Nothing Special   »   [go: up one dir, main page]

US20220184215A1 - Stable cannabinoid formulations - Google Patents

Stable cannabinoid formulations Download PDF

Info

Publication number
US20220184215A1
US20220184215A1 US17/559,155 US202117559155A US2022184215A1 US 20220184215 A1 US20220184215 A1 US 20220184215A1 US 202117559155 A US202117559155 A US 202117559155A US 2022184215 A1 US2022184215 A1 US 2022184215A1
Authority
US
United States
Prior art keywords
cannabidiol
formulations
bql
present
patient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
US17/559,155
Inventor
Kiran Kumar Vangara
Huaguang Li
Ningxin Yan
Hung Q. Nguyen
Venkat R. Goskonda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fresh Cut Development LLC
Original Assignee
Radius Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US17/559,155 priority Critical patent/US20220184215A1/en
Application filed by Radius Pharmaceuticals Inc filed Critical Radius Pharmaceuticals Inc
Assigned to FRESH CUT DEVELOPMENT, LLC reassignment FRESH CUT DEVELOPMENT, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BENUVIA THERAPEUTICS INC.
Assigned to INSYS DEVELOPMENT COMPANY, INC. reassignment INSYS DEVELOPMENT COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: INSYS PHARMA, INC.
Assigned to INSYS DEVELOPMENT COMPANY, INC. reassignment INSYS DEVELOPMENT COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOSKONDA, VENKAT R., LI, HUAGUANG, NGUYEN, HUNG Q., VANGARA, KIRAN KUMAR, YAN, Ningxin
Assigned to FRESH CUT DEVELOPMENT, LLC reassignment FRESH CUT DEVELOPMENT, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: INSYS DEVELOPMENT COMPANY, INC., INSYS PHARMA, INC., INSYS THERAPEUTICS, INC.
Assigned to BENUVIA THERAPEUTICS INC. reassignment BENUVIA THERAPEUTICS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRESH CUT DEVELOPMENT, LLC
Assigned to RADIUS PHARMACEUTICALS, INC. reassignment RADIUS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRESH CUT DEVELOPMENT, LLC
Assigned to RADIUS PHARMACEUTICALS, INC. reassignment RADIUS PHARMACEUTICALS, INC. CHANGE OF ADDRESS Assignors: RADIUS PHARMACEUTICALS, INC.
Publication of US20220184215A1 publication Critical patent/US20220184215A1/en
Assigned to WILMINGTON TRUST, NATIONAL ASSOCIATION reassignment WILMINGTON TRUST, NATIONAL ASSOCIATION SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RADIUS HEALTH, INC.
Assigned to RADIUS HEALTH, INC. reassignment RADIUS HEALTH, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: WILMINGTON TRUST, NATIONAL ASSOCIATION
Assigned to FRESH CUT DEVELOPMENT, LLC reassignment FRESH CUT DEVELOPMENT, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RADIUS PHARMACEUTICALS, INC.
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is generally directed to substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of their use.
  • Cannabinoids are chemicals that are produced by cannabis flowers. Cannabinoids imitate endogenous compounds in humans.
  • Cannabinoids include cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta9-tetrahydrocannabinol, levonantradol, delta-11-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.
  • cannabidiol ( ⁇ )-trans-2-p-mentha-1,8-di en-3 -yl-5-pentylresorcinol, is non-psychoactive and has shown promise in treating numerous diseases and disorders.
  • Synthetic cannabidiol has the same structure as naturally occurring cannabidiol.
  • cannabidiol is usually contaminated with delta 9-tetrahydrocannabinol.
  • the presence of delta-9-tetrahydrocannabinol can be a concern because delta-9-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.
  • delta-9-tetrahydrocannabinol is a hallucinogen and patients receiving cannabidiol wish to avoid this undesirable side effect of the delta-9-tetrahydrocannabinol contaminant. Therefore, there is a need for a substantially pure synthetically synthesized cannabidiol that does not contain delta-9-tetrahydrocannabinol.
  • Cannnabinoids including cannabidiol
  • Cannnabinoids 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.
  • 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
  • the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 50% of a cannabinoid, from about 0.1 to about 40% of a polyethylene glycol, from about 0.1 to about 50% of propylene glycol, and from about 0.1 to about 20% of water, wherein the formulation does not contain alcohol and the formulation has a pH of from about 5 to about 8.
  • the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40% of a cannabinoid, from about 0.1 to about 25% of a polyethylene glycol, from about 0.1 to about 40% of propylene glycol, optionally from about 0.1 to about 50% of water; and from about 0.1 to about 70% of alcohol, wherein the formulation has a pH of from about 5 to about 8.
  • the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40% of a cannabinoid and from about 10 to about 95% of a lipid.
  • the invention is directed to methods of using a cannabinoid or substantially pure, synthetically synthesized cannabidiol: to treat 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, infantile spasms, refractory infantile spasms, tubular sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's Disease, and autism; to assist with withdrawal from opioids, cocaine, heroin, amphetamines and nicotine; and as an analgesic or to assist with handling of adverse emotional stimuli.
  • diseases or disorders such as Dravet Syndrome, Lennox Gastaut Syndrome, mycolonic seizures, juvenile mycolonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, infantile spasms, refractory
  • FIG. 1 shows the results from the study detailed in Example 7 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations for treatment of neuropathic pain.
  • FIG. 2 shows the results from the study detailed in Example 9 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations for treatment of glioblastoma multiforme.
  • Applicant unexpectedly created new storage stable formulations containing cannabinoids.
  • Applicant determined that a pH of from about 5 to about 8 is critical for the formulations to remain stable, preferably from about 6 to about 7.
  • the alcohol-free formulations #AF3 and #AF4 exhibited excellent stability for four weeks regardless of the temperature and humidity conditions.
  • the alcohol containing formulations #A7 and #A8 exhibited excellent stability for at least 12 months regardless of the temperature and humidity conditions.
  • Applicant also determined that an antioxidant is important to maintain stability during long-term storage.
  • Applicant created stable formulations with and without alcohol (see Examples 1 and 3).
  • the formulations that do not contain alcohol are especially suitable for administration to children.
  • the alcohol-free formulations are especially suitable for patients in recovery from drug and alcohol addiction.
  • substantially pure cannabidiol formulations are especially suitable for treatment of epilepsy (see Examples 8, 10 and 11), neuropathic pain (see Example 7 and FIG. 1 ), and glioblastoma multiforme (see Example 9 and FIG. 2 ).
  • the present invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 50% of a cannabinoid, from about 0.1 to about 40% of a polyethylene glycol, from about 0.1 to about 50% of propylene glycol, and from about 0.1 to about 20% of water, wherein the formulation does not contain alcohol and the formulation has a pH of from about 5 to about 8.
  • the formulations contain from about 1 to about 40% of a cannabinoid. In more preferred embodiments, the formulations contain from about 5 to about 35%, from about 20 to about 35% or from about 30 to 35% of a cannabinoid.
  • the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, acids, analogs, and synthetic derivatives thereof.
  • the cannabinoid is cannabidiol.
  • the formulations contain from about 1 to about 40% of a cannabidiol. In more preferred embodiments, the formulations contain from about 5 to about 35%, from about 20 to about 35% or from about 30 to 35% of a cannabidiol.
  • the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98%. In a more preferred embodiment, the cannabidiol is greater than 99% pure. In an even more preferred embodiment, the cannabidiol is greater than 99.5% pure. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.
  • the formulations contain from about 0.001 to about 1% of an antioxidant. In a preferred embodiment, the formulations contain from about 0.01 to about 1% antioxidant. In a more preferred embodiment, the formulations contain from about 0.02 to about 0.5% 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.
  • the formulations contain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorabte, ascobyl palminate or combinations thereof
  • the formulations contain from about 1 to about 40% of a polyethylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 35%, from about 5 to about 35%, from about 20 to about 30%, or from about 25 to about 30% polyethylene glycol.
  • Suitable polyethylene glycols include low molecular weight polyethylene glycols with an average molecular weight of between 200 and 10,000.
  • One preferred polyethylene glycol that can be used is polyethylene glycol 400.
  • the formulations contain from about 1 to about 40% of polyethylene glycol 400. In a preferred embodiment, the formulations contain from about 1 to about 35%, from about 5 to about 35%, from about 20 to about 30%, or from about 25 to about 30% polyethylene glycol 400.
  • the formulations contain from about 1 to about 50% of propylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 40%, from about 5 to about 35%, from about 20 to about 35%, or from about 30 to about 35% propylene glycol.
  • the formulations contain water.
  • the formulations can contain 0% water. If the formulations contain water, they can include from about 1 to about 15% water, from about 1 to about 10% water, or from about 4 to about 8% water.
  • the pH of the formulations may be modified using any pharmaceutically acceptable means.
  • the pH of the formulation is from about 5 to about 8.
  • the pH of the formulations is from about 6 to about 7.
  • the pH of the formulations is from about 6.2 to about 6.7.
  • 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.
  • the formulations contain a sweetener
  • the formulations preferably contain from about 0.001 to about 1% sweetener.
  • the formulations contain a sweetness enhancer
  • the formulations preferably contain from about 0.001 to about 1% 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.
  • the formulations contain strawberry flavor.
  • the formulations contain a flavoring agent
  • the formulations preferably contain from about 0.001 to about 1% flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0.5% of the flavoring agent.
  • the formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration.
  • the formulations are liquids administered orally.
  • the invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 40% of a cannabinoid, from about 0.1 to about 25% of a polyethylene glycol, from about 0.1 to about 40% of propylene glycol, optionally from about 0.1 to about 50% of water, and from about 0.1 to about 70% of alcohol, wherein the formulation has a pH of from about 5 to about 8.
  • the formulations contain from about 1 to about 35% of a cannabinoid. In a more preferred embodiment, the formulations contain from about 1 to about 15%, from about 5 to about 12% or from about 7 to about 11% cannabinoid. Alternatively, the formulations may contain from about 20 to about 35% or from about 30 to about 35% cannabinoid.
  • the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, acids, analogs, and synthetic derivatives thereof.
  • the cannabinoid is cannabidiol.
  • the formulations contain from about 1 to about 35% of a cannabidiol. In a more preferred embodiment, the formulations contain from about 1 to about 15%, from about 5 to about 12% or from about 7 to about 11% cannabidiol. Alternatively, the formulations may contain from about 20 to about 35% or from about 30 to about 35% cannabidiol.
  • the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98%. In a more preferred embodiment, the cannabidiol is greater than 99% pure. In an even more preferred embodiment, the cannabidiol is greater than 99.5% pure. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.
  • the formulations contain from about 0.001 to about 1% of an antioxidant. In a preferred embodiment, the formulations contain from about 0.01 to about 1% antioxidant. In a more preferred embodiment, the formulations contain from about 0.02 to about 0.5% 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, and combinations thereof.
  • the formulations contain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorabte, ascobyl palminate or combinations thereof.
  • the formulations contain from about 1 to about 20% of propylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 15% or from about 5 to about 10% propylene glycol.
  • the formulations contain from about 20 to about 50% of propylene glycol. In a preferred embodiment, the formulations contain from about 30 to about 40% or from about 30 to about 35% propylene glycol.
  • the formulations contain from about 1 to about 20% of a polyethylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 10% or from about 1 to about 5% polyethylene glycol.
  • the formulations contain from about 10 to about 20% of a polyethylene glycol. In a preferred alternative embodiment, the formulations contain from about 15 to about 20% polyethylene glycol.
  • Suitable polyethylene glycols include low molecular weight polyethylene glycols with an average molecular weight of between 200 and 10,000.
  • One preferred polyethylene glycol that can be used is polyethylene glycol 400.
  • the formulations contain from about 1 to about 20% of polyethylene glycol 400. In a preferred embodiment, the formulations contain from about 1 to about 10% or from about 1 to about 5% polyethylene glycol 400.
  • the formulations contain from about 10 to about 20% of polyethylene glycol 400. In a preferred alternative embodiment, the formulations contain from about 15 to about 20% polyethylene glycol 400.
  • the formulations contain water.
  • the formulations can contain 0% water. If the formulations contain water, they can include from about 1 to about 40% water, from about 5 to about 40% water, from about 10 to about 35% water or from about 25 to about 35% water.
  • the formulations contain from about 1 to about 65% alcohol. In a preferred embodiment, the formulations contain from about 10 to about 65%, from about 15 to about 60%, or from about 30 to 55% alcohol.
  • the formulations contain from about 1 to about 20% alcohol. In a preferred alternative embodiment, the formulations contain from about 1 to about 10% or from about 3 to about 7% alcohol.
  • the pH of the formulations may be modified using any pharmaceutically acceptable means.
  • the pH of the formulations is from about 6 to about 7.
  • the pH of the formulations is from about 6.2 to about 6.7.
  • the formulations of the present invention may also contain sweeteners, sweetener enhancers, pH modifiers, preservatives, and flavoring agents.
  • Suitable sweeteners include, but are not limited to, sucrose, aspartame, saccharin, dextrose, mannitol, xylitol, and combinations thereof.
  • the formulations contain a sweetener
  • the formulations preferably contain from about 0.001 to about 1% sweetener.
  • 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.
  • the formulations contain a sweetness enhancer
  • the formulations preferably contain from about 0.001 to about 1% sweetness enhancer.
  • 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.
  • the formulations contain fruit punch flavor, raspberry flavor, grape flavor, or lemon mint flavor.
  • the formulations contain a flavoring agent
  • the formulations preferably contain from about 0.001 to about 1% flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0.5% of the flavoring agent.
  • the formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration.
  • the formulations are liquids administered orally.
  • the invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 40% of a cannabinoid and from about 10 to about 95% of a lipid.
  • 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, medium chain glycerides, decanoyl glycerides, octanoyl glycerides, caprylic/capric triglycerides, oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, polyglyceryl-3 dioleate, glyceryl monolinoleate, glyceryl monocaprylate, oleic acid, and a combination thereof.
  • the lipid is selected from the group consisting of sesame oil, sunflower oil, soybean oil, corn oil, a mixture of decanoyl glycerides and octanoyl glycerides, and a combination thereof.
  • Suitable commercial sources for the lipid include Miglyol® 812N containing a proprietary mixture of decanoyl and octanoyl glycerides (fatty acid esters) and Miglyol® 810N also containing a proprietary mixture of decanoyl and octanoyl fatty acids from coconut oil (Miglyol is available from and a registered trademark of Cremer Oleo GmbH & Co.).
  • the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, acids, analogs, and synthetic derivatives thereof.
  • the cannabinoid is cannabidiol.
  • the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98%. In a more preferred embodiment, the cannabidiol is greater than 99% pure. In an even more preferred embodiment, the cannabidiol is greater than 99.5% pure. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.
  • the formulations contain from about 1 to about 35% of a cannabidiol. In a more preferred embodiment, the formulations contain from about 10 to about 32% cannabidiol. In a most preferred embodiment, the formulations contain from about 17 to about 29% cannabidiol.
  • the formulations contain from about 20 to about 90% of lipids. In a more preferred embodiment, the formulations contain from about 50 to about 90% lipids. In a most preferred embodiment, the formulations contain from about 60 to about 85% lipids.
  • the formulations contain alcohol.
  • the formulations can contain 0% alcohol. If the formulations contain alcohol, they can include from about 0.1 to about 20% alcohol. In a preferred embodiment, the formulations contain from about 3 to about 17% alcohol. In a more preferred embodiment, the formulations contain from about 5 to about 15% alcohol.
  • the formulations contain an antioxidant.
  • the formulations can contain 0% antioxidant. If the formulations contain antioxidant, they can include from about 0.01 to about 1% of an antioxidant. In a preferred embodiment, the formulations contain from about 0.02 to about 0.5% antioxidant. In a more preferred embodiment, the formulations contain from about 0.03 to about 0.1% 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, and combinations thereof.
  • the formulations contain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorabte, ascobyl palminate or combinations thereof.
  • Suitable sweeteners include, but are not limited to, sucrose, aspartame, saccharin, dextrose, mannitol, xylitol, and combinations thereof.
  • the formulations preferably contain from about 0.1 to about 2% sweetener. In a more preferred embodiment, the formulations contain from about 0.1 to about 0.8% sweetener. In a most preferred embodiment, the formulations contain from about 0.2 to about 0.5% sweetener.
  • 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.
  • the formulations contain a sweetness enhancer
  • the formulations preferably contain from about 0.001 to about 1% sweetness enhancer.
  • 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.
  • the formulations contain a flavoring agent
  • the formulations preferably contain from about 0.01 to about 1% flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0.5% of the flavoring agent.
  • the formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration.
  • the formulations are liquids administered orally.
  • compositions 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.
  • 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 methods for treating a brain tumor comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating a brain tumor comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating glioma comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating glioma comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating glioblastoma multiforme comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating glioblastoma multiforme comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating Dravet Syndrome comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating Dravet Syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating Lennox Gastaut Syndrome comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating Lennox Gastaut Syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof
  • the present invention is directed to methods for treating Mycolonic Seizures comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations contain substantially pure cannabidiol.
  • the present invention is directed to methods for treating Mycolonic Seizures comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof
  • the present invention is directed to methods for treating Juvenile Mycolonic Epilepsy comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • the present invention is directed to methods for treating Juvenile Mycolonic Epilepsy comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating Refractory Epilepsy comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • the present invention is directed to methods for treating Refractory Epilepsy comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating juvenile spasms comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • the present invention is directed to methods for treating juvenile spasms comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating West Syndrome comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • the present invention is directed to methods for treating West Syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating infantile spasms comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • the present invention is directed to methods for treating infantile spasms comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating refractory infantile spasms comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • the present invention is directed to methods for treating refractory infantile spasms comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating tubular sclerosis complex comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • the present invention is directed to methods for treating tubular sclerosis complex comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating neuropathic pain comprising administering the formulations of the present invention to a patient in need thereof.
  • 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.
  • 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.
  • the breast, cervical, endometrial and/or ovarian cancer is platinum-resistant.
  • the breast, cervical, endometrial and/or ovarian cancer is recurrent.
  • the present invention is directed to methods for treating neuropathic pain comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • 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.
  • neurotoxic chemotherapy agents such as Paclitaxel, Docetaxel, Cisplatin, Oxaliplatin, Carboplatin, Vincristine, Methotrexate, Cytarabine, Fluorouracil, Ifosfamide, Cyclophosphamide, Procarbazine, etoposide, Carmustine, and Lomustine.
  • 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.
  • the breast, cervical, endometrial and/or ovarian cancer is platinum-resistant.
  • the breast, cervical, endometrial and/or ovarian cancer is recurrent.
  • the present invention is directed to methods for using cannabidiol as an analgesic comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for using cannabidiol as an analgesic comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating opioid addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • the present invention is directed to methods for treating opioid addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating cocaine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • the present invention is directed to methods for treating cocaine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating heroin addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • the present invention is directed to methods for treating heroin addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating nicotine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • the present invention is directed to methods for treating nicotine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating amphetamine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • the present invention is directed to methods for treating amphetamine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating acne comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating acne comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating Parkinson's disease comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating Parkinson's disease comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof
  • the present invention is directed to methods for treating schizophrenia comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating schizophrenia comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating social anxiety disorder comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating social anxiety disorder comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating depression comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating depression comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating patients encountering adverse emotional stimuli comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating patients encountering adverse emotional stimuli comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating nausea comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating nausea comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the present invention is directed to methods for treating multiple sclerosis comprising administering the formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating multiple sclerosis comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the invention is directed to methods for treating symptoms of cannabis use disorder comprising administering formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • the present invention is directed to methods for treating symptoms of cannabis use disorder comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the invention is directed to methods for treating symptoms of early psychosis comprising administering formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating symptoms of early psychosis comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the invention is directed to methods for treating symptoms of Alzheimer' s Disease comprising administering formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating symptoms of Alzheimer's Disease comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the invention is directed to methods for treating symptoms of post-traumatic stress disorder (“PTSD”) comprising administering formulations of the present invention to a patient in need thereof.
  • PTSD post-traumatic stress disorder
  • the present invention is directed to methods for treating symptoms of post-traumatic stress disorder PTSD comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the invention is directed to methods for treating symptoms of anxiety comprising administering formulations of the present invention to a patient in need thereof.
  • the present invention is directed to methods for treating anxiety comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • the invention is directed to methods for treating symptoms of autism comprising administering formulations of the present invention to a patient in need thereof.
  • the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • the present invention is directed to methods for treating symptoms of autism comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • a “patient” refers to a single patient and not a patient population.
  • “synthetic” refers to the chemical synthesis of cannabidiol does not refer to cannabidiol that is extracted from cannabis plant material.
  • substantially pure refers to a preparation having chromatographical purity of cannabidiol of greater than 98%, preferably greater than 98.5%, more preferably greater than 99.0%, and most preferably greater than 99.5%.
  • substantially free of delta-9-tetrahydrocannabinol refers to a preparation of cannabidiol having less than 0.3% of delta-9-tetrahydrocannabinol as determined by HPLC.
  • the preparation contains less than 0.25% of delta-9-tetrahydrocannabinol, more preferably 0.2%, and most preferably less than 0.1% of delta-9-tetrahydrocannabinol.
  • liquid refers to a flowable, fluid pharmaceutical formulation. This type of formulation is not a powder to solid.
  • the term “effective amount” refers to the amount necessary to treat a patient in need thereof.
  • pharmaceutically acceptable refers to ingredients that are not biologically or otherwise undesirable in an oral dosage form.
  • qs means a sufficient quantity of that component to reach a desired volume or concentration.
  • the formulations in Table 1 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 400 (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.
  • PEG400 Polyethylene glycol 400
  • 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.
  • the formulations listed in Table 1 were subjected to stability at 55° C. 2° C., 40° C. ⁇ 2° C. under 75% ⁇ 5% relative humidity, and 25° C. ⁇ 2° C. under 60% ⁇ 5% 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 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Tables 2 to 13 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.
  • RRT Relative retention time
  • 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 6 to about 7 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 6 to about 7 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.
  • Tables 14 and 15 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 400, 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.
  • the formulations listed in Table 14 and Table 15 were subjected to stability at 25° C. ⁇ 2° C. under 60% ⁇ 5% relative humidity and 40° C. ⁇ 2° C. under 75% ⁇ 5% 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 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Table 16 to 22 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.
  • RRT Relative retention time
  • 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.
  • pH modifiers to adjust the pH to the range of 6 to 7 resulted in exceptionally stable formulations (#A7 and #A8).
  • the stability testing data illustrates that the pH range of from about 6 to about 7 is critical. Formulations #A9 and #A10 also showed good stability after four weeks.
  • Table 24 The formulations in Table 24 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 25° C. ⁇ 2° C. under 60% 5% relative humidity and 40° C. ⁇ 2° C. under 75% ⁇ 5% relative humidity.
  • 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 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Table 25 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.
  • RRT Relative retention time
  • formulation #LF1 with sesame oil showed good stability after 3 months at both storage conditions 25° C. ⁇ 2°C./60% ⁇ 5% relative humidity and 40° C. ⁇ 2° C./75% ⁇ 5% relative humidity.
  • 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.
  • mice study was conducted in order to determine the effects of cannabidiol, delta-9-tetrahydrocannabinol, and cannabidiol plus delta-9-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 98%.
  • FIG. 1 A detailed explanation of FIG. 1 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 mg/kg administered intraperitoneally.
  • 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 21 post treatment. *p ⁇ 0.05 from saline control as determined by one-way ANOVA.
  • Applicant found (as illustrated in FIG. 1 ) that cannabidiol when administered alone provided the most effective level of alleviating chemotherapy-induced neuropathic pain compared to delta-9-tetrahydrocannabinol.
  • the presence of delta-9-tetrahydrocannabinol depending on its concentration can inhibit the ability of cannabidiol to alleviate neuropathic pain.
  • the ability of delta-9-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.
  • 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.
  • 60Hz of alternating current 50 mA in mice, 150 in rats
  • an electrolyte solution containing an anesthetic agent (0.5% tetracaine HCl).
  • the mice were tested at various intervals following doses of 10, 30 and 100 mg/kg of cannabidiol given by intraperitoneal injection of a volume of 0.01 mL/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 6 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 60 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 (6 Hz) test.
  • the minimal clonic seizure (6 Hz) test is used to assess a compound's efficacy against electrically induced seizures but uses a lower frequency (6 Hz) and longer duration of stimulation (3 s).
  • Cannabidiol was pre-administered to mic e via intraperitoneal injection.
  • individual mice four per time point
  • 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.
  • mice were euthanized when the external tumors measured greater than 5mm as assessed by callipers. Additionally, mice with tumors measuring >500 ⁇ 10 6 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 3% ethanol, 3% surfactant and 94% saline, and temozolomide was dissolved in 30% dimethyl sulfoxide and 70% saline.
  • Cannabidiol that was synthetically synthesized and substantially pure was used in this study.
  • the treatments were initiated 9 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, 5 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 12 mice per group, for a total of 72 mice. The treatment rates were as follows: cannabidiol (15 mg/kg); cannabidiol/delta-9-tetrahydrocannabinol (1:1, together @ 15mg/kg); and temozolomide (2 mg/kg intraperitoneal injection.
  • FIG. 2 A detailed explanation of FIG. 2 is as follows.
  • the X-axis represents the number of days after treatment and the Y-axis represents the survival rates.
  • cannabidiol alone or cannabidiol/delta-9-tetrahydrocannabinol (1:1) 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 20% of tumors. This effect was not observed following the 1:1 cannabidiol:delta-9-tetrahydrocannabinol treatments.
  • mice weighing 18 to 25 g were pretreated intraperitoneally with the cannabidiol at a dose of 100 mg/kg.
  • the cannabidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than 98%.
  • the cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 ratio of ethanol:polyethoxylated castor oil:PBS.
  • each mouse received a drop of 0.5% tetracaine hydrochloride applied to each eye.
  • the mouse was then challenged with the low-frequency (6 Hz) stimulation for 3 seconds delivered through corneal electrodes.
  • the low-frequency, long-duration stimuli was initially delivered at 32 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 32 mA screen, an additional assay wherein the stimulation current is increased to 44 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.
  • TPE time of peak effect
  • the 6 Hz 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 ⁇ 0.05 determined to be statistically significant.
  • results are expressed as the total number of animals protected out of the number of animals tested over time (i.e., 2/4 represents 2 out of 4 mice tested were protected).
  • cannabidiol in both solvents showed comparable median effective doses that inhibited seizures in 50% of animals (ED50s) in the 100 mg/kg range. While cannabidiol dissolved in the methylcellulose solvent had an ED50 of 103.75 mg/kg (95% Confidence Interval of 53.89 mg/kg to 163.84 mg/kg), it showed an ED50 of 121.52 mg/kg when dissolved in the 1:1:18 ethanol:polyethoxylated castor oil:PBS solvent (95% Confidence Interval of 87.83 mg/kg to 152.96 mg/kg).
  • TD50 median toxicity dose where toxicity is observed in 50% of animals
  • the TD50 was determined to be 262.37 mg/kg (95% Confidence Interval of 232.64 to 301.78) with cannabidiol dissolved in the 1:1:18 ethanol:polyethoxylated castor oil:PBS solvent. Death was reported at 24 hours at 300 mg/kg and at 6 and 24 hours for 500 mg/kg with the with the 1:1:18 ethanol:polyethoxylated castor oil:PBS solvent.
  • 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 IVIES test provides an indication of CBD's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active.
  • the s.c. 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.
  • a dose of Metrazol (85 mg/kg in mice) will induce convulsions in 97% 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 0.01 ml/g body weight. The animals are then placed in isolation cages to minimize stress and continuously monitored for the next 30 min for the presence or absence of a seizure. An episode of clonic spasms, approximately 3 to 5 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.
  • mice All quantitative in vivo antiseizure/behavioral impairment studies are typically conducted at the previously determined TPE. Groups of at least 8 mice were tested with various doses of cannabidiol until at least two points are established between the limits of 100% protection or minimal toxicity and 0% protection or minimal toxicity. The dose of drug required to produce the desired endpoint in 50% of animals (ED50 or TD50) in each test, the 95% confidence interval, the slope of the regression line, and the standard error of the mean (S.E.M.) 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 98%.
  • the cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 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 (1/4 protected at 0.5 hr, 1/4 at 1 hr, 4/8 at 2hr and 2/4 at 4hr).
  • the ED50 for cannabidiol dissolved in the 1:1:18 ethanol:polyethoxlated castor oil:PBS solvent is 92.21 mg/kg (95% Confidence Interval of 78.4 mg/kg to 104.63 mg/kg).
  • the ED50 was 241.03 mg/kg (95% Confidence Interval of 182.23 to 311.87) for cannabidiol dissolved in the methylcellulose solvent and 198.51 mg/kg (95% Confidence Interval of 167.76 mg/kg to 232.58 mg/kg) for cannabidiol dissolved in the 1:1:18 ethanol:polyethoxlated castor oil:PBS solvent. Based on the toxicity data for cannabidiol dissolved in the methylcellulose solvent the TD50 was determined to exceed 500 mg/kg, the highest dose tested.
  • Myoclonic jerks were reported in at 1 hour with 200 mg/kg dose and at 2 hours with 360 mg/kg dose.
  • the TD50 was determined to be 266.76 mg/kg (95% Confidence Interval of 222.28 mg/kg to 317.42 mg/kg) with the cannabidiol dissolved in the 1:1:18 ethanol:polyethoxlated castor oil:PBS solvent.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention is generally directed to substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of their use.

Description

    PRIORITY
  • This application is a divisional of U.S. application Ser. No. 14/724,351, filed May 28, 2015, now U.S. Pat. No. 11,224,660, issued Jan. 18, 2022, which claims priority to U.S. Provisional Patent Application Nos. 62/004,495, filed May 29, 2014, and 62/154,660, filed Apr. 29, 2015. The entire contents of each application are incorporated herein by reference.
    • FIELD OF THE INVENTION
  • The present invention is generally directed to substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of their use.
    • BACKGROUND
  • Cannabinoids are chemicals that are produced by cannabis flowers. Cannabinoids imitate endogenous compounds in humans.
  • Cannabinoids include cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta9-tetrahydrocannabinol, levonantradol, delta-11-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-2-p-mentha-1,8-di en-3 -yl-5-pentylresorcinol, is non-psychoactive and has shown promise in treating numerous diseases and disorders. Synthetic cannabidiol has the same structure as naturally occurring cannabidiol.
  • Figure US20220184215A1-20220616-C00001
  • Commercially available cannabidiol is usually contaminated with delta 9-tetrahydrocannabinol. The presence of delta-9-tetrahydrocannabinol can be a concern because delta-9-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-9-tetrahydrocannabinol is a hallucinogen and patients receiving cannabidiol wish to avoid this undesirable side effect of the delta-9-tetrahydrocannabinol contaminant. Therefore, there is a need for a substantially pure synthetically synthesized cannabidiol that does not contain delta-9-tetrahydrocannabinol.
  • 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.
  • Accordingly, there is a need for new stable cannabinoid formulations. There is also a need for substantially pure cannabidiol.
    • SUMMARY OF THE INVENTION
  • In one aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 50% of a cannabinoid, from about 0.1 to about 40% of a polyethylene glycol, from about 0.1 to about 50% of propylene glycol, and from about 0.1 to about 20% of water, wherein the formulation does not contain alcohol and the formulation has a pH of from about 5 to about 8.
  • In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40% of a cannabinoid, from about 0.1 to about 25% of a polyethylene glycol, from about 0.1 to about 40% of propylene glycol, optionally from about 0.1 to about 50% of water; and from about 0.1 to about 70% of alcohol, wherein the formulation has a pH of from about 5 to about 8.
  • In yet another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40% of a cannabinoid and from about 10 to about 95% of a lipid.
  • In another aspect, the invention is directed to methods of using a cannabinoid or substantially pure, synthetically synthesized cannabidiol: to treat 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, infantile spasms, refractory infantile spasms, tubular sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's Disease, and autism; to assist with withdrawal from opioids, cocaine, heroin, amphetamines and nicotine; and as an analgesic or to assist with handling of adverse emotional stimuli.
    • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 shows the results from the study detailed in Example 7 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations for treatment of neuropathic pain.
  • FIG. 2 shows the results from the study detailed in Example 9 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations for treatment of glioblastoma multiforme.
    •  DETAILED DESCRIPTION
  • Applicant unexpectedly created new storage stable formulations containing cannabinoids. Applicant determined that a pH of from about 5 to about 8 is critical for the formulations to remain stable, preferably from about 6 to about 7. For example, as seen in Example 2 below, the alcohol-free formulations #AF3 and #AF4 exhibited excellent stability for four weeks regardless of the temperature and humidity conditions. Further, in Example 4, Applicant unexpectedly found that the alcohol containing formulations #A7 and #A8 exhibited excellent stability for at least 12 months 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 with and without alcohol (see Examples 1 and 3). 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 formulations lipid formulations (see Example 5). These formulations were also unexpectedly stable during storage (see Example 6).
  • Further, Applicant unexpectedly found that substantially pure cannabidiol formulations are especially suitable for treatment of epilepsy (see Examples 8, 10 and 11), neuropathic pain (see Example 7 and FIG. 1), and glioblastoma multiforme (see Example 9 and FIG. 2).
    • Alcohol-Free Formulations
  • In one embodiment, the present invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 50% of a cannabinoid, from about 0.1 to about 40% of a polyethylene glycol, from about 0.1 to about 50% of propylene glycol, and from about 0.1 to about 20% of water, wherein the formulation does not contain alcohol and the formulation has a pH of from about 5 to about 8.
  • In a preferred embodiment, the formulations contain from about 1 to about 40% of a cannabinoid. In more preferred embodiments, the formulations contain from about 5 to about 35%, from about 20 to about 35% or from about 30 to 35% of a cannabinoid.
  • In yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, 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 1 to about 40% of a cannabidiol. In more preferred embodiments, the formulations contain from about 5 to about 35%, from about 20 to about 35% or from about 30 to 35% 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 98%. In a more preferred embodiment, the cannabidiol is greater than 99% pure. In an even more preferred embodiment, the cannabidiol is greater than 99.5% pure. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.
  • In another embodiment, the formulations contain from about 0.001 to about 1% of an antioxidant. In a preferred embodiment, the formulations contain from about 0.01 to about 1% antioxidant. In a more preferred embodiment, the formulations contain from about 0.02 to about 0.5% 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 1 to about 40% of a polyethylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 35%, from about 5 to about 35%, from about 20 to about 30%, or from about 25 to about 30% polyethylene glycol.
  • Suitable polyethylene glycols include low molecular weight polyethylene glycols with an average molecular weight of between 200 and 10,000. One preferred polyethylene glycol that can be used is polyethylene glycol 400.
  • In another embodiment, the formulations contain from about 1 to about 40% of polyethylene glycol 400. In a preferred embodiment, the formulations contain from about 1 to about 35%, from about 5 to about 35%, from about 20 to about 30%, or from about 25 to about 30% polyethylene glycol 400.
  • In another embodiment, the formulations contain from about 1 to about 50% of propylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 40%, from about 5 to about 35%, from about 20 to about 35%, or from about 30 to about 35% propylene glycol.
  • In a further embodiment, the formulations contain water. The formulations can contain 0% water. If the formulations contain water, they can include from about 1 to about 15% water, from about 1 to about 10% water, or from about 4 to about 8% water.
  • The pH of the formulations may be modified using any pharmaceutically acceptable means. Preferably the pH of the formulation is from about 5 to about 8. In a more preferred embodiment, the pH of the formulations is from about 6 to about 7. In a most preferred embodiment, the pH of the formulations is from about 6.2 to about 6.7.
  • 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 0.001 to about 1% sweetener.
  • If the formulations contain a sweetness enhancer, the formulations preferably contain from about 0.001 to about 1% 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 0.001 to about 1% flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0.5% of the flavoring agent.
  • The formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration. Preferably, the formulations are liquids administered orally.
    • Formulations Containing Alcohol
  • In another embodiment, the invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 40% of a cannabinoid, from about 0.1 to about 25% of a polyethylene glycol, from about 0.1 to about 40% of propylene glycol, optionally from about 0.1 to about 50% of water, and from about 0.1 to about 70% of alcohol, wherein the formulation has a pH of from about 5 to about 8.
  • In a preferred embodiment, the formulations contain from about 1 to about 35% of a cannabinoid. In a more preferred embodiment, the formulations contain from about 1 to about 15%, from about 5 to about 12% or from about 7 to about 11% cannabinoid. Alternatively, the formulations may contain from about 20 to about 35% or from about 30 to about 35% cannabinoid.
  • In yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, 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 1 to about 35% of a cannabidiol. In a more preferred embodiment, the formulations contain from about 1 to about 15%, from about 5 to about 12% or from about 7 to about 11% cannabidiol. Alternatively, the formulations may contain from about 20 to about 35% or from about 30 to about 35% cannabidiol.
  • In yet another embodiment, the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98%. In a more preferred embodiment, the cannabidiol is greater than 99% pure. In an even more preferred embodiment, the cannabidiol is greater than 99.5% pure. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.
  • In another embodiment, the formulations contain from about 0.001 to about 1% of an antioxidant. In a preferred embodiment, the formulations contain from about 0.01 to about 1% antioxidant. In a more preferred embodiment, the formulations contain from about 0.02 to about 0.5% 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, 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 1 to about 20% of propylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 15% or from about 5 to about 10% propylene glycol.
  • In an alternative embodiment, the formulations contain from about 20 to about 50% of propylene glycol. In a preferred embodiment, the formulations contain from about 30 to about 40% or from about 30 to about 35% propylene glycol.
  • In another embodiment, the formulations contain from about 1 to about 20% of a polyethylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 10% or from about 1 to about 5% polyethylene glycol.
  • In an alternative embodiment, the formulations contain from about 10 to about 20% of a polyethylene glycol. In a preferred alternative embodiment, the formulations contain from about 15 to about 20% polyethylene glycol.
  • Suitable polyethylene glycols include low molecular weight polyethylene glycols with an average molecular weight of between 200 and 10,000. One preferred polyethylene glycol that can be used is polyethylene glycol 400.
  • In another embodiment, the formulations contain from about 1 to about 20% of polyethylene glycol 400. In a preferred embodiment, the formulations contain from about 1 to about 10% or from about 1 to about 5% polyethylene glycol 400.
  • In an alternative embodiment, the formulations contain from about 10 to about 20% of polyethylene glycol 400. In a preferred alternative embodiment, the formulations contain from about 15 to about 20% polyethylene glycol 400.
  • In a further embodiment, the formulations contain water. The formulations can contain 0% water. If the formulations contain water, they can include from about 1 to about 40% water, from about 5 to about 40% water, from about 10 to about 35% water or from about 25 to about 35% water.
  • In yet another embodiment, the formulations contain from about 1 to about 65% alcohol. In a preferred embodiment, the formulations contain from about 10 to about 65%, from about 15 to about 60%, or from about 30 to 55% alcohol.
  • In an alternative embodiment, the formulations contain from about 1 to about 20% alcohol. In a preferred alternative embodiment, the formulations contain from about 1 to about 10% or from about 3 to about 7% alcohol.
  • The pH of the formulations may be modified using any pharmaceutically acceptable means. Preferably the pH of the formulations is from about 6 to about 7. In a more preferred embodiment, the pH of the formulations is from about 6.2 to about 6.7.
  • The formulations of the present invention may also contain sweeteners, sweetener enhancers, pH modifiers, preservatives, 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 0.001 to about 1% sweetener.
  • 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.
  • If the formulations contain a sweetness enhancer, the formulations preferably contain from about 0.001 to about 1% sweetness enhancer.
  • 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 fruit punch flavor, raspberry flavor, grape flavor, or lemon mint flavor.
  • If the formulations contain a flavoring agent, the formulations preferably contain from about 0.001 to about 1% flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0.5% of the flavoring agent.
  • The formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration. Preferably, the formulations are liquids administered orally.
    • Formulations Containing Lipids
  • In another embodiment, the invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 40% of a cannabinoid and from about 10 to about 95% 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, medium chain glycerides, decanoyl glycerides, octanoyl glycerides, caprylic/capric triglycerides, oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, polyglyceryl-3 dioleate, glyceryl monolinoleate, glyceryl monocaprylate, oleic acid, and a combination thereof. In a preferred embodiment, the lipid is selected from the group consisting of sesame oil, sunflower oil, soybean oil, corn oil, a mixture of decanoyl glycerides and octanoyl glycerides, and a combination thereof.
  • Suitable commercial sources for the lipid include Miglyol® 812N containing a proprietary mixture of decanoyl and octanoyl glycerides (fatty acid esters) and Miglyol® 810N also containing a proprietary mixture of decanoyl and octanoyl fatty acids from coconut oil (Miglyol is available from and a registered trademark of Cremer Oleo GmbH & Co.).
  • In yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, dronabinol (delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, acids, analogs, and synthetic derivatives thereof. In a preferred embodiment, the cannabinoid is cannabidiol.
  • In yet another embodiment, the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98%. In a more preferred embodiment, the cannabidiol is greater than 99% pure. In an even more preferred embodiment, the cannabidiol is greater than 99.5% pure. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3% delta-9-tetrahydrocannabinol.
  • In a preferred embodiment, the formulations contain from about 1 to about 35% of a cannabidiol. In a more preferred embodiment, the formulations contain from about 10 to about 32% cannabidiol. In a most preferred embodiment, the formulations contain from about 17 to about 29% cannabidiol.
  • In a preferred embodiment, the formulations contain from about 20 to about 90% of lipids. In a more preferred embodiment, the formulations contain from about 50 to about 90% lipids. In a most preferred embodiment, the formulations contain from about 60 to about 85% lipids.
  • In yet another embodiment, the formulations contain alcohol. The formulations can contain 0% alcohol. If the formulations contain alcohol, they can include from about 0.1 to about 20% alcohol. In a preferred embodiment, the formulations contain from about 3 to about 17% alcohol. In a more preferred embodiment, the formulations contain from about 5 to about 15% alcohol.
  • In another embodiment, the formulations contain an antioxidant. The formulations can contain 0% antioxidant. If the formulations contain antioxidant, they can include from about 0.01 to about 1% of an antioxidant. In a preferred embodiment, the formulations contain from about 0.02 to about 0.5% antioxidant. In a more preferred embodiment, the formulations contain from about 0.03 to about 0.1% 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, and combinations thereof. In a preferred embodiment, the formulations contain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorabte, ascobyl palminate or combinations thereof.
  • 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 0.1 to about 2% sweetener. In a more preferred embodiment, the formulations contain from about 0.1 to about 0.8% sweetener. In a most preferred embodiment, the formulations contain from about 0.2 to about 0.5% sweetener.
  • 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.
  • If the formulations contain a sweetness enhancer, the formulations preferably contain from about 0.001 to about 1% sweetness enhancer.
  • 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.
  • If the formulations contain a flavoring agent, the formulations preferably contain from about 0.01 to about 1% flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0.5% of the flavoring agent.
  • The formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration. Preferably, the formulations are liquids administered orally.
  • Exemplary Uses of Formulations of the Present Invention (Alcohol-Containing, Alcohol-Free, and Lipid) and Synthetically Synthesized, Substantially Pure, Cannabidiol
  • 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 U.S. Patent Application No. 62/004,495, 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-9-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).
  • Figure US20220184215A1-20220616-C00002
  • In an embodiment, the present invention is directed to methods for treating a brain tumor comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating a brain tumor comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating glioma comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating glioma comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating glioblastoma multiforme comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating glioblastoma multiforme comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating Dravet Syndrome comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating Dravet Syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In yet another embodiment, the present invention is directed to methods for treating Lennox Gastaut Syndrome comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating Lennox Gastaut Syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof
  • In a further embodiment, the present invention is directed to methods for treating Mycolonic Seizures comprising administering the formulations of the present invention to a patient in need thereof. In a more preferred embodiment, the alcohol-free formulations contain substantially pure cannabidiol.
  • In another embodiment, the present invention is directed to methods for treating Mycolonic Seizures comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof
  • In a further embodiment, the present invention is directed to methods for treating Juvenile Mycolonic Epilepsy comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating Juvenile Mycolonic Epilepsy comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating Refractory Epilepsy comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating Refractory Epilepsy comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating juvenile spasms comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating juvenile spasms comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating West Syndrome comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating West Syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating infantile spasms comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating infantile spasms comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating refractory infantile spasms comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating refractory infantile spasms comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating tubular sclerosis complex comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating tubular sclerosis complex comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the present invention is directed to methods for treating neuropathic pain comprising administering the formulations of the present invention to a patient in need thereof. 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 another embodiment, the present invention is directed to methods for treating neuropathic pain comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof. In a further embodiment, the neuropathic pain is caused by 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 methods for using cannabidiol as an analgesic comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for using cannabidiol as an analgesic comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the present invention is directed to methods for treating opioid addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating opioid addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In yet another embodiment, the present invention is directed to methods for treating cocaine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating cocaine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the present invention is directed to methods for treating heroin addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating heroin addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the present invention is directed to methods for treating nicotine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating nicotine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the present invention is directed to methods for treating amphetamine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating amphetamine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating acne comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating acne comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating Parkinson's disease comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating Parkinson's disease comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof
  • In an embodiment, the present invention is directed to methods for treating schizophrenia comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating schizophrenia comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating social anxiety disorder comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating social anxiety disorder comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the present invention is directed to methods for treating depression comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating depression comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the present invention is directed to methods for treating patients encountering adverse emotional stimuli comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating patients encountering adverse emotional stimuli comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating nausea comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating nausea comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the present invention is directed to methods for treating multiple sclerosis comprising administering the formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating multiple sclerosis comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the invention is directed to methods for treating symptoms of cannabis use disorder comprising administering formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating symptoms of cannabis use disorder comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In another embodiment, the invention is directed to methods for treating symptoms of early psychosis comprising administering formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating symptoms of early psychosis comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In another embodiment, the invention is directed to methods for treating symptoms of Alzheimer' s Disease comprising administering formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating symptoms of Alzheimer's Disease comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In yet another embodiment, the invention is directed to methods for treating symptoms of post-traumatic stress disorder (“PTSD”) comprising administering formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating symptoms of post-traumatic stress disorder PTSD comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In an embodiment, the invention is directed to methods for treating symptoms of anxiety comprising administering formulations of the present invention to a patient in need thereof.
  • In another embodiment, the present invention is directed to methods for treating anxiety comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
  • In a further embodiment, the invention is directed to methods for treating symptoms of autism comprising administering formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.
  • In another embodiment, the present invention is directed to methods for treating symptoms of autism comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.
    • Definitions
  • 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 98%, preferably greater than 98.5%, more preferably greater than 99.0%, and most preferably greater than 99.5%.
  • As used herein, “substantially free of delta-9-tetrahydrocannabinol” refers to a preparation of cannabidiol having less than 0.3% of delta-9-tetrahydrocannabinol as determined by HPLC. Preferably, the preparation contains less than 0.25% of delta-9-tetrahydrocannabinol, more preferably 0.2%, and most preferably less than 0.1% of delta-9-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 10%. For example, the phrase “about 10% w/w” is to be understood as “9% w/w to 11% w/w.” Therefore, amounts within 10% 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.
    • EXAMPLES Example 1 Alcohol-Free Formulations
  • The formulations in Table 1 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 400 (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.
  • TABLE 1
    Alcohol-free Formulations
    Formulation # AF1 # AF2 # AF3 # AF4
    Cannabinoid 32 32 32 32
    PEG400 28 28 27.9 28.4
    Propylene Glycol 34 34 34 34
    Water 6 6 6 6
    Vitamin E (Alpha- 0.05
    Tocopherol)
    Sodium Ascorbate 0.1 0.1
    Methyl Paraben 0.1
    Propyl Paraben 0.02
    Sucralose 0.05
    Flavoring 0.3
    pH adjustment None pH adjusted pH adjusted pH adjusted
    to 6 to 7 to 6 to 7 to 6 to 7
    Final pH of formulation 8.7 6.7 6.4 6.6
    • Example 2 Stability of Alcohol-free Formulations
  • The formulations listed in Table 1 were subjected to stability at 55° C. 2° C., 40° C.±2° C. under 75%±5% relative humidity, and 25° C.±2° C. under 60%±5% 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 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Tables 2 to 13 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.
  • TABLE 2
    Stability Data for Cannabidiol Oral Solution Formulation # AF1
    stored at 55° C. ± 2° C.
    55° C.- 0 1 2 3 4
    Formulation # AF1 RRT Week Week Weeks Weeks Weeks
    Assay (% of 100.00 97.11 97.30 94.47 87.91
    initial
    concentration)
    % Cis-cannabidiol 1.440 0.01 0.02 0.02 0.02 0.02
    % Delta-9- 1.729 ND ND 0.01 ND 0.02
    tetrahydro-
    cannabinol
    % Trans- 1.840 0.05 0.03 0.03 0.03 0.02
    (1R, 6R)-3'-
    methyl-cannabidiol
    % Unknown 0.328 ND BQL BQL BQL 0.06
    Impurity 0.345 ND BQL BQL BQL 0.07
    0.385 ND BQL BQL BQL 0.05
    0.404 ND 0.08 0.13 0.23 0.38
    0.460 ND 0.05 0.07 0.10 0.17
    0.486 ND 0.42 0.65 1.23 2.73
    0.505 BQL 0.22 0.22 0.19 ND
    0.526 ND 0.10 0.14 0.13 0.17
    0.610 ND ND BQL 0.05 0.08
    0.702 ND BQL BQL 0.07 0.08
    0.742 ND BQL BQL 0.05 0.07
    0.774 0.07 0.06 0.06 ND ND
    0.796 ND 0.58 1.04 2.13 3.80
    0.830 BQL 0.31 0.39 0.59 0.87
    0.933 ND BQL 0.06 0.17 0.37
    1.881 ND 0.06 0.09 0.06 0.06
    2.025 ND BQL BQL 0.34 0.39
    2.291 ND 0.06 ND ND ND
    Total Impurities 0.13 1.99 2.91 5.39 9.41
    (% Area)
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 3
    Stability Data for Cannabidiol Oral Solution Formulation # AF2
    stored at 55° C. ± 2° C.
    55° C.- 0 1 2 3 4
    Formulation # AF2 RRT Week Week Weeks Weeks Weeks
    Assay (% of 100.00 100.31 99.90 95.15 96.85
    initial
    concentration)
    % Cis-cannabidiol 1.440 0.01 0.01 0.01 0.01 0.01
    % Delta-9- 1.730 ND ND 0.01 0.03 0.06
    tetrahydro-
    cannabinol
    % Trans- 1.840 0.05 0.07 0.05 0.05 0.04
    (1R, 6R)-3'-
    methyl-cannabidiol
    % Unknown 0.340 ND BQL BQL 0.05 0.07
    Impurity 0.404 ND BQL BQL BQL 0.08
    0.462 ND BQL BQL BQL 0.05
    0.486 ND BQL 0.22 0.35 0.94
    0.506 ND 0.07 0.13 0.15 ND
    0.584 ND BQL BQL 0.05 0.11
    0.776 0.07 0.07 0.06 0.05 ND
    0.795 ND BQL 0.30 0.50 1.09
    0.830 BQL BQL 0.10 0.14 0.22
    0.932 ND BQL 0.07 0.10 0.18
    2.034 ND ND BQL 0.09 BQL
    Total Impurities 0.13 0.22 0.95 1.57 2.85
    (% Area)
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 4
    Stability Data for Cannabidiol Oral Solution Formulation # AF3
    stored at 55° C. ± 2° C.
    55° C.- 0 1 2 3 4
    Formulation # AF3 RRT Week Week Weeks Weeks Weeks
    Assay (% of 100.00 99.25 98.60 98.28 96.12
    initial
    concentration)
    % Cis-cannabidiol 1.440 0.01 0.01 0.01 0.01 0.01
    % Delta-9- 1.736 ND ND ND 0.01 0.02
    tetrahydro-
    cannabinol
    % Trans-(1R, 6R)-3'- 1.840 0.05 0.05 0.05 0.05 0.05
    methyl-cannabidiol
    % Unknown 0.484 ND ND ND BQL 0.14
    Impurity 0.502 ND BQL BQL 0.05 0.09
    0.775 0.06 0.09 0.10 0.06 0.05
    0.793 ND ND ND 0.06 0.27
    0.830 BQL BQL BQL BQL 0.06
    0.951 ND BQL ND BQL 0.05
    1.158 ND 0.06 0.08 0.12 0.05
    Total Impurities 0.12 0.21 0.24 0.36 0.79
    (% Area)
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 5
    Stability Data for Cannabidiol Oral Solution Formulation # AF4
    stored at 55° C. ± 2° C.
    55° C.- 0 1 2 3 4
    Formulation # AF4 RRT Week Week Weeks Weeks Weeks
    Assay (% of 100.00 100.92 99.27 100.16 98.10
    initial
    concentration)
    % Cis-cannabidiol 1.440 0.01 0.01 0.01 0.01 0.01
    % Trans- 1.840 0.05 0.05 0.05 0.06 0.07
    (1R, 6R)-3'-
    methyl-cannabidiol
    % Unknown 0.403 ND BQL BQL BQL 0.06
    Impurity 0.485 ND BQL 0.06 0.18 0.38
    0.505 ND BQL 0.05 0.08 0.12
    0.524 ND ND BQL BQL 0.07
    0.776 0.07 0.08 0.05 0.06 ND
    0.794 ND ND 0.07 0.31 0.70
    0.822 ND ND BQL 0.10 0.15
    0.931 ND ND ND BQL 0.06
    1.159 ND BQL 0.08 0.10 ND
    1.774 ND ND ND 0.05 0.11
    Total Impurities 0.13 0.14 0.37 0.95 1.73
    (% Area)
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 6
    Stability Data for Cannabidiol Oral Solution Formulation # AF1
    stored at 40° C. ± 2° C. under 75% ± 5% relative humidity
    40° C.-Formulation # AF1 RRT 0 Week 2 Weeks 4 Weeks
    Assay (% of initial concentration) 100.00 100.18 95.64
    % Cis-cannabidiol 1.440 0.01% 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.846 0.05% 0.05% 0.03%
    cannabidiol
    % Unknown Impurity 0.404 ND BQL 0.12%
    0.460 ND 0.07% 0.08%
    0.486 ND 0.23% 0.87%
    0.505 BQL 0.30% 0.30%
    0.526 ND 0.05% 0.14%
    0.702 ND BQL 0.06%
    0.774 0.07% 0.07% ND
    0.796 ND 0.25% 1.31%
    0.830 BQL 0.12% 0.44%
    0.931 ND ND 0.06%
    Total Impurities (% Area) 0.13% 1.15% 3.42%
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 7
    Stability Data for Cannabidiol Oral Solution Formulation
    # AF2 stored at 40° C. ± 2° C. under 75% ± 5% relative humidity
    40° C.-Formulation # AF2 RRT 0 Week 2 Weeks 4 Weeks
    Assay (% of initial concentration) 100.00 100.08 98.77
    % Cis-cannabidiol 1.442 0.01% 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.848 0.05% 0.05% 0.04%
    cannabidiol
    % Unknown Impurity 0.484 ND ND 0.08%
    0.506 ND BQL 0.11%
    0.776 0.07% 0.07% 0.06%
    0.794 ND ND 0.09%
    0.830 BQL BQL 0.05%
    Total Impurities (% Area) 0.13% 0.13% 0.44%
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 8
    Stability Data for Cannabidiol Oral Solution Formulation #AF3
    stored at 40° C. ± 2° C. under 75% ± 5% relative humidity
    40° C.-Formulation # AF3 RRT 0 Week 2 Week 4 Week
    Assay (% of initial concentration) 100.00 98.47 96.90
    % Cis-cannabidiol 1.442 0.01% 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.846 0.05% 0.05% 0.05%
    cannabidiol
    % Unknown Impurity 0.775 0.06% 0.08% 0.10%
    1.160 ND ND 0.05%
    Total Impurities (% Area) 0.12% 0.14% 0.21%
    ND—Not Detected
  • TABLE 9
    Stability Data for Cannabidiol Oral Solution Formulation
    # AF4 stored at 40° C. ± 2° C. under 75% ± 5% relative humidity
    40° C.-Formulation # AF4 RRT 0 Week 2 Weeks 4 Weeks
    Assay (% of initial concentration) 100.00 99.63 99.50
    % Cis-cannabidiol 1.437 0.01% 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.840 0.05% 0.05% 0.06%
    cannabidiol
    % Unknown Impurity 0.776 0.07% 0.07% 0.08%
    Total Impurities (% Area) 0.13% 0.13% 0.15%
  • TABLE 10
    Stability Data for Cannabidiol Oral Solution Formulation # AF1
    stored at 25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.-Formulation # AF1 RRT 0 Week 4 Weeks
    Assay (% of initial concentration) 100.00 101.24
    % Cis-cannabidiol 1.440 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.846 0.05% 0.04%
    cannabidiol
    % Unknown Impurity 0.459 ND 0.09%
    0.483 ND 0.11%
    0.505 BQL 0.27%
    0.774 0.07% 0.06%
    0.796 ND 0.10%
    0.836 BQL 0.06%
    Total Impurities (% Area) 0.13% 0.74%
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 11
    Stability Data for Cannabidiol Oral Solution Formulation # AF2
    stored at 25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.-Formulation # AF2 RRT 0 Week 4 Weeks
    Assay (% of initial concentration) 100.00 100.22
    % Cis-cannabidiol 1.442 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.848 0.05% 0.05%
    cannabidiol
    % Unknown Impurity 0.776 0.07% 0.07%
    Total Impurities (% Area) 0.13% 0.13%
  • TABLE 12
    Stability Data for Cannabidiol Oral Solution Formulation # AF3
    stored at 25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.-Formulation # AF3 RRT 0 Week 4 Weeks
    Assay (% of initial concentration) 100.00 97.52
    % Cis-cannabidiol 1.442 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.846 0.05% 0.05%
    cannabidiol
    % Unknown Impurity 0.775 0.06% 0.08%
    Total Impurities (% Area) 0.12% 0.14%
  • TABLE 13
    Stability Data for Cannabidiol Oral Solution Formulation # AF4 stored
    at 25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.-Formulation # AF4 RRT T = 0 4 Weeks
    Assay (% of initial concentration) 100.00 99.26
    % Cis-cannabidiol 1.437 0.01% 0.01%
    % Trans-(1R,6R)-3′-methyl- 1.840 0.05% 0.06%
    cannabidiol
    % Unknown Impurity 0.776 0.07% 0.07%
    Total Impurities (% Area) 0.13% 0.14%
  • 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 6 to about 7 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 6 to about 7 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.
    • Example 3 Alcohol Formulations
  • The formulations in Tables 14 and 15 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 400, 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.
  • TABLE 14
    Formulations with Alcohol
    Formulation # A5 # A6 # A7 # A8
    Cannabinoid 9.1 9.1 9.1 8.8
    Polyethylene glycol 400 3 3 3 3
    Propylene Glycol 7.5 7.5 7.5 7.5
    Ethanol 50.3 50.2 50.2 49.7
    Water 30 30 30 30.5
    Vitamin E (Alpha- 0.05 0.05 0.05
    Tocopherol)
    Ascorbyl Palmitate 0.1 0.1 0.1
    Sucralose 0.05 0.05 0.05 0.05
    Methyl Paraben 0.02 0.02 0.02 0.02
    Propyl Paraben 0.02 0.02 0.02 0.02
    Flavoring 0.3
    pH adjustment None None pH adjusted pH adjusted
    to 6 to 7 to 6 to 7
    Final pH of formulation 6.06 4.9 6.5 6.4
  • TABLE 15
    Additional Formulations with Alcohol
    Formulation # A9 # A10
    Cannabinoid 32 32
    Polyethylene glycol 400 18.8 23.8
    Propylene Glycol 39 39
    Glycerol 5
    Ethanol 5 5
    Vitamin E (Alpha Tocopherol) 0.05 0.05
    Ascorbyl Palmitate 0.1 0.1
    Sucralose 0.05 0.05
    Methyl Paraben 0.02 0.02
    Propyl Paraben 0.02 0.02
    • Example 4 Stability of Formulations with Alcohol
  • The formulations listed in Table 14 and Table 15 were subjected to stability at 25° C.±2° C. under 60%±5% relative humidity and 40° C.±2° C. under 75%±5% 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 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Table 16 to 22 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.
  • TABLE 16
    Stability Data for Cannabidiol Oral Solution Formulation # A5 stored at
    25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.- 0 3 6 9 12
    Formulation # A5 RRT Month Months Months Months Months
    Assay (% of initial 100.00 92.97 83.87 77.31 68.92
    concentration)
    % Cannabinol 1.400 ND ND ND 0.01 ND
    % Cis-cannabidiol 1.455 0.01 0.01 0.01 0.02 0.02
    % Delta-9- 1.761 ND ND 0.01 0.15 0.17
    tetrahydrocannabinol
    % Unknown 0.319 ND 0.08 0.18 0.34 0.39
    Impurity 0.337 ND BQL BQL BQL 0.05
    0.370 ND BQL 0.07 0.08 0.08
    0.389 ND 0.11 0.24 0.42 0.54
    0.448 ND 0.18 0.23 0.24 0.25
    0.479 ND 0.78 1.65 2.66 3.49
    0.494 ND 0.50 0.72 0.82 0.88
    0.522 ND 0.05 BQL BQL BQL
    0.600 ND BQL 0.05 0.09 0.15
    0.678 ND BQL 0.10 0.16 0.21
    0.697 ND BQL 0.08 0.08 0.09
    0.713 ND ND ND 0.06 0.10
    0.770 0.05 ND ND ND ND
    0.790 ND 0.99 2.28 4.19 5.55
    0.819 ND 0.39 0.87 1.44 1.97
    0.930 ND 0.05 0.21 0.38 0.56
    1.189 ND ND ND BQL 0.09
    2.053 ND 0.07 ND BQL 0.14
    3.192 ND ND ND ND 0.09
    3.256 ND ND ND 0.08 0.08
    3.650 ND ND ND ND 0.13
    Total Impurities 0.06 3.21 6.70 11.22 15.03
    (% Area)
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 17
    Stability Data for Cannabidiol Oral Solution Formulation # A6 stored at
    25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.- 0 3 6 9 12
    Formulation # A6 RRT Month Months Months Months Months
    Assay (% of initial 100.00 97.49 94.25 91.14 87.53
    concentration)
    % Cannabinol 1.400 ND ND ND 0.01 ND
    % Cis-cannabidiol 1.455 0.01 0.01 0.01 0.01 ND
    % Delta-9- 1.761 ND 0.06 0.23 0.68 0.82
    tetrahydrocannabinol
    % Unknown 0.390 ND BQL 0.05 0.10 0.14
    Impurity 0.479 ND BQL 0.08 0.17 0.25
    0.496 ND 0.20 0.87 1.80 2.41
    0.577 ND BQL BQL 0.08 0.10
    0.721 ND ND BQL BQL 0.05
    0.770 0.05 0.05 BQL BQL BQL
    0.790 ND 0.05 0.11 0.25 0.43
    0.834 BQL BQL BQL 0.05 0.07
    0.961 ND 0.06 0.33 0.71 0.97
    1.197 ND ND ND ND 0.06
    1.869 BQL BQL BQL 0.06 0.27
    2.066 ND 0.07 0.42 0.59 0.86
    3.247 ND ND ND 0.07 0.08
    3.655 ND ND ND ND 0.11
    Total Impurities 0.06 0.50 2.10 4.58 6.62
    (% Area)
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 18
    Stability Data for Cannabidiol Oral Solution Formulation # A7 stored at
    25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.- 0 3 6 9 12
    Formulation #A7 RRT Month Months Months Months Months
    Assay (% of initial 100.00 98.69 96.52 96.30 96.54
    concentration)
    % Cis-cannabidiol 1.455 0.01 0.01 0.01 0.01 0.01
    % Delta-9- 1.761 ND 0.01 0.02 0.03 0.05
    tetrahydro-
    cannabinol
    % Unknown 0.479 ND BQL BQL BQL 0.07
    Impurity 0.495 ND BQL 0.06 0.14 0.20
    0.770 0.05 0.05 0.05 0.05 BQL
    0.793 ND BQL 0.06 0.06 0.10
    0.958 ND ND ND BQL 0.06
    1.160 ND BQL 0.05 BQL 0.05
    1.883 ND ND ND ND 0.06
    2.057 ND ND BQL BQL 0.06
    3.652 ND ND ND ND 0.05
    Total Impurities 0.06 0.07 0.25 0.29 0.71
    (% Area)
    ND—Not Detected
    BQL—Below Quantification Limit, for unknown impurity only
  • TABLE 19
    Stability Data for Cannabidiol Oral Solution Formulation # A8
    stored at 25° C. ± 2° C. under 60% ± 5% relative humidity
    25° C.-Formulation # A8 RRT 0 Month 3 Months 6 Months
    Assay (% of initial 100.00 100.51 100.14
    concentration)
    % Cis-cannabidiol 1.454 0.04 0.04 0.04
    % Delta-9- 1.762 0.03 0.04 0.05
    tetrahydrocannabinol
    % Unknown Impurity 0.501 BQL BQL 0.07
    1.162 ND BQL 0.07
    1.198 ND ND 0.05
    Total Impurities (% Area) 0.07 0.08 0.28
    ND-Not Detected
    BQL-Below Quantification Limit, for unknown impurity only
  • TABLE 20
    Stability Data for Cannabidiol Oral Solution Formulation # A7 stored at
    40° C. ± 2° C. under 75 % ± 5% relative humidity
    40° C.-Formulation # A7 RRT 0 Month 3 Months 6 Months
    Assay (% of initial 100.00 95.22 89.72
    concentration)
    % Cis-cannabidiol 1.451 0.01 0.01 0.01
    % Delta-9- 1.753 0.01 0.06 0.16
    tetrahydrocannabinol
    % Unknown Impurity 0.390 ND 0.05 0.15
    0.450 ND BQL 0.06
    0.476 BQL 0.23 0.75
    0.501 BQL 0.30 0.80
    0.609 ND BQL 0.05
    0.675 ND BQL 0.05
    0.772 0.05 BQL ND
    0.791 ND 0.36 1.35
    0.830 BQL 0.12 0.37
    0.934 ND BQL 0.25
    0.958 ND BQL 0.18
    1.333 ND ND 0.05
    1.982 ND ND 0.17
    2.062 BQL 0.05 0.32
    3.253 ND BQL 0.09
    3.744 ND ND 0.13
    Total Impurities (% Area) 0.07 1.18 4.94
    ND-Not Detected
    BQL-Below Quantification Limit, for unknown impurity only
  • TABLE 21
    Stability Data for Cannabidiol Oral Solution Formulation # A8 stored at
    40° C. ± 2° C. under 75% ± 5% relative humidity
    40° C.-Formulation # A8 RRT 0 Month 3 Months 6 Months
    Assay (% of initial concentration) 100.00 96.57 92.84
    % Cis-cannabidiol 1.454 0.04 0.03 0.03
    % Delta-9-tetrahydrocannabinol 1.762 0.03 0.13 0.62
    % Unknown Impurity 0.392 ND 0.06 0.14
    0.478 ND 0.22 0.64
    0.501 BQL 0.41 0.84
    0.610 ND BQL 0.05
    0.670 ND BQL 0.05
    0.792 ND 0.38 1.15
    0.821 ND 0.12 0.30
    0.931 ND 0.05 0.19
    0.956 ND 0.09 0.21
    2.068 BQL 0.11 0.23
    3.251 ND BQL 0.09
    3.754 ND ND 0.13
    Total Impurities (% Area) 0.07 1.60 4.67
    ND-Not Detected
    BQL-Below Quantification Limit, for unknown impurity only
  • TABLE 22
    Stability Data for Cannabidiol Oral Solution Formulation # A9 stored at
    40° C. ± 2° C. under 75% ± 5% relative humidity
    40° C.-Formulation # A9 RRT 0 Week 2 Weeks 4 Weeks
    Assay (% of initial concentration) 100.00 99.77 100.65
    % Cis-cannabidiol 1.440 0.01 0.01 0.01
    % Trans-(1R, 6R)-3′-methyl- 1.841 0.05 0.06 0.05
    cannabidiol
    % Unknown Impurity 0.770 0.06 0.07 0.08
    Total Impurities (% Area) 0.12 0.14 0.14
  • TABLE 23
    Stability Data for Cannabidiol Oral Solution Formulation # A10 stored at
    40° C. ± 2° C. under 75 % ± 5% relative humidity
    40° C.-Formulation # A10 RRT 0 Week 2 Weeks 4 Weeks
    Assay (% of initial concentration) 100.00 101.25 100.78
    % Cis-cannabidiol 1.440 0.01 0.01 0.01
    % Delta-9-tetrahydrocannabinol 1.723 ND ND 0.01
    % Trans-(1R, 6R)-3′-methyl- 1.842 0.05 0.05 0.05
    cannabidiol
    % Unknown Impurity 0.770 0.07 0.07 0.06
    Total Impurities (% Area) 0.13 0.13 0.13
    ND-Not Detected
  • 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 6 to 7 resulted in exceptionally stable formulations (#A7 and #A8). The stability testing data illustrates that the pH range of from about 6 to about 7 is critical. Formulations #A9 and #A10 also showed good stability after four weeks.
    • Example 5 Lipid Formulations
  • The formulations in Table 24 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.
  • TABLE 24
    Formulations with Lipids
    Formulation # LF1 # LF2 # LF3 # LF4 # LF5 # LF6 # LF7
    Cannabinoid 24.60 19.50 19.50 19.50 19.50 18.00 28.0 
    Vitamin E  0.05  0.05  0.05  0.05  0.05  0.05
    (Alpha
    Tocopherol)
    Flavor  0.30  0.30  0.30  0.30  0.30
    Sesame oil 75.40 80.15 70.15
    Sunflower oil 80.45
    Soybean oil 81.95
    Corn Oil 80.45
    A mixure of 61.95
    decanoyl and
    octanoyl
    glycerides
    (fatty acid
    esters)
    Ethanol 10.00 10.00
    • Example 6 Stability of a Formulation with Lipids
  • Formulation #LF1 was subjected to stability at 25° C.±2° C. under 60% 5% relative humidity and 40° C.±2° C. under 75%±5% relative humidity. 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 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Table 25 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.
  • TABLE 25
    Three Month Stability Data for Cannabidiol Oral Solution
    Formulation # LF1 stored at 40° C. ± 2° C. under 75% ± 5% relative
    humidity and stored at 25° C. ± 2° C. under 60% ± 5% relative humidity
    3 Months- 3 Months-
    Formulation # LF1 RRT 0 Month 40° C. 25° C.
    Assay (% of initial concentration) 100.00 100.87 100.72
    % Cis-cannabidiol 1.437 0.03 0.04 0.04
    % Delta 9-THC 1.736 0.06 0.06 0.08
    % Trans-(1R, 6R)-3′-methyl- 1.840 0.02 0.06 0.02
    cannabidiol
    Total Impurities (% Area) 0.11 0.16 0.14
  • As seen in Table 25 above, formulation #LF1 with sesame oil showed good stability after 3 months at both storage conditions 25° C.±2°C./60%±5% relative humidity and 40° C.±2° C./75%±5% relative humidity.
    • Example 7 Paclitaxel Induced Neuropathic Pain Study
  • 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-9-tetrahydrocannabinol, and cannabidiol plus delta-9-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 98%.
  • A detailed explanation of FIG. 1 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 mg/kg administered intraperitoneally. 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 21 post treatment. *p<0.05 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.
    • EXAMPLES
      • 1) If 1.25 mg/kg cannabidiol produces 100% alleviation of pain effect and 1.25 mg/kg delta-9-tetrahydrocannabinol produces 0% effect, then those doses added together should be fully effective (as should the 2.5 mg/kg cannabidiol+2.5 mg/kg delta-9-tetrahydrocannabinol).
      • 2) If 0.625 mg/kg cannabidiol and 0.625 delta-9-tetrahydrocannabinol produce 0% effect, then those doses in combination should be ineffective.
  • Applicant found (as illustrated in FIG. 1) that cannabidiol when administered alone provided the most effective level of alleviating chemotherapy-induced neuropathic pain compared to delta-9-tetrahydrocannabinol. The presence of delta-9-tetrahydrocannabinol depending on its concentration can inhibit the ability of cannabidiol to alleviate neuropathic pain. The ability of delta-9-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.
    • Example 8 Anticonvulsant Study
  • This study was conducted as follows according to standard models for anticonvulsant screening including the maximal electroshock test (“MES”), the minimal clonic seizure (“6 Hz”) 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 26 to 29 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 98%. The cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 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, 60Hz of alternating current (50 mA in mice, 150 in rats) was delivered for 0.2s by corneal electrodes which were primed with an electrolyte solution containing an anesthetic agent (0.5% tetracaine HCl). The mice were tested at various intervals following doses of 10, 30 and 100 mg/kg of cannabidiol given by intraperitoneal injection of a volume of 0.01 mL/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 6 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 60 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 (6 Hz) test. Like the maximal electroshock test, the minimal clonic seizure (6 Hz) test is used to assess a compound's efficacy against electrically induced seizures but uses a lower frequency (6 Hz) and longer duration of stimulation (3 s). Cannabidiol was pre-administered to mic e 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 97% of animals (32 mA for 3 s). 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.
  • TABLE 26
    Anticonvulsant Screening, Mice, Methylcellulose
    Time (Hours) 0.5 1.0 2.0
    Test Dose N/F N/F N/F
    6HZ
    10 0/4 0/4 0/4
    6HZ 30 0/4 0/4 0/4
    6HZ 100 1/4 0/4 0/4
    MES 10 0/4 0/4 0/4
    MES 30 0/4 0/4 0/4
    MES 100 0/4 1/4 2/4
    TOX 10 0/8 0/8 0/8
    TOX 30 0/8 0/8 0/8
    TOX
    100 0/8 0/8 0/8
  • TABLE 27
    Anticonvulsant Screening, Mice, Ethanol:Polyethoxylated
    castor oil:PBS
    Time (Hours) 0.5 1.0 2.0
    Test Dose N/F N/F N/F
    6HZ
    10 0/4 0/4 0/4
    6HZ 30 0/4 0/4 0/4
    6HZ 100 2/4 0/4 0/4
    MES 10 0/4 0/4 0/4
    MES 30 0/4 1/4 0/4
    MES 100 0/4 2/4 1/4
    TOX 10 0/8 0/8 0/8
    TOX 30 0/8 0/8 0/8
    TOX
    100 0/8 0/8 0/8
  • TABLE 28
    Anticonvulsant Screening, Rats, Methylcellulose
    Time (Hours) 1.0 2.0 4.0
    Test Dose N/F N/F N/F
    MES 30 0/4 0/4 0/4
    MES 100 0/4 0/4 0/4
    TOX 30 0/4 0/4 0/4
    TOX
    100 0/4 0/4 0/4
  • TABLE 29
    Anticonvulsant Screening, Rats, Ethanol:Polyethoxylated
    castor oil:PBS
    Time (Hours) 1.0 2.0 4.0
    Test Dose N/F N/F N/F
    MES 30 0/4 0/4 0/4
    MES 100 1/4 0/4 0/4
    TOX 30 0/4 0/4 0/4
    TOX
    100 0/4 0/4 0/4
  • As seen in Tables 26 to 29 above, Applicant found that cannabidiol protected the mice and rats from epilepsy.
    • Example 9 Glioblastoma Multiforme Study
  • A study was conducted in order to determine the extent to which systemic administration of cannabidiol or cannabidiol plus delta-9-tetrahydrocannabinol (cannabidiol/delta-9-tetrahydrocannabinol 1:1) 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-9-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 10% fetal bovine serum and then harvested from dishes while in their exponential growth phase in culture with 0.1% 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 0.3×106 U87 cells in 4 μl 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 5mm as assessed by callipers. Additionally, mice with tumors measuring >500×106 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 3% ethanol, 3% surfactant and 94% saline, and temozolomide was dissolved in 30% dimethyl sulfoxide and 70% saline. Cannabidiol that was synthetically synthesized and substantially pure was used in this study. The treatments were initiated 9 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, 5 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 12 mice per group, for a total of 72 mice. The treatment rates were as follows: cannabidiol (15 mg/kg); cannabidiol/delta-9-tetrahydrocannabinol (1:1, together @ 15mg/kg); and temozolomide (2 mg/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 <0.05 defined statistical significance.
  • A detailed explanation of FIG. 2 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. 2, while 15 mg/kg of cannabidiol alone or cannabidiol/delta-9-tetrahydrocannabinol (1:1) 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 20% of tumors. This effect was not observed following the 1:1 cannabidiol:delta-9-tetrahydrocannabinol treatments. It was unexpected that substantially pure, synthetically synthesized, cannabidiol would have these effects because previously it was thought that a 1:1 ratio of cannabidiol (that was extracted from cannabis and not substantially pure):delta-9-tetrahydrocannabinol would produce better effects than cannabidiol alone. However, this study again illustrates the superiority of Applicant's substantially pure, synthetically synthesized, cannabidiol.
    • Example 10 6 Hz Psychomotor Seizure Test
  • 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 (6 Hz) stimulation. This is a study model for therapy-resistant partial seizures.
  • Adult male CF1 mice (weighing 18 to 25 g) were pretreated intraperitoneally with the cannabidiol at a dose of 100 mg/kg. The cannabidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than 98%. The cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 ratio of ethanol:polyethoxylated castor oil:PBS.
  • Each treatment group (n=4 mice/group) was examined for anticonvulsive effects at one of five time points (¼, ½, 1, 2, and 4 hours) following treatment with cannabidiol. Following pretreatment, each mouse received a drop of 0.5% tetracaine hydrochloride applied to each eye. The mouse was then challenged with the low-frequency (6 Hz) stimulation for 3 seconds delivered through corneal electrodes. The low-frequency, long-duration stimuli was initially delivered at 32 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 32 mA screen, an additional assay wherein the stimulation current is increased to 44 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 6 Hz 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<0.05 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., 2/4 represents 2 out of 4 mice tested were protected).
  • TABLE 30
    ED50 Biological Response, Methylcellulose
    Time (Hours) 0.5
    Test Dose N/F
    6 Hz 30 0/8
    6 Hz 65 5/8
    6 Hz 130 5/8
    6 Hz 160  8/16
    6 Hz 190 7/8
  • TABLE 31
    Time to Peak Effect, Methylcellulose
    Time (Hours) 0.25 0.5 1 2 4 6 24
    Test Dose N/F N/F N/F N/F N/F N/F N/F
    6 Hz 300 1/8 0/8 0/8 0/8 0/8 0/8 0/8
    6 Hz 500 1/8 0/8 0/8 0/8 0/8 0/8 2/8
  • TABLE 32
    ED50 Biological Response, Ethanol:Polyethoxylated
    castor oil:PBS
    Test Dose Time N/F
    6 Hz 50 0.5 1/8
    6 Hz 100 0.5 1/8
    6 Hz 130 0.5 4/8
    6 Hz 170 0.5 6/8
    6 Hz 200 0.5 8/8
    TOX 200 2 0/8
    TOX 250 2 4/8
    TOX 300 2 6/8
    TOX 500 2 8/8
  • TABLE 33
    Time to Peak Effect, Ethanol:Polyethoxylated castor oil:PBS
    Time (Hours) 0.25 0.5 1 2 4 6 8 24
    Test Dose N/F N/F N/F N/F N/F N/F N/F N/F
    TOX 200 — — — 0/8 0/8 — — —
    TOX 250 — — — 4/8 3/8 — — —
    TOX 300 — — — 6/8 7/8 4/8 2/8 1/8
    TOX 500 0/8 0/8 0/8 8/8 8/8 8/8 — 4/7
  • As seen in Tables 30 to 33, cannabidiol in both solvents showed comparable median effective doses that inhibited seizures in 50% of animals (ED50s) in the 100 mg/kg range. While cannabidiol dissolved in the methylcellulose solvent had an ED50 of 103.75 mg/kg (95% Confidence Interval of 53.89 mg/kg to 163.84 mg/kg), it showed an ED50 of 121.52 mg/kg when dissolved in the 1:1:18 ethanol:polyethoxylated castor oil:PBS solvent (95% Confidence Interval of 87.83 mg/kg to 152.96 mg/kg). Based on the toxicity data for the cannabidiol in the methylcellulose solvent, the median toxicity dose where toxicity is observed in 50% of animals (“TD50”) was determined to exceed 500 mg/kg at 0.5 hours post administration. Diarrhea at 24 hours and 1 death was reported at 24 hours at 500 mg/kg, the highest dose tested.
  • The TD50 was determined to be 262.37 mg/kg (95% Confidence Interval of 232.64 to 301.78) with cannabidiol dissolved in the 1:1:18 ethanol:polyethoxylated castor oil:PBS solvent. Death was reported at 24 hours at 300 mg/kg and at 6 and 24 hours for 500 mg/kg with the with the 1:1:18 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.
    • Example 11 Maximal Electroshock Seizure and Subcutaneous Metrazol
  • 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 IVIES test provides an indication of CBD's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active. The s.c. 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 IVIES test, 60 Hz of alternating current is delivered by corneal electrodes for 0.2 seconds. Supra-maximal seizures are elicited with a current intensity five times that necessary to evoke a threshold tonic extension seizure, i.e., 50 mA in mice and 150 mA in rats. A drop of anesthetic solution, 0.5% 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 IVIES test.
  • A dose of Metrazol (85 mg/kg in mice) will induce convulsions in 97% 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 0.01 ml/g body weight. The animals are then placed in isolation cages to minimize stress and continuously monitored for the next 30 min for the presence or absence of a seizure. An episode of clonic spasms, approximately 3 to 5 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 8 mice were tested with various doses of cannabidiol until at least two points are established between the limits of 100% protection or minimal toxicity and 0% protection or minimal toxicity. The dose of drug required to produce the desired endpoint in 50% of animals (ED50 or TD50) in each test, the 95% confidence interval, the slope of the regression line, and the standard error of the mean (S.E.M.) 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 98%. The cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18 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.
  • TABLE 34
    ED50 Biological Response, Methylcellulose
    Test Dose Time N/F
    MES 200 2 5/8
    MES 250 2 4/8
    MES 300 2 4/8
    MES 350 2 3/8
    MES 400 2 3/8
    MES 450 2 6/8
    MES 500 2 8/8
    Sc MET 150 2 1/8
    Sc MET 200 2 3/8
    Sc MET 300 2 5/8
    Sc MET 360 2 7/8
    TOX 500 2 0/8
  • TABLE 35
    Time to Peak Effect, Methylcellulose
    Time (Hours) 0.25 0.5 1 2 4
    Test Dose N/F N/F N/F N/F N/F
    MES 300 0/4 1/4 1/4 4/8 2/4
    Sc MET 200 0/4 0/4 2/8 3/8 —
    TOX 300 0/4 0/4 0/4 0/4 0/4
  • TABLE 36
    ED50 Biological Response, Ethanol:Polyethoxylated
    castor oil:PBS
    Test Dose Time N/F
    MES
    75 2 1/8
    MES 95 2 5/8
    MES 120 2 7/8
    MES 150 2 8/8
    Sc MET 120 2 0/8
    Sc MET 160 2 2/8
    Sc MET 220 2 5/8
    Sc MET 260 2 7/8
    TOX 175 2 0/8
    TOX 250 2 4/8
    TOX 325 2 6/8
    TOX 500 2 8/8
  • TABLE 37
    Time to Peak Effect, Ethanol:Polyethoxylated castor oil:PBS
    Time (Hours) 0.25 0.5 1 2 4 6 8
    Test Dose N/F N/F N/F N/F N/F N/F N/F
    TOX 500 0/8 0/8 0/8 8/8 7/8 7/8 4/8
  • The ED50 in the MES model for cannabidiol dissolved in the methylcellulose solvent could not be calculated due to a U shaped dose response (1/4 protected at 0.5 hr, 1/4 at 1 hr, 4/8 at 2hr and 2/4 at 4hr). However, the ED50 for cannabidiol dissolved in the 1:1:18 ethanol:polyethoxlated castor oil:PBS solvent is 92.21 mg/kg (95% Confidence Interval of 78.4 mg/kg to 104.63 mg/kg).
  • For the MET model, the ED50 was 241.03 mg/kg (95% Confidence Interval of 182.23 to 311.87) for cannabidiol dissolved in the methylcellulose solvent and 198.51 mg/kg (95% Confidence Interval of 167.76 mg/kg to 232.58 mg/kg) for cannabidiol dissolved in the 1:1:18 ethanol:polyethoxlated castor oil:PBS solvent. Based on the toxicity data for cannabidiol dissolved in the methylcellulose solvent the TD50 was determined to exceed 500 mg/kg, the highest dose tested.
  • Myoclonic jerks were reported in at 1 hour with 200 mg/kg dose and at 2 hours with 360 mg/kg dose. The TD50 was determined to be 266.76 mg/kg (95% Confidence Interval of 222.28 mg/kg to 317.42 mg/kg) with the cannabidiol dissolved in the 1:1:18 ethanol:polyethoxlated 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.

Claims (17)

1-25. (canceled)
26. A method for treating infantile spasms in a subject, comprising administering to the subject a composition comprising cannabidiol, wherein the cannabidiol has a purity of greater than 98% w/w and wherein the dose of cannabidiol is about 20 to about 100 mg of cannabidiol per kg weight of the subject per day.
27. (canceled)
28. The method of claim 26, wherein the infantile spasms are refractory infantile spasms.
29. The method of claim 26, wherein the dose of cannabidiol is about 20 to about 30 mg of cannabidiol per kg weight of the subject per day.
30. The method of claim 26, wherein the dose of cannabidiol is about 20 mg of cannabidiol per kg weight of the subject per day.
31. The method of claim 26, wherein the dose of cannabidiol is about 30 mg of cannabidiol per kg weight of the subject per day.
32. The method of claim 26, wherein the dose of cannabidiol is about 100 mg of cannabidiol per kg weight of the subject per day.
33. The method of claim 26, wherein the composition is a liquid solution.
34. The method of claim 26, wherein the composition does not contain alcohol.
35. The method of claim 26, wherein the cannabidiol is a synthetically prepared cannabidiol.
36. The method of claim 26, wherein the composition comprises about 10 to about 32% w/w of cannabidiol.
37. The method of claim 26, wherein the composition comprises:
about 10 to about 32% w/w of cannabidiol;
about 60 to about 95% of a lipid; and
an antioxidant.
38. The method of claim 37, wherein the lipid comprises caprylic/capric triglycerides.
39. The method of claim 37, wherein the composition comprises about 0.01 to about 1% w/w of an antioxidant.
40. The method of claim 37, wherein the antioxidant is alpha-tocopherol.
41. The method of claim 26, wherein the subject is a human subject with West syndrome.
US17/559,155 2014-05-29 2021-12-22 Stable cannabinoid formulations Pending US20220184215A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/559,155 US20220184215A1 (en) 2014-05-29 2021-12-22 Stable cannabinoid formulations

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462004495P 2014-05-29 2014-05-29
US201562154660P 2015-04-29 2015-04-29
US14/724,351 US11224660B2 (en) 2014-05-29 2015-05-28 Stable cannabinoid formulations
US17/559,155 US20220184215A1 (en) 2014-05-29 2021-12-22 Stable cannabinoid formulations

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US14/724,351 Division US11224660B2 (en) 2014-05-29 2015-05-28 Stable cannabinoid formulations

Publications (1)

Publication Number Publication Date
US20220184215A1 true US20220184215A1 (en) 2022-06-16

Family

ID=54700061

Family Applications (4)

Application Number Title Priority Date Filing Date
US14/724,351 Active US11224660B2 (en) 2014-05-29 2015-05-28 Stable cannabinoid formulations
US17/367,876 Pending US20210330797A1 (en) 2014-05-29 2021-07-06 Stable cannabinoid formulations
US17/519,844 Pending US20220125932A1 (en) 2014-05-29 2021-11-05 Stable cannabinoid formulations
US17/559,155 Pending US20220184215A1 (en) 2014-05-29 2021-12-22 Stable cannabinoid formulations

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US14/724,351 Active US11224660B2 (en) 2014-05-29 2015-05-28 Stable cannabinoid formulations
US17/367,876 Pending US20210330797A1 (en) 2014-05-29 2021-07-06 Stable cannabinoid formulations
US17/519,844 Pending US20220125932A1 (en) 2014-05-29 2021-11-05 Stable cannabinoid formulations

Country Status (12)

Country Link
US (4) US11224660B2 (en)
EP (2) EP3148589B1 (en)
JP (1) JP6659933B2 (en)
KR (1) KR20170008311A (en)
CN (2) CN114191420A (en)
AU (1) AU2015266897B2 (en)
CA (1) CA2950424C (en)
IL (2) IL302782A (en)
MX (2) MX2016015636A (en)
NZ (1) NZ726746A (en)
WO (1) WO2015184127A2 (en)
ZA (1) ZA201608209B (en)

Families Citing this family (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2471523A (en) 2009-07-03 2011-01-05 Gw Pharma Ltd Use of tetrahydrocannibivarin (THCV) and optionally cannabidiol (CBD) in the treatment of epilepsy
TWI583374B (en) 2010-03-30 2017-05-21 Ｇｗ伐瑪有限公司 Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy
GB2495118B (en) 2011-09-29 2016-05-18 Otsuka Pharma Co Ltd A pharmaceutical composition comprising the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD)
US11911361B2 (en) 2014-05-29 2024-02-27 Radius Pharmaceuticals, Inc. Stable cannabinoid formulations
US11331279B2 (en) 2014-05-29 2022-05-17 Radius Pharmaceuticals, Inc. Stable cannabinoid formulations
GB2530001B (en) 2014-06-17 2019-01-16 Gw Pharma Ltd Use of cannabidiol in the reduction of convulsive seizure frequency in treatment-resistant epilepsy
GB2527599A (en) 2014-06-27 2015-12-30 Gw Pharma Ltd Use of 7-OH-Cannabidiol (7-OH-CBD) and/or 7-OH-Cannabidivarin (7-OH-CBDV) in the treatment of epilepsy
GB2531278A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabidiol in the treatment of intractable epilepsy
GB2531282A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabinoids in the treatment of epilepsy
GB2531281A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabidiol in the treatment of intractable epilepsy
US20170021029A1 (en) * 2015-04-15 2017-01-26 Jeffrey Charles Raber Topical formulations and uses
AU2016255707A1 (en) * 2015-04-28 2017-11-30 The Regents Of The University Of California Uses of cannabidiol for treatment of infantile spasms
GB201508656D0 (en) 2015-05-20 2015-07-01 Sunstone Ip Systems Ltd Portable power generating apparatus
WO2016191651A1 (en) * 2015-05-28 2016-12-01 Insys Development Company, Inc. Stable cannabinoid formulations
GB2539472A (en) 2015-06-17 2016-12-21 Gw Res Ltd Use of cannabinoids in the treatment of epilepsy
GB2541191A (en) 2015-08-10 2017-02-15 Gw Pharma Ltd Use of cannabinoids in the treatment of epilepsy
BR102015024165A2 (en) * 2015-09-18 2017-03-28 Prati Donaduzzi & Cia Ltda oral pharmaceutical composition comprising cannabinoid, process for its preparation and use
GB2544468A (en) * 2015-11-12 2017-05-24 Jaytee Biosciences Ltd Liquid formulation
GB2548873B (en) 2016-03-31 2020-12-02 Gw Res Ltd Use of Cannabidiol in the Treatment of SturgeWeber Syndrome
GB2549278B (en) * 2016-04-11 2021-02-17 Gw Res Ltd Use of cannabidivarin in the treatment of autism spectrum disorder
GB2549277B (en) * 2016-04-11 2021-02-17 Gw Res Ltd Cannabidiolic Acid for use in the Treatment of Autism Spectrum Disorder
CA3025702C (en) * 2016-05-27 2022-12-20 Insys Development Company, Inc. Stable cannabinoid formulations
WO2017218629A1 (en) * 2016-06-15 2017-12-21 India Globalization Capital, Inc. Method and composition for treating seizure disorders
GB2551987A (en) * 2016-07-01 2018-01-10 Gw Res Ltd Oral cannabinoid formulations
GB2551986A (en) 2016-07-01 2018-01-10 Gw Res Ltd Parenteral formulations
GB2553139A (en) 2016-08-25 2018-02-28 Gw Res Ltd Use of cannabinoids in the treatment of multiple myeloma
AU2017344040A1 (en) 2016-10-11 2019-04-18 Gbs Global Biopharma, Inc. Cannabinoid-containing complex mixtures for the treatment of neurodegenerative diseases
WO2018096504A1 (en) * 2016-11-28 2018-05-31 Kalytera Therapeutics, Inc Cbd prodrugs, compositions, and methods of administering cbd and cbd prodrugs
GB2557921A (en) 2016-12-16 2018-07-04 Gw Res Ltd Use of cannabinoids in the treatment of angelman syndrome
CN107753560A (en) * 2016-12-28 2018-03-06 汉义生物科技（北京）有限公司 A kind of composition and application containing Cannador
CA3052146A1 (en) 2017-02-01 2018-08-09 Gbs Global Biopharma, Inc. Cannabinoid-containing complex mixtures for the treatment of mast cell-associated or basophil-mediated inflammatory disorders
GB2559774B (en) 2017-02-17 2021-09-29 Gw Res Ltd Oral cannabinoid formulations
NL2018504B1 (en) * 2017-03-13 2018-09-21 Pharma Unlimited B V Tobacco- and smoke-less products consumable by humans as epicurean or medical products and method of treating smoking addiction
JP2020517727A (en) 2017-04-27 2020-06-18 インシス・ディベロップメント・カンパニー・インコーポレイテッド Stable cannabinoid formulation
GB2564383B (en) * 2017-06-23 2021-04-21 Gw Res Ltd Use of cannabidiol in the treatment of tumours assoicated with Tuberous Sclerosis Complex
WO2019018705A1 (en) * 2017-07-21 2019-01-24 Masaya World, Llc Cannabidiol-enriched caprylic acid
US10220061B1 (en) 2017-09-26 2019-03-05 Cynthia Denapoli Method of reducing stress and anxiety in equines
CA3077330A1 (en) 2017-09-28 2019-04-04 Zynerba Pharmaceuticals, Inc. Treatment of fragile x syndrome with cannabidiol
GB2568471B (en) * 2017-11-15 2022-04-13 Gw Res Ltd Use of cannabinoids in the treatment of epilepsy
GB2572126B (en) * 2018-01-03 2021-01-13 Gw Res Ltd Pharmaceutical
GB2572125B (en) * 2018-01-03 2021-01-13 Gw Res Ltd Pharmaceutical
GB2569961B (en) * 2018-01-03 2021-12-22 Gw Res Ltd Pharmaceutical
EP3749297A4 (en) 2018-02-07 2021-04-14 SCF Pharma Inc. Polyunsaturated fatty acid monoglycerides, compositions, methods and uses thereof
BR102018002843A2 (en) * 2018-02-09 2019-08-27 Prati Donaduzzi & Cia Ltda pharmaceutical composition and use thereof
GB201806953D0 (en) 2018-04-27 2018-06-13 Gw Res Ltd Cannabidiol Preparations
CN112423740A (en) 2018-05-01 2021-02-26 奇比有限公司 Eye drop formulations and methods for sustained drug delivery to the retina
CA3097927A1 (en) 2018-05-01 2019-11-07 Chibi, Inc. Liquid depot for non-invasive sustained delivery of agents to the eye
WO2019210424A1 (en) 2018-05-03 2019-11-07 Scf Pharma Inc. Polyunsaturated fatty acid monoglycerides, compositions, methods and uses thereof
CN110575448A (en) * 2018-06-08 2019-12-17 云南汉素生物科技有限公司 Cannabidiol composition and application thereof
CN109627148B (en) * 2018-11-28 2021-09-03 中国农业科学院麻类研究所 Preparation method of cannabidiol, prepared cannabidiol and application thereof
JP7326445B2 (en) 2018-12-11 2023-08-15 ディスラプション・ラブズ・インコーポレイテッド Compositions and methods of use and manufacture thereof for delivery of therapeutic agents
US11458109B2 (en) 2018-12-14 2022-10-04 Zynerba Pharmaceuticals, Inc. Treatment of 22Q11.2 deletion syndrome with cannabidiol
DE102019100483A1 (en) * 2019-01-10 2020-07-16 Lts Lohmann Therapie-Systeme Ag Oral thin film
GB2584341B (en) 2019-05-31 2023-03-01 Gw Res Ltd Cannabinoid formulations
US20220288014A1 (en) * 2019-08-08 2022-09-15 Neptune Wellness Solutions Inc. Oral formulations of cannabis extracts and methods of making same
CN111202767A (en) * 2019-09-04 2020-05-29 汉义生物科技（北京）有限公司 Application of hemp whole plant extract in improving pathological injury of tau protein and β -amyloid protein
MX2022002548A (en) * 2019-09-09 2022-03-22 Cardiol Therapeutics Inc Stable medicinal cannabidiol compositions.
US12016829B2 (en) 2019-10-11 2024-06-25 Pike Therapeutics Inc. Pharmaceutical composition and method for treating seizure disorders
US12121617B2 (en) 2019-10-14 2024-10-22 Pike Therapeutics Inc. Transdermal delivery of cannabidiol
MX2022004258A (en) 2019-10-14 2022-05-26 Pike Therapeutics Inc Transdermal delivery of cannabidiol.
US20210169795A1 (en) * 2019-12-06 2021-06-10 Joshua Steindler Colloidal Suspensions of Plant Extracts in Aqueous Solutions
GB201918846D0 (en) 2019-12-19 2020-02-05 Gw Res Ltd Oral cannabinoid formulations
EP4088723A4 (en) * 2020-01-08 2024-02-21 Chengdu Baiyu Pharmaceutical Co., Ltd. Cannabidiol derivative, and preparation method therefor and medical use thereof
GB202002754D0 (en) 2020-02-27 2020-04-15 Gw Res Ltd Methods of treating tuberous sclerosis complex with cannabidiol and everolimus
KR102213253B1 (en) * 2020-04-29 2021-02-08 한국과학기술원 Method for evaluating neuroprotective effect of cannabidiol against oxidative stress and Pharmaceutical composition containing cannabidiol As the active ingredient for the prevention or treatment of neurodegenerative diseases
AU2021347760B2 (en) * 2020-09-24 2024-07-25 Nicoventures Trading Limited Formulation
US11160757B1 (en) 2020-10-12 2021-11-02 GW Research Limited pH dependent release coated microparticle cannabinoid formulations
JP2024500187A (en) 2020-12-21 2024-01-04 アイソセレス ファーマシューティカルズ，インコーポレイテッド Parenteral cannabinoid formulations and their uses
US11242328B1 (en) 2021-02-25 2022-02-08 Acid Neutral Alkaline Laboratory Heterogeneous catalyst and method for preparation of aromatic tricyclic pyrans
US11242330B1 (en) 2021-02-25 2022-02-08 Acid Neutral Alkaline Laboratory Organic catalyst and method for preparation of aromatic tricyclic pyrans
CN113398104B (en) * 2021-07-14 2022-04-08 北京森宏健康科技有限公司 Use of cannabidiol in the treatment of bilirubin encephalopathy
CA3239914A1 (en) * 2021-12-03 2023-06-08 Avicanna Inc. Oral cannabinoid compositions and methods for treating neurological diseases and disorders
WO2023200906A1 (en) 2022-04-12 2023-10-19 Shackelford Pharma Inc. Treatment of seizure disorders
WO2024079542A1 (en) * 2022-10-12 2024-04-18 Leiutis Pharmaceuticals Llp Novel liquid oral formulations of cannabidiol

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE308314T1 (en) 1999-08-20 2005-11-15 Unimed Pharmaceuticals Inc COMPOSITION FOR INHALATION CONTAINING DELTA-9-TETRAHYDROCANNABINOL IN A SEMI-AQUEOUS SOLVENT
DK1361864T3 (en) 2001-02-14 2014-03-03 Gw Pharma Ltd FLYLDENDE SPRAY FORMULATIONS FOR buccal administration of cannabinoids
GB0103638D0 (en) * 2001-02-14 2001-03-28 Gw Pharmaceuticals Ltd Pharmaceutical formulations
CN1652766A (en) * 2002-03-18 2005-08-10 免疫力药品有限公司 Topical formulations of resorcinols and cannibinoids and methods of use
WO2003101357A1 (en) * 2002-05-31 2003-12-11 University Of Mississippi Transmucosal delivery of cannabinoids
GB0222077D0 (en) * 2002-09-23 2002-10-30 Gw Pharma Ltd Methods of preparing cannabinoids from plant material
GB2393182B (en) * 2002-09-23 2007-03-14 Gw Pharma Ltd Method of preparing cannabidiol from plant material
NZ555701A (en) * 2004-12-09 2011-05-27 Insys Therapeutics Inc Room-temperature stable dronabinol formulations
EP2578561A1 (en) * 2005-09-29 2013-04-10 Albany Molecular Research, Inc. Processes for the production of cannabidiol derivatives and intermediates thereof
US20100291205A1 (en) 2007-01-16 2010-11-18 Egalet A/S Pharmaceutical compositions and methods for mitigating risk of alcohol induced dose dumping or drug abuse
US8222292B2 (en) 2007-08-06 2012-07-17 Insys Therapeutics, Inc. Liquid cannabinoid formulations
US20090181080A1 (en) * 2007-08-06 2009-07-16 Insys Therapeutics Inc. Oral cannabinnoid liquid formulations and methods of treatment
GB2471987B (en) * 2008-06-04 2012-02-22 Gw Pharma Ltd Anti-tumoural effects of cannabinoid combinations
AT509000B1 (en) * 2009-10-23 2012-12-15 Rausch Peter WATER-SOLUBLE PREPARATIONS OF CANNABINOIDS AND CANNABIC PREPARATIONS AND THEIR APPLICATIONS
EP2642982A2 (en) * 2010-11-22 2013-10-02 Johnson Matthey Public Limited Company Stable cannabinoid compositions and methods for making and storing them
US20130289019A1 (en) 2012-04-26 2013-10-31 Amazing Grace, Inc. Methods of treating behaviorial and/or mental disorders
US9345771B2 (en) * 2012-10-04 2016-05-24 Insys Development Company, Inc. Oral cannabinoid formulations

Also Published As

Publication number Publication date
AU2015266897B2 (en) 2020-07-30
NZ763449A (en) 2024-02-23
EP3148589A2 (en) 2017-04-05
US20210330797A1 (en) 2021-10-28
CN106999598A (en) 2017-08-01
KR20170008311A (en) 2017-01-23
JP2017519742A (en) 2017-07-20
EP3148589B1 (en) 2024-10-30
EP3148589A4 (en) 2018-01-17
US20150343071A1 (en) 2015-12-03
WO2015184127A9 (en) 2016-05-19
WO2015184127A2 (en) 2015-12-03
NZ726746A (en) 2020-08-28
WO2015184127A3 (en) 2016-03-17
US20220125932A1 (en) 2022-04-28
EP4151234A1 (en) 2023-03-22
CA2950424C (en) 2023-03-14
ZA201608209B (en) 2023-06-28
MX2016015636A (en) 2017-08-02
MX2021006035A (en) 2021-07-06
CA2950424A1 (en) 2015-12-03
IL249197B1 (en) 2024-05-01
US11224660B2 (en) 2022-01-18
AU2015266897A1 (en) 2016-12-15
CN114191420A (en) 2022-03-18
IL302782A (en) 2023-07-01
IL249197B2 (en) 2024-09-01
CN106999598B (en) 2022-02-08
JP6659933B2 (en) 2020-03-04
IL249197A0 (en) 2017-01-31

Similar Documents

Publication Publication Date Title
US20220184215A1 (en) Stable cannabinoid formulations
US20220280446A1 (en) Stable cannabinoid formulations
AU2022201441B2 (en) Stable cannabinoid formulations
US20160271252A1 (en) Stable cannabinoid formulations
US20170224634A1 (en) Stable cannabinoid formulations
CA3062814C (en) Stable cannabinoid formulations
US20160367496A1 (en) Stable cannabinoid formulations
US20220054450A1 (en) Stable cannabinoid formulations
WO2017204986A1 (en) Stable cannabinoid formulations

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

AS Assignment

Owner name: RADIUS PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FRESH CUT DEVELOPMENT, LLC;REEL/FRAME:059566/0295

Effective date: 20201230

Owner name: FRESH CUT DEVELOPMENT, LLC, ARIZONA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BENUVIA THERAPEUTICS INC.;REEL/FRAME:059566/0272

Effective date: 20191210

Owner name: INSYS DEVELOPMENT COMPANY, INC., ARIZONA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:INSYS PHARMA, INC.;REEL/FRAME:059566/0102

Effective date: 20160202

Owner name: FRESH CUT DEVELOPMENT, LLC, ARIZONA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:INSYS THERAPEUTICS, INC.;INSYS PHARMA, INC.;INSYS DEVELOPMENT COMPANY, INC.;REEL/FRAME:059566/0202

Effective date: 20191031

Owner name: BENUVIA THERAPEUTICS INC., ARIZONA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FRESH CUT DEVELOPMENT, LLC;REEL/FRAME:059566/0246

Effective date: 20191129

Owner name: INSYS DEVELOPMENT COMPANY, INC., ARIZONA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:VANGARA, KIRAN KUMAR;LI, HUAGUANG;YAN, NINGXIN;AND OTHERS;REEL/FRAME:059566/0156

Effective date: 20160923

AS Assignment

Owner name: RADIUS PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: CHANGE OF ADDRESS;ASSIGNOR:RADIUS PHARMACEUTICALS, INC.;REEL/FRAME:059678/0492

Effective date: 20211011

AS Assignment

Owner name: WILMINGTON TRUST, NATIONAL ASSOCIATION, MINNESOTA

Free format text: SECURITY INTEREST;ASSIGNOR:RADIUS HEALTH, INC.;REEL/FRAME:061179/0001

Effective date: 20220815

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

AS Assignment

Owner name: RADIUS HEALTH, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:WILMINGTON TRUST, NATIONAL ASSOCIATION;REEL/FRAME:068051/0671

Effective date: 20240722

AS Assignment

Owner name: FRESH CUT DEVELOPMENT, LLC, CANADA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RADIUS PHARMACEUTICALS, INC.;REEL/FRAME:068543/0020

Effective date: 20240724

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER