers to adjust the pH to the range of <NUM> to <NUM> resulted in exceptionally stable formulations (# A7 and # A8). The stability testing data illustrates that the pH range of from about <NUM> to about <NUM> is critical. Formulations # A9 and # A10 also showed good stability after four weeks.

The formulations in Table <NUM> were created by mixing all the solid and liquid excipients in the lipid. Cannabidiol was then dissolved. Synthetically synthesized, substantially pure, cannabidiol used as the source of the cannabinoid. Strawberry was used as the source of flavoring.

Formulation #LF1 was subjected to stability at <NUM> ± <NUM> under <NUM> % ± <NUM> % relative humidity and <NUM> ± <NUM> under <NUM> % ± <NUM> % relative humidity. Formulations #LF10 and #LF11 were subjected to stability at <NUM> ± <NUM> and <NUM> ± <NUM> under <NUM> % ± <NUM> % relative humidity. Formulations #LF8, #LF9 and #LF12-#LF15 were subjected to stability at all <NUM> storage conditions. The stability of the formulation was analyzed at specified time points by evaluating the potency (assay value) and impurity levels. Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at <NUM> and indicated as a % of initial concentration. For all impurities, analysis was performed at <NUM> and expressed as a % area. Amounts of particular impurities are listed in Table <NUM> as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.

As seen in Table <NUM> above, formulation # LF1 with sesame oil showed good stability after <NUM> months at both storage conditions <NUM> ± <NUM>/<NUM> % ± <NUM> % relative humidity and <NUM> ± <NUM>/<NUM> % ± <NUM> % relative humidity. Also, formulation #LF8 with olive oil showed good stability after four weeks at storage conditions <NUM> ± <NUM>, after three months at <NUM> ± <NUM>/<NUM> % ± <NUM> % relative humidity and <NUM> ± <NUM>/<NUM> % ± <NUM> % relative humidity.

Formulations #LF9-#LF15 each contain capyrlic/capric triglyceride and one of alpha-tocopherol (Vitamin E), ascorbyl palmitate, or a combination thereof as an antioxidant. Formulations #LF13-#LF15 each additionally contain ethanol. Each of formulations #LF9-#LF15 showed good stability after four weeks at storage conditions <NUM> ± <NUM>, <NUM> ± <NUM>/<NUM> % ± <NUM> % relative humidity and <NUM> ± <NUM>/<NUM> % ± <NUM> % relative humidity. #LF9-#LF12 demonstrate the ability of alpha-tocopherol (Vitamin E) to surprisingly achieve less than <NUM>% total impurities after four weeks at <NUM> ± <NUM>/<NUM> % ± <NUM> % relative humidity. #LF13-#LF15 demonstrate the ability of ascorbyl palmitate to surprisingly achieve less than <NUM>% total impurities after four weeks at all <NUM> storage conditions in formulations containing from <NUM>% to <NUM>% ethanol. #LF14 demonstrates that the addition of alpha tocopherol (Vitamin E) does not improve the surprising stability from the use of ascorbyl palmitate.

Paclitaxel is an antineoplastic agent that has activity against several types of cancer including ovary, breast, lung and the head and neck. Paclitaxel works by promoting microtubule assembly which results in neuropathy as a toxic side effect. Peripheral sensory neuropathy is the most commonly reported neurotoxic side effect of paclitaxel and it 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 is not a highly effective treatment for this type of pain. Therefore, there is a need for a highly effective treatment to relieve the symptoms of paclitaxel induced neuropathy.

A mouse study was conducted in order to determine the effects of cannabidiol, delta-<NUM>-tetrahydrocannabinol, and cannabidiol plus delta-<NUM>-tetrahydrocannabinol combinations to alleviate neuropathic pain caused by chemotherapy-induced peripheral neuropathy. The cannadidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than <NUM> %.

A detailed explanation of <FIG> is as follows. The Y-axes represent the threshold sensitivity to mechanical stimulation, expressed as a percent of baseline sensitivity. The X-axes represent the dose of drug in milligrams per kilogram ("mg/kg") administered intraperitoneally ("IP". ) Whereas the dotted lines represent withdrawal threshold level to mechanical stimulation of saline controls, the dashed lines represent paclitaxel-treated animals. The points along the dashed line indicate neuropathic pain while points along the dotted line represent protection from neuropathic pain. The data shown are mean +SEM sensitivity measured on Day <NUM> post treatment. * p< <NUM> from saline control as determined by one-way ANOVA.

Specific doses of agents producing similar overt behavioral effects when added to together should produce the additive effect level.

Applicant found (as illustrated in <FIG>) that cannabidiol when administered alone provided the most effective level of alleviating chemotherapy-induced neuropathic pain compared to delta-<NUM>-tetrahydrocannabinol. The presence of delta-<NUM>-tetrahydrocannabinol depending on its concentration can inhibit the ability of cannabidiol to alleviate neuropathic pain. The ability of delta-<NUM>-tetrahydrocannabinol to block the pain alleviating activity of cannabidiol is also dependent of the concentration of cannabidiol. This test illustrates that a substantially pure cannabidiol formulation is highly desirable.

Paclitaxel was administered on days <NUM>, <NUM>, <NUM>, and <NUM> following baseline mechanical sensitivity, and cannabinoids were administered <NUM> minutes prior to each paclitaxel injection. Mechanical sensitivity was then reassessed on days <NUM>, <NUM>, and <NUM>. For mechanical sensitivity testing, mice are placed on a wire mesh surface inside individual clear Plexiglas chambers, and the plantar surface of their hindpaw is touched with increasing thicknesses of Von Frey filaments (<NUM> - <NUM> grams of force) until they withdraw their paw from the stimulation. Von Frey hairs are a series of fine, calibrated filaments that are pressed against the plantar surface of the mouse into a bent "C" shape for <NUM> seconds. For each treatment group the final sample size was <NUM> animals. Two-way ANOVA were used to determine significant effects of CBD and THC treatment.

Single agent dose effect curves are shown as percent level of mechanical sensitivity at baseline to normalize data. Dose equivalence analysis was used to determine significant synergistic effects of CBD+THC compared with predicted additive values derived from single agent dose response curves. To obtain predicted and observed effect levels, data were transformed into percent maximal possible effect (MPE) of the cannabinoid to reverse paclitaxel-induced mechanical sensitivity. To determine this value for each animal, the mean sensitivity score of the paclitaxel control group on given test day is set at zero and the animal's baseline score prior to treatment is set at <NUM>. For example, if an animal has a mechanical sensitivity score of <NUM> at baseline and a score of <NUM> on day <NUM>, and the paclitaxel group shows an average score of <NUM> on day <NUM>, then the animal's percent MPE score is <NUM>%. A %MPE score of <NUM>% would indicate that the animal was at least as sensitive as the paclitaxel control group. A %MPE score of <NUM>% would indicate that the animal was as sensitive or less sensitive on test day as it was at baseline. This transformation of the data is necessary to determine effective dose levels (ED50s, ED25s, etc).

Pretreatment with CBD or THC significantly attenuated paclitaxel-induced mechanical sensitivity, P<<NUM> for each agent. CBD produced this effect with higher potency, in that the minimal effective dose for CBD was <NUM>/kg IP, while the minimal effective dose for THC was <NUM>/kg IP. Two-way ANOVA also revealed a significant difference between the CBD and THC dose response curves, with the <NUM>/kg dose of CBD producing a significantly higher % baseline score as compared to <NUM>/kg dose of THC. Both drugs appeared to be efficacious.

Across a wider range of doses, it becomes apparent that both CBD and THC do not produce monotonic dose effects but instead follow an inverted-U or N shaped function. For both CBD and THC at each time point, the curve turns over at between <NUM> and <NUM>/kg, but the treatments regain efficacy at higher doses. See <FIG>, top center and middle center panels. In the combination groups, the data appear more U-shaped, although it is unclear whether the rise would again emerge with larger dose combinations. See <FIG>, bottom middle panel.

Dose equivalence analysis was used to predict the combined effects of CBD and THC based on their effects alone on the ascending limbs of their dose response curves. The individual dose effect equations are E=<NUM>D<NUM>/D<NUM>+<NUM> for CBD, and E=<NUM>D<NUM>/D<NUM>+<NUM> for THC. In 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 so that the sum is the effective dose of the predicted combination. For example, to predict the additive effect of <NUM>/kg CBD and <NUM>/kg THC, a dose of THC is identified that is equi-effective to <NUM>/kg CBD using the determined dose effect equation for CBD. CBD <NUM>/kg produces a %MPE of <NUM>%. From this, the dose of THC to produce a %MPE of <NUM> is calculated using the determined dose effect equation for THC. The dose of THC required to achieve a %MPE is <NUM>/kg, and this represents a dose that is equi-effective to <NUM>/kg CBD. The <NUM>/kg is added to the <NUM>/kg to give <NUM>/kg THC, whose effect level will equal the predicted effect level of <NUM>/kg CBD + <NUM>/kg THC. This predicted effect level is determined to be <NUM> %MPE. When the actual combination experiment was conducted, <NUM>/kg CBD + <NUM>/kg THC (labeled on the graph as <NUM>/kg combination), was actually the ED78 (<NUM>% maximum possible effect; <FIG> bottom panel). Modified t-test statistics are applied and it was determined that the predicted combination dose response curve was statistically significantly different from the observed dose response curve, demonstrating a synergistic effect of CBD+THC combinations.

A study was designed to test the efficacy of CBD+THC combinations outside of the <NUM>:<NUM> dose ratio. Six additional combinations were tested: <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, and <NUM>:<NUM>. Four doses of each treatment combination were tested in groups of mice treated with paclitaxel. For each treatment group the final sample size was <NUM> animals.

The <NUM>:<NUM> combination of CBD to THC produced a similar effect to CBD alone, while <NUM>:<NUM> and <NUM>:<NUM> ratios of CBD to THC were more potent than CBD alone. Two-way ANOVA revealed an overall effect of treatment and of dose (p<<NUM>) but no significant interaction. Combinations higher in THC than in CBD produced an effect similar to THC alone, with a significant effect of dose (p<<NUM>) but no main effect of treatment and no significant interaction.

A 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 chemotherapeutic agents. Oxaliplatin was administered once at a dose of <NUM>/kg. CBD was administered <NUM> minutes prior to the single oxaliplatin injection. Vincristine was administered once daily for <NUM> days at a dose of <NUM>/kg. CBD was administered <NUM> minutes prior to each vincristine injection. For each treatment group the final sample size was <NUM> animals.

Pretreatment with CBD attenuated oxaliplatin but not vincristine-induced mechanical sensitivity. Two-way ANOVA for oxaliplatin revealed a significant effect of time and a significant effect of treatment (p<<NUM>) and no significant interaction. Two-way ANOVA for vincristine revealed a significant effect of time (p<<NUM>), but no main effect of treatment and no interaction.

This study was conducted as follows according to standard models for anticonvulsant screening including the maximal electroshock test ("MES"), the minimal clonic seizure ("<NUM>") test and evaluations of toxicity ("TOX"). The data was recorded as number of animals protected (N) out of the number of animals tested (F), see Tables <NUM> to <NUM> below. The test was repeated one time. The cannabidiol administered to the mice and rats was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than <NUM> %. The cannabidiol was dissolved in <NUM>% methylcellulose or a <NUM>:<NUM>:<NUM> ratio of ethanol:polyethoxylated castor oil:phosphate buffered saline ("PBS").

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 are electrophysiologically consistent with human seizures. For all tests based on maximal electroshock convulsions, <NUM> of alternating current (<NUM> mA in mice, <NUM> in rats) was delivered for <NUM> by corneal electrodes which were primed with an electrolyte solution containing an anesthetic agent (<NUM>% tetracaine HCl). The mice were tested at various intervals following doses of <NUM>, <NUM> and <NUM>/kg of cannabidiol given by intraperitoneal injection of a volume of <NUM>/g. An animal was considered "protected" from maximal electroshock-induced seizures upon abolition of the hindlimb tonic extensor component of the seizure.

The minimal motor impairment test was used to determine the compounds' undesirable side effects or toxicity. During this test, the animals were monitored for overt signs of impaired neurological or muscular function. The rotorod procedure was used to disclose minimal muscular or neurological impairment. When a control mouse is placed on a rod that rotates at a speed of <NUM> rpm, the animal can maintain its equilibrium for long periods of time. The animal was considered toxic if it fell off this rotating rod three times during a <NUM> second period. In addition to minimal motor impairment, the animals may have exhibited a circular or zigzag gait, abnormal body posture and spread of the legs, tremors, hyperactivity, lack of exploratory behavior, somnolence, stupor, catalepsy, loss of placing response and changes in muscle tone.

The third test was the minimal clonic seizure (<NUM>) test. Like the maximal electroshock test, the minimal clonic seizure (<NUM>) test is used to assess a compound's efficacy against electrically induced seizures but uses a lower frequency (<NUM>) and longer duration of stimulation (<NUM>). Cannabidiol was pre-administered to mice via intraperitoneal injection. At varying times, individual mice (four per time point) were challenged with sufficient current delivered through corneal electrodes to elicit a psychomotor seizure in <NUM> % of animals (<NUM> mA for <NUM>). Untreated mice will display seizures characterized by a minimal clonic phase followed by stereotyped, automatistic behaviors described originally as being similar to the aura of human patients with partial seizures. Animals not displaying this behavior are considered protected.

As seen in Tables <NUM> to <NUM> above, Applicant found that cannabidiol protected the mice and rats from epilepsy.

This study was conducted in order to determine the ability of synthetically-syntheisized, substantially pure cannabidiol to block a psychomotor seizure induced by long-duration frequency (<NUM>) stimulation. This is a study model for therapy-resistant partial seizures.

Adult male CF1 mice (weighing <NUM> to <NUM>) were pretreated intraperitoneally with the cannabidiol at a dose of <NUM>/kg. The cannabidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than <NUM> %. The cannabidiol was dissolved in <NUM>% methylcellulose or a <NUM>:<NUM>:<NUM> ratio of ethanol:polyethoxylated castor oil:PBS.

Each treatment group (n = <NUM> mice/group) was examined for anticonvulsive effects at one of five time points (<NUM>/<NUM>, <NUM>/<NUM>, <NUM>, <NUM>, and <NUM> hours) following treatment with cannabidiol. Following pretreatment, each mouse received a drop of <NUM> % tetracaine hydrochloride applied to each eye. The mouse was then challenged with the low-frequency (<NUM>) stimulation for <NUM> seconds delivered through corneal electrodes. The low-frequency, long-duration stimuli was initially delivered at <NUM> mA intensity. Animals were manually restrained and released immediately following the stimulations and observed for seizure activity. If the test compound was effective in the <NUM> mA screen, an additional assay wherein the stimulation current is increased to <NUM> mA is employed using the same protocol as described above. Additionally, a dose response curve can be generated at the time of peak effect (TPE) at the specific stimulation intensity.

Typically, the <NUM> stimulation results in a seizure characterized by a minimal clonic phase that is followed by stereotyped, automatistic behaviors, including twitching of the vibrissae, and Straub-tail. Animals not displaying such behaviors were considered protected. Data was analyzed by Mann-Whitney U test, with p<<NUM> determined to be statistically significant.

For each time group, the results are expressed as the total number of animals protected out of the number of animals tested over time (i.e., <NUM>/<NUM> represents <NUM> out of <NUM> mice tested were protected).

As seen in Tables <NUM> to <NUM>, cannabidiol in both solvents showed comparable median effective doses that inhibited seizures in <NUM> % of animals (ED50s) in the <NUM>/kg range. While cannabidiol dissolved in the methylcellulose solvent had an ED50 of <NUM>/kg (<NUM> % Confidence Interval of <NUM>/kg to <NUM>/kg), it showed an ED50 of <NUM>/kg when dissolved in the <NUM>:<NUM>:<NUM> ethanol: polyethoxylated castor oil:PBS solvent (<NUM> % Confidence Interval of <NUM>/kg to <NUM>/kg). Based on the toxicity data for the cannabidiol in the methylcellulose solvent, the median toxicity dose where toxicity is observed in <NUM> % of animals ("TD50") was determined to exceed <NUM>/kg at <NUM> hours post administration. Diarrhea at <NUM> hours and <NUM> death was reported at <NUM> hours at <NUM>/kg, the highest dose tested.

The TD50 was determined to be <NUM>/kg (<NUM> % Confidence Interval of <NUM> to <NUM>) with cannabidiol dissolved in the <NUM>:<NUM>:<NUM> ethanol: polyethoxylated castor oil:PBS solvent. Death was reported at <NUM> hours at <NUM>/kg and at <NUM> and <NUM> hours for <NUM>/kg with the with the <NUM>:<NUM>:<NUM> ethanol: polyethoxylated castor oil:PBS solvent.

These results further illustrate that cannabidiol is likely to be effective in humans for the treatment of epilepsy and other conditions. Further, synthetically synthesized cannabidiol will likely be less toxic than cannabidiol that is derived from plants and not substantially pure.

The maximal electroshock seizure ("MES") and subcutaneous Metrazol ("sc Met") tests have been the two most widely employed preclinical seizure models for the early identification and high through-put screening of investigational anti-seizure drugs. These tests have been extremely effective in identifying new anti-seizure drugs that may be useful for the treatment of human generalized tonic-clonic seizures and generalized myoclonic seizures. The MES test provides an indication of CBD's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active. Met test detects the ability of CBD to raise the chemoconvulsant-induced seizure threshold of an animal and, thus, protect it from exhibiting a clonic, forebrain seizure.

For the MES test, <NUM> of alternating current is delivered by corneal electrodes for <NUM> seconds. Supra-maximal seizures are elicited with a current intensity five times that necessary to evoke a threshold tonic extension seizure, i.e., <NUM> mA in mice and <NUM> mA in rats. A drop of anesthetic solution, <NUM> % tetracaine hydrochloride, is placed on the eyes of each animal just before the corneal electrodes are applied to the eyes to elicit electrical stimulation. The animals are restrained by hand and released immediately following stimulation to allow observation of the entire seizure. Inhibition of the hind leg tonic extensor component is taken as the endpoint for the MES test.

A dose of Metrazol (<NUM>/kg in mice) will induce convulsions in <NUM> % of mice (CD97). The CD97 dose of Metrazol is injected into a loose fold of skin in the midline of the neck. The CD97 doses for Metrazol are confirmed annually in mice. It is administered to mice at a volume of <NUM>/g body weight. The animals are then placed in isolation cages to minimize stress and continuously monitored for the next <NUM> for the presence or absence of a seizure. An episode of clonic spasms, approximately <NUM> to <NUM> seconds, of the fore and/or hind limbs, jaws, or vibrissae is taken as the endpoint. Animals not displaying fore and/or hind limb clonus, jaw chomping, or vibrissae twitching are considered protected.

All quantitative in vivo antiseizure/behavioral impairment studies are typically conducted at the previously determined TPE. Groups of at least <NUM> mice were tested with various doses of cannabidiol until at least two points are established between the limits of <NUM> % protection or minimal toxicity and <NUM> % protection or minimal toxicity. The dose of drug required to produce the desired endpoint in <NUM> % of animals (ED50 or TD50) in each test, the <NUM>% confidence interval, the slope of the regression line, and the standard error of the mean (S. ) of the slope is then calculated by probit analysis.

The cannabidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than <NUM> %. The cannabidiol was dissolved in <NUM>% methylcellulose or a <NUM>:<NUM>:<NUM> ratio of ethanol: polyethoxylated castor oil:PBS. The maximal electric shock (MES) and subsucanteous Metrazol ("sc MET") are the most widely used preclinical seizure models for the early identification and screening of new antiepileptic drugs.

The ED50 in the MES model for cannabidiol dissolved in the methylcellulose solvent could not be calculated due to a U shaped dose response (<NUM>/<NUM> protected at <NUM> hr, <NUM>/<NUM> at 1hr, <NUM>/<NUM> at 2hr and <NUM>/<NUM> at 4hr). However, the ED50 for cannabidiol dissolved in the <NUM>:<NUM>:<NUM> ethanol:polyethoxlated castor oil:PBS solvent is <NUM>/kg (<NUM> % Confidence Interval of <NUM>/kg to <NUM>/kg).

For the MET model, the ED50 was <NUM>/kg (<NUM>% Confidence Interval of <NUM> to <NUM>) for cannabidiol dissolved in the methylcellulose solvent and <NUM>/kg (<NUM> % Confidence Interval of <NUM>/kg to <NUM>/kg) for cannabidiol dissolved in the <NUM>:<NUM>:<NUM> ethanol:polyethoxlated castor oil:PBS solvent. Based on the toxicity data for cannabidiol dissolved in the methylcellulose solvent the TD50 was determined to exceed <NUM>/kg, the highest dose tested.

Myoclonic jerks were reported in at <NUM> hour with <NUM>/kg dose and at <NUM> hours with <NUM>/kg dose. The TD50 was determined to be <NUM>/kg (<NUM> % Confidence Interval of <NUM>/kg to <NUM>/kg) with the cannabidiol dissolved in the <NUM>:<NUM>:<NUM> ethanol:polyethoxlated castor oil:PBS solvent.

A study was conducted in order to determine the extent to which systemic administration of cannabidiol or cannabidiol plus delta-<NUM>-tetrahydrocannabinol (cannabidiol/delta-<NUM>-tetrahydrocannabinol <NUM>:<NUM>) can inhibit glioblastoma multiforme progression and enhance the activity of temozolomide, a chemotherapy drug, in an orthotopic mouse model of glioblastoma multiforme utilizing U87 cells. It was previously suggested that the combination of cannabidiol plus delta-<NUM>-tetrahydrocannabinol is the most effective treatment for targeting tumors derived from U87 serum-derived glioblastoma multiforme cells.

The study was conducted as follows. Human U87 luciferase labeled cells were grown in Roswell Park Memorial Institute media with <NUM> % fetal bovine serum and then harvested from dishes while in their exponential growth phase in culture with <NUM> % trypsin/ethylenediaminetetraacetic acid and washed twice with serum-free Roswell Park Memorial Institute media. For the intracranial model, tumors were generated in female athymic nu/nu mice by the intracranial injection of <NUM>×<NUM><NUM> U87 cells in 4µl of Roswell Park Memorial Institute media. Using this model, you can assess drug efficacy (in vivo imaging) as well as survival in the same group of animals. Survival studies were carried out in accordance with the National Institutes of Health's guidelines involving experimental neoplasia and our approved Institutional Animal Care and Use Committees protocol. Animals in all groups are removed from the study when they demonstrate any single sign indicative of significant tumor burden development, including hunched back, sustained decreased general activity, or a significant decrease in weight. In limited cases where tumors were able to escape the intracranial space, the mice were euthanized when the external tumors measured greater than <NUM> as assessed by callipers. Additionally, mice with tumors measuring ><NUM>×<NUM><NUM> radiance where removed from the study even if symptoms were not observed to assure spontaneous deaths related to seizures did not occur do to the existence of the large intracranial tumor.

The cannabinoids were dissolved in a mixture of <NUM> % ethanol, <NUM> % surfactant and <NUM> % saline, and temozolomide was dissolved in <NUM> % dimethyl sulfoxide and <NUM> % saline. Cannabidiol that was synthetically synthesized and substantially pure was used in this study. The treatments were initiated <NUM> days after the injection of the tumor cells. Mice were imaged the morning before the first injection to determine initial tumor size and then groups were organized to have equal distribution of tumor size before the initiation of the first injection. Mice were treated once a day for five days with temozolomide. Mice were treated once a day, <NUM> days a week (Monday through Friday), with the cannabinoids until the completion of the study, except for the first week of the study where mice were injected over the weekend. All mice were administered the treatments via intraperitoneal injection. There were <NUM> mice per group, for a total of <NUM> mice. The treatment rates were as follows: cannabidiol (<NUM>/kg); cannabidiol/delta-<NUM>-tetrahydrocannabinol (<NUM>:<NUM>, together @ <NUM>/kg); and temozolomide (<NUM>/kg intraperitoneal injection.

Significant differences were determined using a one-way ANOVA. Bonferroni-Dunn post-hoc analyses were conducted when appropriate. Survival between groups was compared using a long-rank Mantel-Cox test. P values <<NUM> defined statistical significance.

A detailed explanation of <FIG> is as follows. The X-axis represents the number of days after treatment and the Y-axis represents the survival rates.

As seen in <FIG>, while <NUM>/kg of cannabidiol alone or cannabidiol/delta-<NUM>-tetrahydrocannabinol (<NUM>:<NUM>) did not inhibit glioblastoma multiforme progression, it enhanced the antitumor activity of suboptimal doses of temozolomide leading to a significant increase in survival. Further, the substantially pure, synthetically synthesized, cannabidiol produced full regression of <NUM> % of tumors. This effect was not observed following the <NUM>:<NUM> cannabidiol:delta-<NUM>-tetrahydrocannabinol treatments. It was unexpected that substantially pure, synthetically synthesized, cannabidiol would have these effects because previously it was thought that a <NUM>:<NUM> ratio of cannabidiol (that was extracted from cannabis and not substantially pure):delta-<NUM>-tetrahydrocannabinol would produce better effects than cannabidiol alone. However, this study again illustrates the superiority of Applicant's substantially pure, synthetically synthesized, cannabidiol.

Human U251 luciferase labeled cells were grown in Roswell Park Memorial Institute media with <NUM>% fetal bovine serum and then harvested from dishes while in their exponential growth phase in culture with <NUM>% trypsin/ ethylenediaminetetraacetic acid, and washed twice with serum-free Roswell Park Memorial Institute media. For the intracranial model, tumors were generated in female athymic nu/nu mice by the intracranial injection of <NUM>×<NUM><NUM> U251 cells in 4µl of Roswell Park Memorial Institute media. Using this model, you can assess drug efficacy (in vivo imaging) as well as survival in the same group of animals. Survival studies were carried out in accordance with the National Institutes of Health's guidelines involving experimental neoplasia and our approved Institutional Animal Care and Use Committees protocol. Animals in all groups are removed from the study when they demonstrate any single sign indicative of significant tumor burden development, including hunched back, sustained decreased general activity, or a significant decrease in weight. In limited cases where tumors were able to escape the intracranial space, the mice were euthanized when the external tumors measured greater than <NUM> as assessed by calipers. Additionally, mice with tumors measuring ><NUM>×<NUM><NUM> radiance where removed from the study even if symptoms were not observed to assure spontaneous deaths related to seizures did not occur due to the existence of the large intracranial tumor. There were <NUM> mice per group, for a total of <NUM> mice. The treatment rates were as follows: cannabidiol (<NUM>/kg); temozolomide (<NUM>/kg intraperitoneal injection; and cannabidiol/temozolomide (<NUM>:<NUM>, together at <NUM>/kg.

For drug treatment studies, cannabinoids were dissolved in a mixture of <NUM> % ethanol, <NUM> % Tween® <NUM> and <NUM>% saline, and temozolomide was dissolved in <NUM>% dimethyl sulfoxide and <NUM>% saline. The treatments were initiated <NUM> days after the injection of the tumor cells. Mice were imaged the morning before the first injection to determine initial tumor size and then groups were organized to have equal distribution of tumor size before the initiation of the first injection. Mice were treated once a day for five days with temozolomide. Mice were treated once a day, <NUM> days a week (Monday through Friday), with cannabinoids until the completion of the study, except for the first week of the study where mice were inject over the weekend. All mice were injected intraperitoneally.

Significant differences were determined using a one-way ANOVA. Bonferroni-Dunn post-hoc analyses were conducted when appropriate. Survival between groups was compared using a Kaplan-Meier analysis and long-rank Mantel-Cox test or The Gehan-Breslow-Wilcoxon test. P values <<NUM> defined statistical significance.

One of tumors in the vehicle group fully regressed overtime creating an outlier in the study. Tumor regression in a vehicle treated animal is a rare occurrence but it can occur. Since during the start of the study, the tumor did demonstrate a small increase in growth as assessed by IVIS imaging, it could not be removed from the data set. The data is presented with (<FIG>) and without (<FIG>) the outlier for comparison. With the vehicle outlier included, temozolomide alone did not increase survival (p=<NUM>, <FIG>, p<<NUM> is considered significant). Cannabidiol alone also did not increase survival. However, the combination of temozolomide + <NUM>/kg of cannabidiol almost reached significance (p=<NUM>) for increasing survival using a Log-rank Mantel-Cox test, p<<NUM> is considered significant. If this same data set was analyzed with the Gehan-Breslow-Wilcoxon test then the treatment of temozolomide + cannabinoid did produce a significant increase in survival. The Gehan-Breslow-Wilcoxon test however is a less stringent statistical test in comparison to the Log-rank Mantel-Cox test. It should be noted that <NUM> of the <NUM> mice are still alive in the temozolomide + cannabinoid group, and in one of the mice the tumor has fully regressed based on in vivo imaging of the tumor.

If the vehicle outlier was removed from the data set, then treatment with temozolomide significantly increased survival (p<<NUM>, <FIG>). The combination of temozolomide + <NUM>/kg of cannabidiol, however was highly significant at increasing survival (p=<NUM>). Thus, cannabidiol enhanced the antitumor activity of temozolomide.

A Phase <NUM>/<NUM>, open label, Multiple Ascending Dose study will be conducted to evaluate the effect of multiple doses of cannabidiol oral solution on pediatric subjects experiencing treatment-resistant seizures. The study will assess pharmacokinetics, safety, tolerability and preliminary efficacy of <NUM> doses (<NUM>, <NUM>, and <NUM> milligrams per kilogram per day ("mg/kg/day") of cannabidiol oral solution administered in a sequential fashion. Specifically, twenty subjects will be enrolled in each dose cohort that A) fit the following criteria: <NUM>. subject and/or parent(s)/caregiver(s) fully comprehend the informed consent form (ICF) and assent form, understand all study procedures, and can communicate satisfactorily with the Investigator and study coordinator; <NUM>. provide informed consent and/or assent (as applicable) of subjects and/or parent(s)/caregiver(s) in accordance with applicable laws, regulations, and local requirements; <NUM>. male or female between <NUM> and <NUM> years of age (inclusive) at the time of consent; <NUM>. diagnosed with a treatment-resistant seizure disorder in the opinion of the Investigator and as defined as continued seizures despite: a. adequate trials of ≥<NUM> antiepileptic drugs ("AEDs"), and b. ≥<NUM> prior adequate treatment course with ≥<NUM> AEDs in combination (i.e., concurrently); <NUM>. willingness to remain on established AEDs (stable dosing for ≥<NUM> days prior to Day <NUM> and throughout the duration of the study) a. neither a vagus nerve stimulation (VNS) procedure nor ketogenic diet are considered an AED for the purposes of this study; <NUM>. willingness to not start a ketogenic diet during the Treatment Period or, if already on the diet, to make no changes in the diet during the study; <NUM>. a female subject is eligible to participate in the study if she is: a. premenarchal, or b. of childbearing potential with a negative urine pregnancy test at the Screening Visit and at Day <NUM>. If sexually active, she must agree to fulfill one of the following requirements: i. complete abstinence from intercourse ≥<NUM> weeks prior to administration of the first dose of the investigational product, throughout the Treatment Period, and <NUM> weeks after completion or premature discontinuation from the investigational product, and agreement to use a double-barrier method if she becomes sexually active; ii. use of acceptable methods of contraception throughout the study and <NUM> weeks after completion or premature discontinuation from investigational product. The acceptable method of contraception is double barrier method (i.e., condom plus spermicide or a condom plus diaphragm); <NUM>. a sexually active male subject must be willing to use acceptable methods of contraception throughout the study and for <NUM> weeks completion of study participation or premature discontinuation from investigational product. The acceptable methods of birth control are abstinence or double barrier birth control (i.e., condom plus spermicide or a condom plus diaphragm); <NUM>. in the opinion of the Investigator, the parent(s)/caregiver(s) are willing and able to comply with the study procedures and visit schedules, including venipuncture, inpatient stay at the study center, dosing at the study center (twice a day as needed while an outpatient), and the Follow-up Visits (if applicable); <NUM>. general good health (defined as the absence of any clinically relevant abnormalities as determined by the Investigator) based on physical and neurological examinations, medical history, and clinical laboratory values (hematology, chemistry, and urinalysis) completed during the Screening Visit; and <NUM>. body weight of ≥ <NUM>; and B) do not meet the following criteria: <NUM>. subject or parent(s)/caregiver(s) have daily commitments during the study duration that would interfere with attending all study visits; <NUM>. currently taking concomitant medications that are strong cytochrome P450 3A4 ("CYP3A4") inhibitors or inducers or CYP3A4 sensitive substrates with a narrow therapeutic index; <NUM>. currently taking any other disallowed medications; <NUM>. currently taking felbamate if they had been receiving it for <<NUM> months prior to the Screening Visit; <NUM>. in the opinion of the Investigator, any clinically significant, unstable medical abnormality, chronic disease, or a history of a clinically significant abnormality of the cardiovascular, gastrointestinal, respiratory, hepatic, or renal systems; <NUM>. any disorder or history of a condition (e.g., malabsorption or gastrointestinal surgery) that may interfere with drug absorption, distribution, metabolism, or excretion; <NUM>. history or presence of abnormal electrocardiograms ("ECGs") that are clinically significant in the opinion of the Investigator; <NUM>. for appropriate subjects, an affirmative answer to queries regarding active suicidal ideation with some intent to act but without a specific plan or active suicidal ideation with specific plan and intent on the Columbia Suicide Severity Rating Scale ("C-SSRS") assessment at the Screening Visit, subjects who have significant findings for suicidal ideation as assessed by the C-SSRS must be referred to the Investigator for follow-up evaluation; <NUM>. any history of attempted suicide; <NUM>. history of poor toleration of venipuncture or poor venous access that would cause difficulty in collecting blood samples; <NUM>. participation in any investigational study currently or within <NUM> days or <NUM> half-lives (t½) of the investigational product (whichever is longer) prior to the Screening Visit; <NUM>. taken any cannabinoids (cannabidiol, Δ9-tetrahydrocannabinol [Δ9-THC], hemp oil, Realm Oil or marijuana) in the <NUM> days prior to the Screening Visit; <NUM>. history of an allergic reaction or a known or suspected sensitivity to any substance that is contained in the investigational product formulation; <NUM>. known infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV); <NUM>. In the opinion of the Investigator, the subject is unsuitable in any other way to participate in this study; and <NUM>. body weight of ><NUM>.

Each subject will be enrolled in only one dose cohort. No fewer than <NUM> subjects between <NUM> and <NUM> years of age must be dosed through Day <NUM> prior to dosing any subject <<NUM> years of age. Each of the <NUM> planned dose cohorts will include <NUM> subjects for a study total of <NUM> subjects: <NUM> to <<NUM> years of age: <NUM> subjects; <NUM> to <<NUM> years of age: <NUM> subjects with at least <NUM> under the age of <NUM>; and <NUM> to ≤<NUM> years of age: <NUM> subjects with at least <NUM> subjects under age <NUM>. Each subject will complete a Screening Period of up to <NUM> days and a Treatment Period of <NUM> days. Subjects will have a Follow-up Visit on Day <NUM> and a Follow-up Phone Call on Day <NUM>. On Day <NUM>, the investigational product will be administered once in the morning according to the subject's assigned dose level cohort. The evening dose of the investigational product will not be administered on Day <NUM>. Thus, the subject will receive a half-daily dose only (<NUM>, <NUM>, or <NUM> millgrams/kilogram "mg/kg" total) of the investigational product on Day <NUM>. Subjects will not receive a dose from Day <NUM> through Day <NUM> but they will remain in an inpatient setting and complete planned assessments. Subjects will be dosed twice daily (i.e., full daily dose of <NUM>, <NUM>, or <NUM>/kg/day) from Day <NUM> through Day <NUM> according to the subject's assigned cohort. Doses will be administered at approximately <NUM>-hour intervals. Doses will be administered to subjects in a fasting state on days on which the serial PK samples will be collected (i.e., Day <NUM> and Day <NUM>. ) Fasting times include <NUM> hour for ages <NUM> to less than <NUM> years and <NUM> hours for ages <NUM> to <NUM> years.

During the Screening, Treatment, and Follow-up Periods, subjects are not to receive the following: (<NUM>) medication(s) that are strong CYP3A4 inhibitors or inducers or CYP3A4-sensitive substrates with a narrow therapeutic index; (<NUM>) any cannabinoids (cannabidiol, Δ9-THC, hemp oil, Realm Oil or marijuana); corticotrophins; systemic steroid therapy (excluding inhaled medication for asthma treatment); felbamate (if used for <<NUM> months) or (<NUM>) any other investigational drug or investigational device. Subjects will remain on established antiepilepsy therapies (i.e., AEDs for which dosing has been stable ≥<NUM> days prior to Day <NUM>) throughout the duration of the Treatment and Follow-up Periods.

In summary, for subjects ages <NUM> to <<NUM> years, serial blood sampling for pharmacokinetic ("PK") analysis will occur at <NUM>, <NUM>, <NUM>, and <NUM> hours post the Day <NUM> dose. Serial blood sampling for PK analysis will also occur at predose, <NUM>, <NUM>, <NUM>, and <NUM> hours post the Day <NUM> morning dose. For subjects ages <NUM> to <<NUM> years, serial blood sampling will occur at predose and at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (Day <NUM>), and <NUM> (Day <NUM>) hours post the Day <NUM> morning dose. Blood samples for PK trough values for cannabidiol and its <NUM>-hydroxy ("OH") metabolite will be evaluated on Day <NUM>. Collection will occur prior to the morning dose of the investigational product; no investigational product will be administered on Day <NUM>. Serial blood sampling for PK analysis will also occur at predose, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> (Day <NUM>) hours post the Day <NUM> morning dose. For subjects ages <NUM> to ≤<NUM> years, serial blood sampling for PK analysis will occur predose and at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (Day <NUM>), <NUM> (Day <NUM>), <NUM> (Day <NUM>), and <NUM> (Day <NUM>) hours post the Day <NUM> morning dose. Blood samples for PK trough values for cannabidiol and its <NUM>-OH metabolite will be evaluated on Day <NUM> (age ≥<NUM> only), Day <NUM> and Day <NUM>. Collection will occur prior to the morning dose of the investigational product; no investigational product will be administered on Day <NUM>. Serial blood sampling for PK analysis will also occur at predose and at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> (Day <NUM>) hours post the Day <NUM> morning dose. In addition to the above measurements of cannabidiol and its <NUM>-OH metabolite, levels of clobazam and norclobazam will be measured from the samples taken predose on Day <NUM> (baseline), Day <NUM>, and Day <NUM> (predose) for subjects who are aged ≥<NUM> years and are currently taking clobazam.

Endpoints of the study will include the following: (<NUM>) Incidence, type, and severity of adverse events ("AEs") and serious adverse events ("SAEs") occurring during the Treatment Period (i.e., treatment-emergent adverse events ["TEAEs"]); (<NUM>) Changes from baseline in vital signs; (<NUM>) Changes from baseline in ECG findings; (<NUM>) Changes from baseline in laboratory values (hematology, chemistry, and urinalysis); (<NUM>) Plasma PK variables for cannabidiol (parent compound) and its <NUM>-OH metabolite as appropriate: (a) Maximum plasma concentration (Cmax) and dose normalized Cmax (Cmax/D) (b) time to Cmax (tmax); (c) Half-life (t<NUM>/<NUM>); (d) Elimination rate; (e) Oral clearance (cannabidiol only); (f) Volume of distribution (cannabidiol only); (g) Area under the plasma concentration-time curve from <NUM> to <NUM> hours [AUC(<NUM>-<NUM>)] and dose normalized AUC(<NUM>-<NUM>) [AUC(<NUM>-<NUM>)/D] on Day <NUM>; (h) Area under curve from time <NUM> to the last quantifiable concentration [AUC(<NUM>-last)] on Day <NUM>: (i) Area under the plasma concentration-time curve from <NUM> to infinity (AUC[<NUM>-inf]) and dose normalized AUC(<NUM>-inf) [AUC(<NUM>-inf)/D] on Day <NUM> for study subjects ≥<NUM> years of age; (j) Metabolite to parent ratios for Cmax, AUC(<NUM>-inf), AUC(<NUM>-<NUM>) on Day <NUM> and Day <NUM>; (k) AUC(<NUM>-<NUM>) and AUC(<NUM>-<NUM>)/D on Day <NUM>; (l) Minimum plasma concentration (Cmin) on Day <NUM>; (m) Average plasma concentration (Cavg) on Day <NUM>; (n) Accumulation ratios for Cmax and AUC(<NUM>-<NUM>) on Day <NUM>; (o) Time linearity; (<NUM>) clinical global impressions of improvement ("CGI-I") assessment on Day <NUM>; and (<NUM>) Change from baseline in clinical global impressions of severity ("CGI-S") assessment from the Screening Visit to Day <NUM>.

Subjects will be assessed by measurement of vital signs and neurological examination daily. A Physical Examination will be completed at the Screening Visit, as well as Day <NUM>, Day <NUM> and Day <NUM>. A <NUM>-lead ECG, will be completed at the Screening Visit, as well as Day <NUM>, Day <NUM>, Day <NUM>, Day <NUM>, and Day <NUM> (if clinically indicated). Hematology, chemistry, and urine analysis will be performed at the Screening Visit, as well as Day <NUM>, Day <NUM>, Day <NUM>, and Day <NUM>. Hematology, chemistry, and urine analysis will also be performed on Day <NUM> if clinically indicated.

The PK concentrations and parameters for cannabidiol and its <NUM>-OH metabolite in plasma will be summarized by study day, sampling time (where appropriate) and dose using descriptive statistics and graphic displays as appropriate. These results will be graphically displayed by age and mg/kg dose, as appropriate. Exposure relationship with age and body weight will be evaluated using regression and/or inferential analyses, as appropriate. Dose proportionality of cannabidiol and its <NUM>-OH metabolite exposure will be investigated using graphical methods and statistically using a power model approach, as appropriate. Accumulation of cannabidiol and its <NUM>-OH metabolite will be assessed using an appropriate analysis of variance model for exposure PK parameters. Time linearity will also be assessed. Trough concentrations samples collected prior to dosing at the scheduled time points will be assessed graphically for attainment of steady state. Also, time to reach steady state will be assessed with a stepwise linear trend analysis. Levels of clobazam and norclobazam will be measured from the samples taken predose on Day <NUM> (baseline), Day <NUM>, and Day <NUM> (predose) for subjects who are age ≥ <NUM> and currently taking clobazam and summarized by time point and treatment. All safety assessments, including AEs, clinical laboratory evaluations, vital signs, <NUM>-lead ECGs, C-SSRS, and physical and neurological examinations will be listed. When appropriate, they will be summarized with descriptive statistics by age and dose cohort. The results of the CGI-I, CGI-S, and daily seizure diary assessments will be summarized by descriptive statistics as appropriate.

Preliminary results are shown in Table <NUM> below. Cohort #<NUM> was administered a single dose of <NUM>/kg of an alcohol based formulation and then <NUM>/kg BID (<NUM>/kg/day) for <NUM> days. Cohort #<NUM> was administered a single dose of <NUM>/kg of a lipid based formulation and then <NUM>/kg BID (<NUM>/kg/day) for <NUM> days. For cohort #<NUM> single dosing resulted in a mean Cmax of <NUM> ng/mL, mean Tmax of <NUM> hours and an AUCinf of <NUM>*ng/mL. For cohort #<NUM> single dosing resulted in a mean Cmax of <NUM> ng/mL, mean Tmax of <NUM> hours and an AUCinf of <NUM>*ng/mL. As demonstrated, lipid based formulations at twice the dosage and at a single dosing achieved nearly twice the maximum plasma concentration of the alcohol based formulations in nearly an hour and half longer.

At repeated BID dosing, administration of alcohol based oral cannabinoid formulations resulted in a mean Cmax of <NUM> ng/mL, mean Tmax of <NUM> hours and an AUCtau of <NUM>*ng/mL and the lipid based or al cannabinoid formulations resulted in a Cmax of <NUM> ng/mL, mean Tmax of <NUM> hours and an AUCtau of <NUM>*ng/mL. As demonstrated, lipid based formulations at twice the dosage and at administered BID for <NUM> days achieved less than twice the maximum plasma concentration of the alcohol based formulations twelve minutes faster.

An open label, randomized, single-dose, two-period, two-way crossover food-effect study was conducted on healthy subjects. The study assessed pharmacokinetics and safety of single-dose of <NUM>/kg/day cannabidiol (i.e. formulation #LF10 from Table <NUM>, above) administered under fasted or fed conditions. Twenty-four (<NUM>) subjects were enrolled in the study and each were subjected to the fasted and fed treatment arms in separate periods followed by a <NUM>-day wash-out period. For pharmacokinetic analysis, nominal time and default lambda-z selections were used. All below quantifiable limit values were set to zero and all subjects were included in the analysis.

Safety was assessed using the following parameters: inclusion/exclusion criteria, medical history and demographics, medical history update, continuing eligibility, physical examination, clinical laboratory testing, <NUM>-lead electrocardiogram (ECG), urine drug and alcohol screens, prior medication history, concomitant medication, seated blood pressure, pulse, respiration rate, and oral temperature, and adverse event (AE) assessments.

Data from <NUM> subjects from the fasted treatment and <NUM> subject from the fed treatment were included in the pharmacokinetic and statistical analyses.

Blood samples (<NUM> × <NUM>) for cannabidiol and <NUM>-OH-cannabidiol analysis were collected in Vacutainer tubes containing K<NUM>-EDTA as a preservative at <NUM> hour (predose), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> hours postdose (<NUM> time points) in each study period. The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), last quantifiable concentration determined directly from individual concentration-time data (Clast), time of last quantifiable concentration (Tlast), elimination rate constant (λz), terminal half-life (T<NUM>/<NUM>), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUC<NUM>-t), area under the plasma concentration time curve from time-zero extrapolated to infinity (AUCinf), percentage of AUCinf obtained by extrapolation (AUCextrap), calculated as AUCextrap = [(AUCinf - AUC<NUM>-t)/AUCinf]*<NUM>, apparent oral clearance (CL/F), calculated as: CL/F = Dose/AUCinf for dronabinol only, and volume of distribution in the terminal elimination phase (Vd/F), calculated as Vd/F = (CL/F)/ λZ for cannabidiol only.

Results of the pharmacokinetic and statistical analyses for the oral cannabinoid solutions of the present invention are shown in Tables <NUM>-<NUM>. Tables <NUM>-<NUM> shows the pharmacokinetic parameters of cannabidiol comparing administration to subjects in a fasted or fed condition.

Substantial increases in cannabidiol maximum and total exposure, based on ln(Cmax), ln(AUC<NUM>-t), and ln(AUC<NUM>-inf), were observed after administration of <NUM>/kg cannabidiol oral solution with food compared to <NUM>/kg cannabidiol oral solution administered under fasted conditions. Cannabidiol Cmax was approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. Cannabidiol AUC<NUM>-t and AUC<NUM>-inf were approximately <NUM>-fold and <NUM>-fold higher, respectively, after administration with food compared to administration under fasted conditions. Median time to reach maximum concentration of cannabidiol (Tmax) occurred approximately <NUM> hours earlier with food (<NUM> hours) compared to that under fasted conditions (<NUM> hours). Inter-subject variability was substantially reduced with food: <NUM>% CV from <NUM>% for Cmax and <NUM>% CV from <NUM>% for AUC<NUM>-inf.

Administration of oral cannabinoid solutions of the present invention under fed conditions resulted in an appreciable AUC difference in cannabidol over administration under fasted conditions within <NUM> minutes. Additionally, administration of oral cannabinoid solutions of the present invention under fed conditions resulted in <NUM> times greater AUC of cannabidol over administration under fasted conditions at <NUM> hours.

Tables <NUM>-<NUM> shows the pharmacokinetic parameters of <NUM>-OH-cannabidiol, the primary and active metabolite of cannabidiol, comparing oral cannabinoid solutions of the present invention under fasted and fed conditions.

Substantial increases in <NUM>-OH-cannabidiol maximum and total exposure, based on ln(Cmax), ln(AUC<NUM>-t), and ln(AUC<NUM>-inf), were observed after administration of <NUM>/kg cannabidiol oral solution with food compared to <NUM>/kg cannabidiol oral solution administered under fasted conditions. <NUM>-OH-cannabidiol Cmax was approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. <NUM>-OH-cannabidiol AUC<NUM>-t and AUC<NUM>-inf were both approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. Additionally, Tmax occurs <NUM> hours sooner under fed conditions.

Administration of oral cannabinoid solutions of the present invention under fed conditions resulted in an appreciable AUC difference in <NUM>-OH-cannabidiol over administration under fasted conditions within <NUM> minutes. Additionally, administration of oral cannabinoid solutions of the present invention under fed conditions resulted in <NUM> times greater AUC of <NUM>-OH-cannabidiol over administration under fasted conditions at <NUM> hours.

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

An open label, randomized, single-dose, four-treatment four-period, four-way crossover food-effect study of multiple formulations was conducted on healthy subjects. The study assessed pharmacokinetics of a single-dose of <NUM>/kg of <NUM> separate cannabidiol formulations (#LF41and #LF42 from Table <NUM> above and #A11 from Table <NUM> above) administered under fed conditions and <NUM> cannabidiol formulation (#LF42 above) under fasted conditions. Subjects were enrolled in the study and each was subjected to the fasted and fed treatment arms in separate periods followed by a <NUM>-day wash-out period. For pharmacokinetic analysis, nominal time and default lambda-z selections were used. All below quantifiable limit values were set to zero and all subjects were included in the analysis.

Substantial increases in both cannabidiol and <NUM>-OH-cannabidiol maximum and total exposure, based on ln(Cmax), ln(AUC<NUM>-t), and ln(AUC<NUM>-inf), were observed after administration of formulation #LF42 at <NUM>/kg with food compared to formulation #LF42 at <NUM>/kg administered under fasted conditions. Cannabidiol Cmax was approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. Cannabidiol AUC<NUM>-t and AUC<NUM>-inf were approximately <NUM>-fold and <NUM>-fold higher, respectively, after administration with food compared to administration under fasted conditions. <NUM>-OH-cannabidiol Cmax was approximately <NUM>. <NUM>-fold higher after administration with food compared to administration under fasted conditions. <NUM>-OH-cannabidiol AUC<NUM>-t and AUC<NUM>-inf were approximately <NUM>-fold and <NUM>-fold higher, respectively, after administration with food compared to administration under fasted conditions. Thus, there is a substantial food effect when administering lipid formulations of the present invention.

Substantial increases in both cannabidiol and <NUM>-OH-cannabidiol maximum and total exposure, based on ln(Cmax), ln(AUC<NUM>-t), and ln(AUC<NUM>-inf), were observed after administration of formulation #LF41 at <NUM>/kg with food compared to formulation #LF42 at <NUM>/kg administered under fasted conditions. Cannabidiol Cmax was approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. Cannabidiol AUC<NUM>-t and AUC<NUM>-inf were approximately <NUM>-fold and <NUM>-fold higher, respectively, after administration with food compared to administration under fasted conditions. <NUM>-OH-cannabidiol Cmax was approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. <NUM>-OH-cannabidiol AUC<NUM>-t and AUC<NUM>-inf were approximately <NUM>-fold and <NUM>-fold higher, respectively, after administration with food compared to administration under fasted conditions. Thus, there is a substantial food effect when administering medium chain glyceride formulations of the present invention.

Substantial increases in both cannabidiol and <NUM>-OH-cannabidiol maximum and total exposure, based on ln(Cmax), ln(AUC<NUM>-t), and ln(AUC<NUM>-inf), were observed after administration of formulation #A11 at <NUM>/kg with food compared to formulation #LF42 at <NUM>/kg administered under fasted conditions. Cannabidiol Cmax was approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. Cannabidiol AUC<NUM>-t and AUC<NUM>-inf were approximately <NUM>-fold and <NUM>-fold higher, respectively, after administration with food compared to administration under fasted conditions. <NUM>-OH-cannabidiol Cmax was approximately <NUM>-fold higher after administration with food compared to administration under fasted conditions. <NUM>-OH-cannabidiol AUC<NUM>-t and AUC<NUM>-inf were approximately <NUM>-fold and <NUM>-fold higher, respectively, after administration with food compared to administration under fasted conditions. Thus, there is a substantial food effect when administering hydro-alcohol formulations of the present invention.

A long-term safety study was conducted in pediatric patients with refractory epilepsy who had previously participated in a Phase <NUM>/<NUM> pharmacokinetic study to assess the pharmacokinetics and safety of multiple doses of pharmaceutical cannabidiol oral solution (MCT formulation, <NUM>/mL, administered BID) in pediatric subjects with treatment-resistant seizure disorder. This was a long-term, open-label, <NUM>-week study for pediatric subjects aged <NUM> year to <NUM> years with refractory epilepsy. This study is detailed in Example <NUM>, above.

<NUM> subjects (<NUM> infants, <NUM> children, and <NUM> adolescents) were enrolled and had received at least one dose of cannabidiol oral solution in the study. Seven subjects prematurely discontinued treatment and study participation. Eleven subjects completed treatment in the study, and thirty-four (<NUM>) subjects remained on treatment after the study. The study included <NUM> subjects aged <NUM> to <<NUM> years (infants); <NUM> subjects aged <NUM> to <<NUM> years (children), with ≥<NUM> subjects under the age of <NUM> years; <NUM> subjects aged <NUM> to ≤<NUM> years (adolescents), with ≥<NUM> subjects under the age of <NUM> years.

A preliminary review of the data from the long-term safety study showed weight loss. Analysis of the median percent change in weight showed a dose-dependent decrease in weight change at week <NUM>. The dose-dependency became less prominent over the course of the study (up to week <NUM>). This may be due to a fewer number of patients being included in the analysis and frequent shifting of dosing during the later time periods.

The mean modal dose (i.e., the dose with the longest duration) was <NUM>/kg/day, and the mean number of days on-study for all subjects was <NUM>. Overall, <NUM> subjects (<NUM>%) had dose reductions resulting from an Adverse Event ("AE"), and <NUM> subjects (<NUM>%) had dose reductions due to other reasons. The frequency of dose reductions was greater in the subjects receiving <NUM>/kg/day compared with subjects receiving <NUM>/kg/day (<NUM> subjects [<NUM>%] and <NUM> subjects [<NUM>%], respectively). Dose reductions resulting from an AE were more frequent among subjects receiving <NUM>/kg/day compared with subjects receiving <NUM>/kg/day (<NUM> subjects [<NUM>%] and <NUM> subject [<NUM>%], respectively). No subjects receiving <NUM>/kg/day and no infants had dose reductions.

Among children, <NUM> subjects (<NUM>%) had dose reductions resulting from an AE, and <NUM> subjects (<NUM>%) had dose reductions due to other reasons. The frequency of dose reductions was greater in the subjects receiving <NUM>/kg/day compared with subjects receiving <NUM>/kg/day (<NUM> subjects [<NUM>%] and <NUM> subjects [<NUM>%], respectively).

Among infants, <NUM> subjects (<NUM>%) were taking <NUM> to <<NUM>/kg/day, and <NUM> subjects (<NUM>%) were taking <NUM>/kg/day. Among children, <NUM> subjects (<NUM>%) were taking <NUM> to <<NUM>/kg/day, <NUM> subjects (<NUM>%) were taking <NUM> to <<NUM>/kg/day, and <NUM> subjects (<NUM>%) were taking <NUM>/kg/day. Among adolescents, <NUM> subjects (<NUM>%) were taking <NUM> to <<NUM>/kg/day, <NUM> subjects (<NUM>%) were taking <NUM> to <<NUM>/kg/day, and <NUM> subjects (<NUM>%) were taking <NUM>/kg/day.

Among adolescents, <NUM> subject (<NUM>%) had a dose reduction resulting from an AE, and <NUM> subject (<NUM>%) had a dose reduction due to other reasons. Both dose reductions occurred in subjects receiving <NUM>/kg/day.

Overall, <NUM> subject (<NUM>%) was taking <<NUM>/kg/day, <NUM> subjects (<NUM>%) were taking between <NUM> and <<NUM>/kg/day, <NUM> subjects (<NUM>%) were taking between <NUM> and <<NUM>/kg/day, and <NUM> subjects (<NUM>%) were taking ≥<NUM>/kg/day as of the data cut-off.

A total of <NUM> AEs were reported in <NUM> subjects; the most frequently reported AEs were anemia, diarrhea, constipation, pyrexia, upper respiratory tract infection, seizure, somnolence, and aggression. Overall, <NUM>% of subjects on the <NUM>/kg/day dose required dose reductions due to adverse events (AEs). However, many patients increased their dose over the duration of the study, with <NUM> subjects (<NUM>%) taking <NUM> to <<NUM>/kg/day and <NUM> subjects (<NUM>%) taking <NUM>/kg/day as of the data cut-off. Cannabidiol oral solution was safe and well-tolerated even at doses as high as <NUM>/kg/day.

Weight increase and somnolence that were related to the CBD were each reported in <NUM> subjects (<NUM>%). Compared with the mean weight of all subjects at baseline (<NUM>), mean weight increased at Week <NUM> (+<NUM>). Mean weight continued to increase during the study (+<NUM> at week <NUM>, +<NUM> at Final Visit/Discontinuation Visit, and +<NUM> at Follow-Up Visit).

There was a dose-response decrease in weight gain with the maximum effect seen at the <NUM>/kg/day dose (Figure <NUM>). These data indicate that cannabidiol oral solution at <NUM>/mL up to doses of <NUM>/kg/day are safe and generally well-tolerated, and data from the long-term safety study indicate that the <NUM>/kg/day may be the most efficacious for both seizure control as well as the effect on weight gain.

Prader-Willi Syndrome ("PWS"), is a multifaceted developmental disorder and the most common genetic syndrome associated with obesity (McAllister and Whittington, <NUM>; Gunay-Aygun et al. It is caused by the absent expression of paternally-inherited genes in the PWS region on 15q11-q13 (Ledbetter et al. While it presents with generalized hypotonia and developmental delay in infancy, PWS then manifests with uncontrollable appetite, hyperphagia, and excessive weight gain leading to severe obesity (Grechi et al.

Clinically, PWS patients suffer a complex pattern of physical, behavioral, endocrine, and intellectual deficiencies. Endocrine abnormalities lead to hypogonadism and short stature. In particular, growth hormone deficiency is reported to occur in <NUM>% to <NUM>% of the population (Griggs et al. , <NUM>) and is commonly treated with growth hormone (Butler et al. Behavioral disorders include obsessive compulsive behaviors such as skin picking, hoarding, re-doing and repetitive speech (Griggs et al, <NUM>).

The greatest unmet medical need in Prader-Willi Syndrome is the hyperphagia and related behaviors leading to morbid obesity and diabetes and their resulting cardiovascular complications. Cannabidiol (CBD) is a low-affinity antagonist of CB1, but it may also modulate CB1 receptor signaling through its inhibition of the metabolism of the endogenous cannabinoid, anandamide (Ibeas Bih et al. As for appetite, CBD has been shown to decrease food intake in rats under stressful conditions and reduce ad lib intake of high-sugar feed when compared to vehicle-treated controls (Silveira Filho and Tufik, <NUM>). In addition, CBD has been shown to diminish daily food consumption without affecting daily water intake (Wierbucka-Ryback and Bojanowska, <NUM>) as well as inhibited hyperphagia induced by cannabinoid (CB1) or <NUM>- hydroxytryptamine (<NUM>-HT1A) serotonin receptor agonists suggesting a role for CBD as a regulator of food intake (Scopinho et al. Thus, cannabidiol (CBD) may have the potential to address the hyperphagia associated with Prader-Willi Syndrome patients.

The following study is ongoing and no results yet been recorded.

A Phase <NUM>, multi-center, randomized, placebo-controlled, parallel-group study will be conducted to assess the efficacy, safety of cannabidiol oral solution as an adjunctive therapy in infantile spasm patients with either vigabatrin or adrenocorticotropic hormone ("ACTH") as the initial therapy.

The study will be comprised of Part A and Part B. Part A includes <NUM> periods: a Screening Period (<NUM> to <NUM> days), a Titration period (<NUM> or more days), a Treatment Period (<NUM> days), a Taper Period (approximately <NUM>±<NUM> days) for patients who elect not to enroll in the open-label long-term safety study, and a Follow-up Period (<NUM>±<NUM> days). The overall maximum study duration is expected to be approximately <NUM> days. Part B will consist of a Safety Treatment Period (<NUM> weeks), Tapering (<NUM> weeks), and a follow up period (<NUM> days). The overall study duration is expected to be <NUM> weeks for those patients who complete the Safety period.

<NUM> Eligible subjects will be selected from children aged <NUM> months through <NUM> months with a diagnosis of infantile spasms and will be randomized equally into one of six treatment groups:
<NUM>) vigabatrin, <NUM>) vigabatrin plus <NUM> milligrams per kilogram per day ("mg/kg/day") cannabidiol oral solution <NUM>) vigabatrin plus <NUM>/kg/day cannabidiol oral solution vigabatrin, <NUM>) ACTH, <NUM>) ACTH plus <NUM> milligrams per kilogram per day ("mg/kg/day") cannabidiol oral solution and <NUM>) ACTH plus <NUM>/kg/day cannabidiol oral solution.

Specifically, twenty subjects will be enrolled in each dose cohort that A) fit the following criteria: <NUM>. parent(s)/caregiver(s) fully comprehends and signs the informed consent form, understands all study procedures, and can communicate satisfactorily with the Investigator and study coordinator; <NUM>. provide informed consent of patients and /or parent(s)/caregiver(s) in accordance with applicable laws, regulations, and local requirements; <NUM>. male or female between <NUM> month to <NUM> months of age (inclusive) at time of consent; <NUM>. clinical diagnosis of infantile spasms, confirmed by video-EEG analysis (including at least one cluster of electro clinical spasms [≥<NUM> in any <NUM>-minute epoch]) obtained during the Screening Period and read by the Investigator. general good health (defined as the absence of any clinically relevant abnormalities as determined by the Investigator) based on physical and neurological examinations, medical history, and clinical laboratory values completed during the Screening Visit (Visit <NUM>); and <NUM>. in the opinion of the Investigator, the parent(s)/caregiver(s) are willing and able to comply with the study procedures and visit schedules, and B) do not meet the following criteria: <NUM>) is considered by the Investigator, for any reason (including, but not limited to, the risks described as precautions, warnings, and contraindications in the current version of the Investigator's Brochure for Cannabidiol Oral Solution) to be an unsuitable candidate to receive the study drug; <NUM>) known or suspected allergy to Cannabidiol Oral Solution; <NUM>) use of any Cannabidiol/cannabis product within <NUM> days of study entry; <NUM>) patient is diagnosed or suspected of having Tuberous Sclerosis; <NUM>) patient has received treatment with either Vigabatrin, ACTH, or high-dose steroids previously; <NUM>) previous therapy with felbamate, clobazam, or the ketogenic diet; <NUM>) positive drug screen for THC; or <NUM>) patient currently on any disallowed medication listed in Appendix <NUM> (e.g., phenytoin, fluvoxamine, carbamazepine, and St. Johns Wort).

The study will be conducted in the following parts. Part A: video-electroencephalography ("EEG") will be conducted during the screening period and repeated at Day <NUM> and overnight at Day <NUM> for each treatment group. Response to treatment will be scored using the following methodology: <NUM>) complete response- complete resolution of spasms and hypsarrythmia (if present at baseline) confirmed by video-EEG at Day <NUM>; <NUM>) partial response- substantive change in background EEG or reduction in spasms on video-EEG obtained at Day <NUM>; and <NUM>) no response- no improvement or worsening of spasms/hypsarrythmia burden at Day <NUM>.

Part B: After Day <NUM>, patients who volunteer may participate in the long-term safety phase. Treatment visits will be scheduled monthly for <NUM> months, and then quarterly thereafter.

The primary efficacy endpoint will be the percent of subjects who are considered complete responders at Day <NUM>, defined as complete resolution of spasms and hypsarrhythmia, confirmed by video-EEG as determined by the Independent Central Reader.

The secondary efficacy endpoints will be: <NUM>) percent of subjects with absence of infantile spasms at Day <NUM>; <NUM>) percent of subjects with absence of hypsarrhythmia at Day <NUM>; <NUM>) median reduction in seizure-burden comparing video-EEG at Screening to repeat video-EEG at Day <NUM>; and <NUM>) parent impression of efficacy and tolerability of study drug (CGIC) at Study Completion/Early Discontinuation (Visit <NUM>).

The exploratory efficacy endpoints will be <NUM>) percent of spasm-free days at Day <NUM> comparing either vigabatrin or ACTH with CBD versus vigabatrin or ACTH alone and <NUM>) correlation between plasma drug levels and response.

The safety endpoints will be: <NUM>) the incidence of treatment-emergent adverse events ("AE"); <NUM>) clinical laboratory assessments; <NUM>) vital signs (blood pressure, pulse rate, respiration rate, and temperature); <NUM>) physical and neurological examination assessments; <NUM>) urine; <NUM>) THC screen; <NUM>) medical history and <NUM>) prior and concomitant medications.

The pharmacokinetic endpoints will be trough concentrations (Ctrough) of cannabidiol and metabolite <NUM>-hydoxy-cannabidiol ("<NUM> OH-CBD") drawn prior to dosing and at hours <NUM>,<NUM>, and <NUM> after dose at Visits <NUM> and <NUM> to assess exposure-response relationships. A food diary will be used to record the type of meals consumed in relation to the pharmacokinetic blood draws.

Once the patient has been approved for the study, they will return to the study clinic where the physician will prescribe either vigabatrin or ACTH and the patient will be randomized to the appropriate study arm. The following activities will be completed: <NUM>. review of inclusion and exclusion criteria; <NUM>) obtain a urine sample for urinalysis; <NUM>. record concomitant medications and concomitant procedures; <NUM>. record vital signs (blood pressure, pulse rate, respiratory rate, and temperature measurements); <NUM>. perform a complete physical examination including height and weight. The weight obtained on during this visit will be used to calculate the dose volume. The dosing volume will remain constant throughout the Titration and Treatment Periods. Draw blood samples for hematology and chemistry; <NUM>. perform a brief neurology examination and <NUM>. record AEs and serious AEs ("SAE").

Once the prescribed ACTH or vigabatrin is ready to be dispensed, the subject will be admitted to the study center as an inpatient on Day <NUM>. The following procedures and assessments must be performed on Day <NUM> for all subjects prior to IP administration on Day <NUM>; <NUM>. record concomitant medications and concomitant procedures; <NUM>. Perform a brief neurology examination; <NUM>. record vital signs (blood pressure, pulse rate, respiratory rate, and temperature measurements), <NUM>. record and Review Daily Seizure Diary; <NUM>. record AEs and SAEs and <NUM>. perform a <NUM>-hour video-EEG.

Patients will be dosed twice daily (i.e., full daily dose of <NUM>, <NUM>, or <NUM>/kg/day) from Day <NUM> through Day <NUM> according to the subject's assigned cohort. Doses will be administered at approximately <NUM>-hour intervals. Patients will be released from the study center after assessments and the <NUM>-hour pharmacokinetic blood draw are complete. The final dose of the investigational product will be administered in the evening on Day <NUM>. Patients will be admitted for an End of Therapy visit on Day <NUM>, which will include a <NUM>-hour video EEG.

Claim 1:
An oral pharmaceutical formulation comprising:
cannabidiol; and
a vehicle selected from the group consisting of a lipid, water, ethanol, glycerin, propylene glycol, polyethylene glycol <NUM> and a combination thereof;
wherein the formulation is for use in a method of treating hyperphagia as a symptom of Prader-Willi syndrome;
and wherein the effective amount administered is from <NUM> to <NUM> milligrams cannabidiol per kilogram per day.