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.

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, mycolonic seizures, juvenile mycolonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, refractory infantile spasms, infantile spasms, tubular 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.

<CIT> relates to oral cannabinoid formulations, including an aqueous-based oral dronabinol solution that are stable at room or refrigerated temperatures and may possess improved in vivo absorption profiles with faster onset and lower inter-subject variability.

<CIT> relates to a room temperature stable cannabinoid formulation. Preferably the cannabinoid formulation is dronabinol in an oil-based carrier contained within a hard gelatin capsule.

Accordingly, there is a need for new stable cannabinoid formulations.

The present invention is directed to stable pharmaceutical formulations for oral administration comprising from about <NUM> to about <NUM> % of a cannabinoid, from about <NUM> to about <NUM> % of a polyethylene glycol, 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>.

Applicant unexpectedly created new storage stable formulations containing cannabinoids. Applicant determined that a pH of from about <NUM> to about <NUM> is critical for the formulations to remain stable, preferably from about <NUM> to about <NUM>. For example, as seen in Example <NUM> below, the alcohol-free formulations # AF3 and # AF4 exhibited excellent stability for four weeks regardless of the temperature and humidity conditions. Applicant also determined that an antioxidant is important to maintain stability during long-term storage. These results were not expected because formulation science is incredibly difficult to predict and many otherwise suitable formulations for pharmaceutical use are not stable during storage.

As indicated above, Applicant created stable formulations 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.

The present invention is directed to stable pharmaceutical formulation for oral administration comprising from about <NUM> to about <NUM> % of a cannabinoid, from about <NUM> to about <NUM> % of a polyethylene glycol, 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>.

The present invention is defined by the claims below.

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

In yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, 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 cannabinoid is cannabidiol.

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, 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, monothioglycerol and combinations thereof. In a preferred embodiment, the formulations contain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorabte, ascobyl palminate or combinations thereof.

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> %, from about <NUM> to about <NUM> %, from about <NUM> to about <NUM> %, or 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> %, 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, 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.

The formulations of the present invention are especially suitable for treatment of many diseases or disorders or symptoms of diseases and disorders. Further, cannabidiol which is synthetically synthesized and substantially pure will be even more effective and suitable for the treatment of diseases or symptoms of these diseases.

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).

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating a brain tumor
In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating glioma.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating glioblastoma multiforme.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating Dravet Syndrome.

In yet another embodiment, the present invention is directed to formulations of the present invention for use in methods of treating Lennox Gastaut Syndrome.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating Mycolonic Seizures. In a more preferred embodiment, the alcohol-free formulations contain substantially pure cannabidiol.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating Juvenile Mycolonic Epilepsy. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating Refractory Epilepsy. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating juvenile spasms. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating West Syndrome. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating infantile spasms. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating refractory infantile spasms. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating tubular sclerosis complex. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods for treating neuropathic pain. In a further embodiment, the neuropathic pain is caused by neurotoxic chemotherapy agents such as Paclitaxel, Docetaxel, Cisplatin, Oxaliplatin, Carboplatin, Vincristine, Methotrexate, Cytarabine, Fluorouracil, Ifosfamide, Cyclophosphamide, Procarbazine, etoposide, Carmustine, and Lomustine. In yet another embodiment, the neuropathic pain is caused by Paclitaxel and the patient is receiving Paclitaxel due to a diagnosis of breast, cervical, endometrial and/or ovarian cancer. In a further embodiment, the breast, cervical, endometrial and/or ovarian cancer is platinum-resistant. In another embodiment, the breast, cervical, endometrial and/or ovarian cancer is recurrent.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of using cannabidiol as an analgesic.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating opioid addiction withdrawal.

In yet another embodiment, the present invention is directed to formulations of the present invention for use in methods of treating cocaine addiction withdrawal.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating heroin addiction withdrawal.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating nicotine addiction withdrawal.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating amphetamine addiction withdrawal.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating acne.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating Parkinson's disease.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating schizophrenia.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating social anxiety disorder.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating depression comprising administering the formulations of the present invention to a patient in need thereof.

In a further embodiment, the present invention is directed to formulations of the present invention for use in methods of treating patients encountering adverse emotional stimuli.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating nausea.

In an embodiment, the present invention is directed to formulations of the present invention for use in methods of treating multiple sclerosis.

In an embodiment, the invention is directed to formulations of the present invention for use in methods of treating symptoms of cannabis use disorder.

In another embodiment, the invention is directed to formulations of the present invention for use in methods of treating symptoms of early psychosis.

In another embodiment, the invention is directed to formulations of the present invention for use in methods of treating symptoms of Alzheimer's Disease.

In yet another embodiment, the invention is directed to formulations of the present invention for use in methods of treating symptoms of post-traumatic stress disorder ("PTSD").

In an embodiment, the invention is directed to formulations of the present invention for use in methods of treating symptoms of anxiety.

In a further embodiment, the invention is directed to formulations of the present invention for use in methods of treating symptoms of autism.

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 to 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.

Claim 1:
A stable pharmaceutical formulation for oral administration comprising
from <NUM> to <NUM> % w/w of a cannabinoid;
from <NUM> to <NUM> % w/w of a polyethylene glycol;
from <NUM> to <NUM> % w/w of propylene glycol; and
optionally from <NUM> to <NUM> % w/w of water,
wherein the formulation does not contain alcohol and
the formulation has a pH of from <NUM> to <NUM>.