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WO2025049544A1 - Formulations parentérales d'inhibiteurs de cb1 et procédés d'utilisation - Google Patents

Formulations parentérales d'inhibiteurs de cb1 et procédés d'utilisation Download PDF

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Publication number
WO2025049544A1
WO2025049544A1 PCT/US2024/044144 US2024044144W WO2025049544A1 WO 2025049544 A1 WO2025049544 A1 WO 2025049544A1 US 2024044144 W US2024044144 W US 2024044144W WO 2025049544 A1 WO2025049544 A1 WO 2025049544A1
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pharmaceutical composition
compound
instances
excipient
subject
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Kenneth C. Cundy
Margaret COURTNEY
Peter Van Hoogevest
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Anebulo Pharmaceuticals Inc
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Anebulo Pharmaceuticals Inc
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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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

Definitions

  • formulations and methods for treating cannabinoid-related diseases or disorders Provided herein are formulations and methods for treating cannabinoid toxicity via parenteral administration. Provided herein are formulations and methods for treating cannabinoid intoxication, cannabinoid overdose, or cannabinoid poisoning via parenteral administration. Provided herein are formulations and methods for treating acute cannabinoid intoxication (ACI), acute cannabinoid overdose (ACO), or cannabinoid poisoning via parenteral administration.
  • ACI acute cannabinoid intoxication
  • ACO acute cannabinoid overdose
  • cannabinoid poisoning via parenteral administration cannabinoid poisoning via parenteral administration.
  • compositions configured for parenteral administration comprising a compound having the structure: least one excipient, wherein the parenteral formulation comprises a nanosuspension, oil and water emulsion, liposome, or micelle.
  • pharmaceutical composition wherein Further provided herein are pharmaceutical composition wherein the parenteral formulation comprises a liposome.
  • pharmaceutical composition wherein the at least one excipient comprises a lipid.
  • pharmaceutical composition wherein the at least one excipient comprises a phospholipid.
  • pharmaceutical composition wherein the at least one excipient comprises a phosphatidylcholine.
  • compositions wherein the ratio of the first excipient to the second excipient is about 90:10 to about 99:1.
  • T Further provided herein are pharmaceutical composition wherein the first excipient comprises HSPC, DMPC, phosphatidylcholine, DOPG, POPC, or a salt thereof.
  • pharmaceutical composition wherein the first excipient comprises HSPC, DMPC, soybean phosphatidylcholine, DOPG, POPC, or a salt thereof.
  • pharmaceutical composition wherein the second excipient comprises DSPG, DMPG, DMPC, or a salt thereof.
  • the pharmaceutical composition comprises about 10-50 mg/mL phospholipid.
  • compositions wherein the pharmaceutical composition are stable at room temperature for at least one week, one month, two months, six months, or at least a year. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is stable at no more than 0 degrees C for at least one week, one month, two months, six months, or at least a year. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is stable at no more than -20 degrees C for at least one week, one month, two months, six months, or at least a year. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is essentially unchanged at room temperature for at least one week, one month, two months, six months, or at least a year as measured by HPLC.
  • compositions wherein the pharmaceutical composition comprises about 5:1 to about 1:5 mixture of soybean oil to any one of coconut oil, olive oil, or Miglyol 812
  • pharmaceutical composition wherein the compound is present at 5-20 mg/mL.
  • pharmaceutical composition wherein the parenteral formulation comprises micelles.
  • pharmaceutical composition wherein the parenteral formulation comprises a phospholipid.
  • pharmaceutical composition wherein the excipient comprises Miglyol 812, Lipoid E80, saline, or a combination thereof.
  • pharmaceutical composition comprises about 0.5-3% Lipoid E80.
  • pharmaceutical composition is present at about 1-20 mg/mL.
  • the amount of compound administered to the subject is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 50 mg. Further provided herein are methods wherein the amount of compound administered to the subject is 1-200 mg, 1-10 mg, 1-25 mg, 5-20 mg, 10-50 mg, 10-30 mg, or 20-30 mg. Further provided herein are methods wherein the method further comprises administering 5-300 mg, 5-100 mg, or 10-30 mg of delta-9-tetrahydrocannabinol (THC) to the subject. Further provided herein are methods wherein the acute cannabinoid toxicity results from ingestion of an edible form of cannabis.
  • THC delta-9-tetrahydrocannabinol
  • the acute cannabinoid toxicity results from ingestion of a synthetic cannabinoid.
  • the synthetic cannabinoid, edible form of cannabis, or THC is self- administered.
  • the parenteral route of administration comprises intravenous (IV), intramuscular (IM), or subcutaneous (SC).
  • the parenteral route of administration comprises intravenous (IV).
  • intravenous (IV) comprises IV bolus, IV drip, or IV push.
  • the pharmaceutical composition is delivered in a liquid volume of about 0.1-5 mL.
  • compositions wherein the pharmaceutical composition is delivered in a liquid volume of about 50-1000 mL. Further provided herein are methods wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng/mL within 10 minutes. Further provided herein are methods wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng/mL within 5 minutes. Further provided herein are methods wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng/mL within 2 minutes.
  • compositions the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng/mL within 60 seconds. Further provided herein are methods wherein the subject exhibits symptoms of cannabinoid hyperemesis syndrome. Further provided herein are methods wherein the subject is experiencing one or more of nausea, vomiting, coughing, and choking. Further provided herein are methods wherein the subject is experiencing respiratory depression. Further provided herein are methods wherein the subject is experiencing anaphylactic shock. Further provided herein are methods wherein the subject is experiencing trauma or swelling to the face, mouth, throat, esophagus, or digestive tract. Further provided herein are methods wherein the subject is unwilling or unable to ingest an oral medicament.
  • methods wherein one or more symptoms of overdose are ameliorated in no more than 5 minutes. Further provided herein are methods wherein one or more symptoms of overdose are ameliorated in no more than 1 minute. Further provided herein are methods wherein the subject is a pediatric patient. Further provided herein are methods wherein the subject is selected from an adolescent, child, infant, or neonate. Further provided herein are methods wherein the patient is no more than 28 days, 2 years, 12 years, or 21 years old. Further provided herein are methods wherein the patient is 1-28 days old, 29 days to less than 2 years old, 2 years to less than 12 years old, or 12 years to less than 21 years old.
  • first solution is mixed at about room temperature.
  • second solution is mixed at about 40-60 degrees C.
  • combining occurs at about room temperature.
  • aqueous phase comprises a buffer.
  • shearing occurs at about 3000-5000 RPM with a square mixing screen.
  • extruding comprises 1-2 passes through a 200 nm filter.
  • concentrating comprises tangential flow filtration.
  • the method further comprises freezing or lyophilizing after step (f).
  • FIG.1 depicts two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 Lipoid E80-Miglyol 812N (1.2%w/v) 6mg/ml + blank, on Day 10, at 50°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from - 100 to 500 at 100 unit intervals.
  • FIG.2 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w/v), 6mg/ml + blank, Day 10, at 2-8°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from -100 to 500 at 100 unit intervals.
  • FIG.3 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w/v), 60mg/ml + blank, Day 10, at 50°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from -100 to 500 at 100 unit intervals.
  • FIG.4 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w/v), 60mg/ml + blank, Day 10, at 2-8°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from -100 to 500 at 100 unit intervals.
  • FIG.5 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w/v), 6 mg/ml + blank, Day 10, at 50°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from -100 to 600 at 100 unit intervals.
  • FIG.6 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w/v), 6 mg/ml + blank, Day 10, at 2-8°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from -300 to 600 at 100 unit intervals.
  • FIG.7 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w/v), 60mg/ml + blank, Day 14, at 50°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from -100 to 600 at 100 unit intervals.
  • FIG.8 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w/v), 60mg/ml + blank, Day 14, at 2-8°C.
  • the x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals.
  • the y-axis is mAU from -300 to 500 at 100 unit intervals.
  • FIG.9 depicts a plot of PSD (particle size distribution) analysis: 10% ANEB-001 in 1% PVP k17 and 0.15% Na Deoxy suspension (50C; T1-week).
  • the x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals.
  • the left y-axis is q (%) from 0 to 12 at 2 unit intervals.
  • the right y-axis is undersize (%) from 0 to 100 at 10 unit intervals.
  • FIG.10 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.15% Na Deoxy suspension (250C; T1-week).
  • the x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals.
  • the left y-axis is q (%) from 0 to 12 at 2 unit intervals.
  • FIG.11 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 40 mg/mL (50C; T1-week).
  • the x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals.
  • the left y-axis is q (%) from 0 to 12 at 2 unit intervals.
  • the right y- axis is undersize (%) from 0 to 100 at 10 unit intervals.
  • FIG.12 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 40 mg/mL (250C; T1-week).
  • the x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals.
  • the left y-axis is q (%) from 0 to 12 at 2 unit intervals.
  • the right y-axis is undersize (%) from 0 to 100 at 10 unit intervals.
  • FIG.13 depicts a PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 100 mg/mL (50C; T1-week).
  • the x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals.
  • the left y-axis is q (%) from 0 to 12 at 2 unit intervals.
  • the right y- axis is undersize (%) from 0 to 100 at 10 unit intervals.
  • FIG.14 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 100 mg/mL (250C; T1-week).
  • the x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals.
  • the left y-axis is q (%) from 0 to 12 at 2 unit intervals.
  • FIG.15 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV Bolus and IV infusion for a liposomal formulation (IV bolus, squares; IV infusion, circles) and emulsion formulation (triangles) of compound 1.
  • the y-axis is labeled ANEB-001 concentration in plasma (ng/mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 6 at 1 hour intervals.
  • FIG.16 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IM administration for a liposomal formulation (squares), a nanosuspension formulation (inverted triangles) and an emulsion formulation (circles) of compound 1.
  • the y-axis is labeled ANEB-001 concentration in plasma (ng/mL) from 1 to 1000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 24 at 6 hour intervals.
  • FIG.17 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IM, IV and SC administration for a liposomal formulation (IV, squares; IM, triangles; SC, inverted triangles), of compound 1.
  • the y-axis is labeled ANEB-001 concentration in plasma (ng/mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 6 at 1 hour intervals.
  • FIG.18 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV administration for a liposomal formulation (squares) and an emulsion formulation (circles) of compound 1.
  • the y-axis is labeled ANEB-001 concentration in plasma (ng/mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 24 at 6 hour intervals.
  • FIG.19 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV (circles) and IM (inverted triangles) administration for an emulsion formulation of compound 1.
  • the y-axis is labeled ANEB-001 concentration in plasma (ng/mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 24 at 6 hour intervals.
  • FIG.20 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV (squares), SC (inverted triangles), IV infusion (diamonds) and IM administration (triangles) for an emulsion formulation of compound 1.
  • the y-axis is labeled ANEB-001 concentration in plasma (ng/mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 6 at 1 hour intervals.
  • DETAILED DESCRIPTION Provided herein are compositions and methods of treating cannabinoid toxicity.
  • cannabinoid toxicity comprises acute or chronic toxicity.
  • cannabinoid toxicity comprises acute cannabinoid overdose, acute cannabinoid poisoning, acute cannabinoid-induced CNS depression, or other cannabinoid-related toxicity.
  • metrics and assessments for identifying cannabinoid toxicity, and measuring amelioration of cannabinoid toxicity after treatment Further provided herein are methods of treating acute cannabinoid toxicity caused by ingestion or inhalation of an edible form of cannabis. In some instances, ingestion or inhalation is intentional or accidental. In some instances, compositions and methods provided herein are used to treat pediatric patients.
  • Cannabinoid Intoxication [0030] Provided herein are methods for treating acute cannabinoid overdose via parenteral administration.
  • cannabinoid intoxication occurs from ingestion of an edible form of cannabis, cannabis extract, or synthetic cannabinoid.
  • metrics are used for determining if a patient is intoxicated with a cannabinoid.
  • metrics are used by healthcare providers to determine if a cannabinoid overdose treatment is provided.
  • metrics are used to measure the effect of treatment on a patient suffering from cannabinoid intoxication.
  • metrics are obtained at a first time before administration of a treatment (i.e., pre- administration) and later obtained at a second time after administration of the treatment.
  • Metrics may generally comprise physical measurements, self-reported assessments, or answers to other written or verbal questions (e.g., cognitive measurements). Any number of metrics may be used with the methods described herein, such as 1, 2, 3, 4, 5, 10, 15, 20, or more than 50 metrics. Metrics in some instances are compared to baseline or threshold levels established for a particular patient or patient population. In some instances, baseline or threshold levels take into consideration age, weight, sex, or other factor.
  • administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or more than 200% improvement in a metric relative to a baseline value.
  • improvements are defined as a metric’s value trending closer to a baseline value (e.g., sobriety).
  • administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or about 200% improvement in a metric relative to a baseline value.
  • administration of a treatment results in 5-200%, 5-100%, 5-80%, 5-50%, 5-25%, 10-200%, 10-100%, 10-75%, 20- 200%, 20-100%, 20-75%, 50-300%, 50-200%, 50-100%, 75-300%, 100-300%, or 150-300% improvement in a metric relative to a baseline value.
  • the improvement is realized no more than 8, 6, 5, 4, 3, 2.5, 2, 1.5, 1.2, 1.0, 0.8, or 0.5 hours after treatment.
  • Metrics may be defined categorically (e.g., high, medium, or low), or on a continuous scale (e.g., VAS).
  • Physical measurements may be used to measure cannabinoid intoxication.
  • physical measurements are made directly on the patient.
  • physical measurements are taken in response to specific actions or tasks given to the patient to complete.
  • physical measurements comprise measurement of body movement.
  • body movement comprises body sway or eye movement.
  • eye movement comprises Saccadic movement, adaptive tracking, or smooth pursuit.
  • body sway comprises antero-posterior sway.
  • body sway is measured by a pot string meter (celesco).
  • body sway is measured by a pot string meter based on the Wright ataxiameter (Bowdle, et al.).
  • mm sway In an exemplary protocol with a string attached to the waist, all body movements over a period of time are integrated and expressed as mm sway. Subjects are instructed to wear a pair of comfortable, low-heeled shoes on each session. Before starting a measurement, subjects are asked to stand still and comfortable, with their feet approximately 10 cm part and their hands in a relaxed position alongside the body and eyes closed. Subjects may not talk during the measurement. The total period of body-sway measurement in some instances is two minutes. Physical measurements in some instances comprise heart rate, body temperature, blood pressure, or other physical measurement. In some instances, metrics comprise one or more of eye opening response, best motor response, and best verbal response.
  • administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or more than 200% improvement in a physical measurement relative to a baseline value.
  • improvements are defined as a metric’s value trending closer to a baseline value (e.g., sobriety).
  • administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or about 200% improvement in a physical measurement relative to a baseline value.
  • a treatment e.g., Compound 1
  • administration of a treatment results in 5-200%, 5-100%, 5-80%, 5-50%, 5-25%, 10- 200%, 10-100%, 10-75%, 20-200%, 20-100%, 20-75%, 50-300%, 50-200%, 50-100%, 75-300%, 100-300%, or 150-300% improvement in a physical measurement relative to a baseline value.
  • the improvement is realized no more than 8, 6, 5, 4, 3, 2.5, 2, 1.5, 1.2, 1.0, 0.8, or 0.5 hours after treatment.
  • Cognitive metrics may also be obtained for use with the methods described herein.
  • Cognitive metrics in some instances are obtained by self-report via verbal interrogation of a subject, or by subject’s responses to a questionnaire. In some instances, questions are answered by the subject, and another party (healthcare provider, family member, emergency responder, or other third party) fills out the questionnaire. In some embodiments, a metric is measured by a healthcare provider or emergency responder. In some embodiments, a metric is measured by self-reporting. Questions may address any aspect of cognition experienced by the subject, including but not limited to intoxication, anxiety, alertness, mood, or internal/external perception. In some instances, questions are directed to one or more of orientation of person, place, time, and situation. In some instances, questions are directed to levels of the Glasgow coma scale.
  • treatment with CB1 inhibitors described herein improves a Glasgow coma metric by at least one level.
  • questions are directed to one or more of alertness/fuzzy/clearheaded, coordinate/clumsy, lethargic/energetic, contented/discontented, troubled/tranquil, mentally slow/quick witted, tense/relaxed, attentive/dreamy, drowsy, calm/excited, strong/feeble, incompetent/proficient, happy/sad, antagonistic/friendly, interested/bored, withdrawn/sociable, self-centered/outward going or depressed/elated.
  • metrics comprise measurement of working memory.
  • working memory is measured using an n-back test.
  • the n-back test comprises a zero back, one back, or two back test.
  • cognitive metrics are measured using a VAS (visual analog scale) measurement system.
  • VAS comprises choosing a position along a line wherein each end of the line comprises an opposing/opposite feeling or state (e.g., troubled vs. tranquil, calm vs. excited).
  • a metric comprises the distance along the line that is chosen. In some instances, the distance on the line is measured in metric units (e.g., centimeters or millimeters) or in English units (e.g., inches).
  • administration of a treatment results in 5-200%, 5-100%, 5-80%, 5-50%, 5-25%, 10-200%, 10-100%, 10-75%, 20- 200%, 20-100%, 20-75%, 50-300%, 50-200%, 50-100%, 75-300%, 100-300%, or 150-300% improvement in a cognitive measurement relative to a baseline value.
  • the improvement is realized no more than 8, 6, 5, 4, 3, 2.5, 2, 1.5, 1.2, 1.0, 0.8, or 0.5 hours after treatment.
  • Compound 1 is crystalline.
  • crystalline form As used herein, “crystalline form,” “polymorph,” “Form,” and “form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the crystalline form is a single solid state form.
  • method described herein comprises treatment with a crystalline form of Compound 1.
  • additional compounds may be used alternatively, or in addition to Compound 1 in the parenteral (e.g., liposomal or other) formulations described herein.
  • the additional compounds comprise a CB1 modulator.
  • the CB1 modulator is a CB1 inhibitor.
  • the CB1 inhibitor comprises antagonist, inverse agonist, or reverse agonist.
  • the CB1 inhibitor comprises rimonabant, taranabant, MK-0364, AM251, AM1387, AM4113, cannabigerol, ibipinabant, otenabant, surinabant, tetrahydrocannabivarin and virodamine, TM-38837, AM6545, or a CB1 targeting- antibody.
  • the CB1 inhibitor comprises methylphosphonofluoridic acid 5,8,11,14-eicosatetraenyl ester (MAFP, CAS 188404-10-6), NESS 0327 (8-chloro-1-(2,4- dichlorophenyl)-1,4,5,6-tetrahydro-N-1-piperidinyl-benzo[6,7]cyclohepta[1,2-c]pyrazole-3- carboxamide, CAS 494844-07-4), AM-251 (CAS 183232-66-8), LY-320135 (CAS 176977-56-3), AM 281 (CAS 202463-68-1), MJ 15 (CAS 944154-76-1), amauromine (CAS 88360-87-6), AM 404 (183718-77-6), virodhamine hydrochloride (443129-35-9), NIDA-41020 (CAS 502486-89-7), SLV 319 (CAS 362519-49-1), URB447 (CAS 1132922-57-6), falcar
  • MAFP
  • the CB1 modulator comprises rimonabant, taranabant, surinabant or drinabant.
  • R 1 is aryl or heteroaryl
  • R 2 is alkyl, aryl or heteroaryl
  • R 3 is alkyl, aryl, heteroaryl, NR 9 R 10 , OR 15 , or NR 16 C(O)R 17
  • Y is C ⁇ O, C ⁇ S, SO2, or (CR 7 R 8 )p
  • R 7 and R 8 are independently selected from H and lower alkyl
  • R 9 is selected from H, alkyl, aryl, heteroaryl, and non-aromatic heterocyclic groups, or together with R 10 forms a saturated 4, 5, 6, or 7 membered ring optionally containing an additional heteroatom selected from N and O
  • R 10 is selected from H and lower alkyl, or together with R 9 forms a saturated 4, 5, 6, or 7 membered ring optionally containing an additional heteroatom selected from N and O
  • R 10 is
  • R 1 and/or R 2 is substituted with 1 to 3 substituents. In some embodiments, R 1 and/or R 2 is substituted with 1 or 2 substituents. In one embodiment, R 1 and R 2 are independently selected from a group -A(R 4 )(R 5 )(R 6 ), where A is an aryl or heteroaryl ring, and where A may be selected from phenyl, naphthyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl and isobenzofuryl.
  • R 1 and R 2 is aryl and the other is heteroaryl, or both R 1 and R 2 are aryl. In some embodiments, both R 1 and R 2 are monocyclic.
  • R 4 , R 5 , and R 6 are independently selected from hydrogen, halo, alkyl (including haloalkyl), thioalkyl, alkoxy (including haloalkoxy), alkylsulfonyl, amino, mono- and di-alkyl amino, mono- and di-aryl amino, alkylarylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, NR 14 C(O)R 19 , NR 14 SO2R 20 , COOR 19 , OC(O)R 20 , CONR 13 R 14 and SO2NR 13 R 14 , wherein R 13 and R 14 are independently selected from hydrogen and alkyl or may form a 5 or 6 membered ring optionally containing 1 or 2 additional
  • R 1 and R 2 may be the same or different, and in one embodiment are different.
  • R 3 is NR 9 R 10 .
  • R 3 is NR 9 R 10 , and R 9 and R 10 are independently lower alkyl or hydrogen.
  • Y is C ⁇ O.
  • Y is C ⁇ O and R 3 is NR 9 R 10 .
  • R 3 is NR 9 R 10 , R 9 is lower alkyl, and R 10 is hydrogen.
  • the halo group is fluoro, chloro, bromo or iodo. In some embodiments, the halo group is chloro or bromo.
  • R 4 , R 5 , and R 6 are selected from alkyl, thioalkyl, alkoxy and alkylsulfonyl. In some embodiments, R 4 , R 5 , and R 6 are selected from lower alkyl. In some embodiments, R 4 , R 5 , and R 6 are selected from methyl and ethyl.
  • R 4 , R 5 , and R 6 are selected from haloalkyl
  • the alkyl is in some embodiments methyl, and the R 4 , R 5 , or R 6 group is trifluoromethyl.
  • R 4 , R 5 , and R 6 are selected from haloalkoxy
  • the alkyl is in some embodiments methyl and the R 4 , R 5 , or R 6 group is trifluoromethoxy or difluoromethoxy.
  • one or two of R 4 , R 5 , and R 6 are hydrogen.
  • at least one of the R 1 and R 2 groups has a non-hydrogen substituent in the ortho-position(s) relative to the point of attachment to the [—CH—O—] group.
  • the R 1 or R 2 groups may independently have one or two non-hydrogen substituents in said ortho position(s).
  • Preferred ortho-substituents include halo and haloalkyl, as described herein. In some embodiments, ortho-substituents are chloro and trifluoromethyl.
  • R 1 and/or R 2 is selected from heteroaryl; and/or m and/or n is 2; and/or R 11 and/or R 12 is lower alkyl.
  • R 1 and/or R 2 is selected from aryl, and m and n are 1.
  • R 1 and/or R 2 is selected from aryl, and m and n are 1.
  • R 3 is selected from NR 9 R 10 . In an alternative embodiment R 3 is selected from alkyl, aryl and heteroaryl. In some embodiments, Y is selected from C ⁇ O, C ⁇ S and SO 2 . Where Y is selected from (CR 7 R 8 ) p , then R 7 and/or R 8 in some embodiments are hydrogen or methyl, and p is 1 or 2. Where Y is SO2, R 3 is in some embodiments selected from alkyl, aryl and heteroaryl. Where Y is (CR 7 R 8 )p, in some embodiments p is 1, and R 3 is selected from alkyl, aryl, heteroaryl.
  • R 9 is selected from piperidinyl (such as 1-piperidinyl) and morpholinyl (such as 4-morpholinyl).
  • R 9 is cyclic, such as aryl or heteroaryl, and the R 9 group may be substituted with one or more substituent groups.
  • R 9 is substituted with halo, nitro, or alkoxy haloalkyl.
  • the ring formed by NR 9 R 10 may be substituted, and substituents include hydroxy, methoxy, mono- and di-alkyl amino and alkoxycarbonyl.
  • R 9 is selected from aryl, heteroaryl and a non-aromatic heterocyclic group, and R 10 is selected from H and lower alkyl.
  • R 9 is selected from alkyl and R 10 is selected from lower alkyl.
  • R 9 and R 10 form a 4, 5, 6, or 7-membered ring, or a 5, 6, or 7-membered ring, optionally containing an additional heteroatom selected from N and O.
  • m is 1 and/or n is 1.
  • both m and n are 1. Where m is 2, the R 11 groups may be the same or different, but at least one of the R 11 groups in the (CHR 11 )2 moiety is hydrogen. Where n is 2, the R 12 groups may be the same or different, but at least one and optionally both of the R 12 groups in the (CHR 12 ) 2 moiety is/are hydrogen. In some embodiments, R 11 and R 12 are independently selected from hydrogen and methyl. In some embodiments, at least one of R 11 and R 12 is hydrogen. In some embodiments, R 15 is selected from alkyl, such as lower alkyl (substituted or unsubstituted).
  • R 15 is selected from aryl, such as phenyl (substituted or unsubstituted). In one embodiment, R 15 is selected from lower alkyl, benzyl and phenyl. In some embodiments, R 16 is hydrogen. In some embodiments, R 17 is lower alkyl, aryl, or heteroaryl, and in one embodiment is aryl.
  • R 1 and R 2 are independently selected from aryl or heteroaryl; and R 9 is hydrogen or alkyl; wherein at least one of R 1 and R 2 has a non-hydrogen substituent in the ortho-position(s) thereof relative to the point of attachment to the [—CH—O—] group.
  • R 3 has the structure: —(CHR 9 )n(CH2)mCR 10 R 11 R 12 wherein n is 0 or 1; m is 0, 1, 2 or 3; R 9 , R 10 , R 11 , and R 12 are selected from hydrogen, alkyl, hydroxy, alkoxy, thioalkyl, amino, mono- and di-alkyl amino, alkoxycarbonyl and R 13 ; wherein R 13 is selected from aryl, heteroaryl and non-aromatic heterocyclic optionally substituted by one or more groups selected from alkyl, halogen, alkoxy, oxo, aryl, heteroaryl and non-aromatic heterocycle.
  • m is 0 or 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1 and m is 1. In one embodiment, at least one or two of R 10 , R 11 , and R 12 are selected from hydrogen. In a further embodiment, at least two of R 10 , R 11 , and R 12 are selected from methyl. In a further embodiment, R 9 is selected from cyclic alkyl, including cyclopentyl, cyclohexyl, norbornanyl and adamantyl.
  • R 9 groups are tertiary butyl, sec-butyl, isobutyl, isopropyl, n-propyl and ethyl.
  • the CB1 antagonist of Formula (I) or (Ia) is ((R)-(+)-N-tert-butyl-3- [(4-chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-1-carboxamide (Compound ANEB- 001).
  • the CB1 antagonist is ((S)-(-)-N-tert-butyl-3-[(4-chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-1-carboxamide. In some embodiments, the CB1 antagonist is (N-tert-butyl-3-[(4-chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-1- carboxamide. In some embodiments, the CB1 antagonist is Cannabigerol. In some embodiments, the CB1 antagonist is ibipinabant. In some embodiments, the CB1 antagonist is otenabant.
  • the CB1 antagonist is tetrahydrocannabivarin. In some embodiments, the CB1 antagonist is virodhamine. In some embodiments, the CB1 inverse agonist is rimonabant. In some embodiments, the CB1 inverse agonist is taranabant. In some embodiments, the CB1 inverse agonist is surinabant or drinabant. In some embodiments, a composition or formulation described herein comprises two or more CB1 inhibitors. In some embodiments, the CB1 inhibitor is a neutral antagonist. In some instances, the CB1 inhibitors comprise one or more substitutions at the phenyl groups that function as effective neutral antagonists of CB1.
  • a CB1 inhibitor comprises a structure of formula (Ia), wherein R 1 and R 2 are substituted aromatic groups, and R 3 is an optionally substituted C1-C6 alkyl group.
  • R 3 is tert-butyl.
  • R 3 is isopropyl.
  • R 3 is sec-butyl.
  • R 1 is a substituted aromatic group.
  • R 1 is an optionally substituted phenyl group.
  • R 1 is a phenyl group substituted with a halogen (e.g., F, Cl, Br, I).
  • R 1 is a phenyl group substituted with Cl.
  • R 1 is a phenyl group para substituted in (4-position) with a halogen (e.g., F, Cl, Br, I). In some instances, R 1 is a 4-chlorophenyl group.
  • R 2 is a substituted aromatic group. In some instances, R 2 is an optionally substituted phenyl group. In some instances, R 2 is a phenyl group substituted with a C1-C5 alkyl group. In some instances, R 2 is a phenyl group substituted with a C1- C 5 trifluoroalkyl group. In some instances, R 2 is a phenyl group substituted with a trifluoromethyl group.
  • R 2 is a phenyl group ortho substituted in (4-position) with a C1-C5 trifluoroalkyl group. In some instances, R 2 is a 2-trifluoromethylphenyl group.
  • the CB1 inhibitor is compound ANEB-001, having the following structure: . Methods of producing ANEB-001 and related compounds (and enantiomers thereof) are known in the art (see Example 81 of US 7,504,522 which is incorporated by reference). In some embodiments, the CB1 inhibitor has the structure:
  • the CB1 inhibitor has the structure: .
  • a CB1 inhibitor is a compound of Table 1.
  • Table 1 the additional compounds herein can include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.
  • the additional compounds are crystalline.
  • Compositions and Formulations [0060] In another aspect, the present disclosure provides compositions, including pharmaceutical compositions and injectable compositions.
  • compositions [0062] In one aspect, the present disclosure provides a pharmaceutical composition comprising the (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide, and at least one pharmaceutically acceptable excipient.
  • Compound 1 (or polymorphs thereof) are formulated into pharmaceutical compositions.
  • pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds/polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the present disclosure provides pharmaceutical compositions comprising Compound 1 and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the pharmaceutical compositions include Compound 1 or polymorphs thereof.
  • a pharmaceutical composition refers to a mixture of Compound 1 with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates the administration of the polymorphs to an organism.
  • therapeutically effective amounts of Compound 1 or polymorphs thereof are administered in a pharmaceutical composition to a subject having a condition or disorder to be treated.
  • the subject is a human.
  • therapeutically effective amounts vary depending on the severity of the condition or disorder, the age and relative health of the subject and other factors.
  • Compound 1 or polymorphs thereof described herein are used singly or in combination with one or more therapeutic agents as components of mixtures. [0066] In some embodiments, the polymorphs of Compound 1 are subjected to spray drying prior to being formulated.
  • the pharmaceutical composition is formulated for oral, parenteral, inhalation, intravenous (IV), intramuscular (IM), or subcutaneous (SC) administration.
  • pharmaceutical composition is formulated for intravenous (IV) administration.
  • intravenous (IV) comprises IV bolus, IV drip, or IV push.
  • the pharmaceutical composition is delivered in a liquid volume of 0.1-5 mL, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.1-0.5, 0.5-5 mL, 0.5-4, 0.5-3, 0.5-2, 0.5-1, 1-5 mL, 1-4, 1-3, or 1-2 mL.
  • the pharmaceutical composition is delivered in an IV liquid volume of 10-1000 mL, 10-500 mL, 10-400 mL, 10-300 mL, 10-200 mL, 10-100 mL, 10-50 mL, 100-1000 mL, 100-500 mL, 200-500 mL, 200-1000 mL, 500-1000 mL, or 750-1000 mL.
  • the pharmaceutical composition is formulated to deliver a therapeutically effective amount of the (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 10 minutes.
  • the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in no more than 5 minutes. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 2 minutes.
  • the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 1 minute. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in no more than 30 seconds.
  • the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 10 seconds.
  • the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in 10-120, 10-100, 10-75, 10-60, 10-45, 10-30, 10-15, 20-120, 20-100, 20-75, 20-60, 20-45, 20-30, 30-120, 30-100, 30-75, 30-60, 30-45, 45-120, 45-100, 45-75, 45-60, 60-120, 60-100, 60-75, 75-120, or 100-120 minutes.
  • Compound 1 or polymorphs thereof are formulated in an aqueous solution. In one embodiment, Compound 1 or polymorphs thereof are formulated in an aqueous solution for parenteral injection. In other embodiments, Compound 1 or polymorphs thereof are formulated for transmucosal administration. In still other embodiments, wherein the one or more polymorphs described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients. [0070] In still other embodiments, the polymorphs described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical composition of a polymorph of Compound 1 is formulated in a form suitable for parenteral injection as sterile suspension, solution, or emulsion in oily or aqueous vehicles.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active polymorphs in water-soluble form.
  • suspensions of the active polymorphs are prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the polymorphs to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a powder comprises a lyophilized form.
  • pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable.
  • Pharmaceutical compositions comprising Compound 1 or polymorphs thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one polymorph of Compound 1 described herein as an active ingredient.
  • the active ingredient is in acid-free or base-free form, or in a pharmaceutically acceptable salt form. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • Methods for the preparation of compositions, comprising Compound 1 or polymorphs thereof described herein include formulating the polymorphs with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions, and creams.
  • the form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, isotonizing agents, and so forth.
  • pharmaceutically acceptable carriers or excipients for formulations described herein may comprise one or more polymers.
  • the pharmaceutically acceptable carrier is a polymer. Examples of polymers suitable for oral, buccal, intranasal, transdermal, thin-film, suppository or other administration include biocompatible and biodegradable polymers.
  • biocompatible polymers include natural or synthetic polymers such as polystyrene, polylactic acid, polyketal, butadiene styrene, styreneacrylic-vinyl terpolymer, polymethylmethacrylate, polyethylmethacrylate, polyalkylcyanoacrylate, styrene- maleic anhydride copolymer, polyvinyl acetate, polyvinylpyridine, polydivinylbenzene, polybutyleneterephthalate, acrylonitrile, vinylchloride-acrylates, polycaprolactone, poly(alkyl cyanoacrylates), poly(lactic-co-glycolic acid), and the like.
  • natural or synthetic polymers such as polystyrene, polylactic acid, polyketal, butadiene styrene, styreneacrylic-vinyl terpolymer, polymethylmethacrylate, polyethylmethacrylate, polyalkylcyan
  • the carrier is Labrasol. In some instances, the carrier is methyl cellulose.
  • the pharmaceutically acceptable carrier comprises one or more biodegradable polymers.
  • biodegradable polymers provide the advantages of using a formulation that will eventually disintegrate, which facilitates release of the benzofuran compound and elimination of the carrier in vivo.
  • benzofuran compounds can also be released from the matrix of non-biodegradable polymers as a result of gradual efflux from channels within the polymer matrix, including those formed by soluble materials included in the polymer matrix.
  • biodegradable polymers include polylactide polymers include poly(D,L- lactide)s; poly(lactide-co-glycolide) (PLGA) copolymers; polyglycolide (PGA) and polydioxanone; caprolactone polymers; chitosan; hydroxybutyric acids; polyanhydrides and polyesters; polyphosphazenes; and polyphosphoesters.
  • the biodegradable polymer for use in the nanoparticles is poly-(D,L-lactide-co-glycolide).
  • a PLGA copolymer comprises a lactide to glycolide ratio of 10:90, 20:80, 30:70, 40:60, or 50:50.
  • Functionalized poly (D,L-lactide)s can also be used as biodegradable polymers in the nanoparticles described herein.
  • Examples of functionalized poly(D,L-lactide)s include poly(L- lactide), acrylate terminated; poly(L-lactide), amine terminated; poly(L-lactide), azide terminated; poly(L-lactide), 2-bromoisobutyryl terminated; poly(L-lactide), 2-bromoisobutyryl terminated; poly(L-lactide) 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentonate; poly(L-lactide) N-2- hydroxyethylmaleimide terminated; poly(L-lactide) 2-hydroxyethyl, methacrylate terminated; poly(L-lactide), propargyl terminated; or poly(L-lactide), thiol terminated.
  • AB - 38 -eblock copolymers such as poly(ethylene glycol) methyl ether-block-poly(D,L-lactide); poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) PEG; poly(ethylene glycol)- block-poly(.epsilon.-caprolactone) methyl ether PEG; and polypyrrole-block-poly(caprolactone).
  • biodegradable polymers include ABA triblock copolymers such as polylactide-block- poly(ethylene glycol)-block-polylactide PLA; poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide); poly(lactide-co-caprolactone)-block-poly(ethylene glycol)-block-poly(lactide-co-caprolactone); polycaprolactone-block-polytetrahydrofuran-block- polycaprolactone; and polyglycolide-block-poly(ethylene glycol)-block-polyglycolide PEG.
  • Biodegradable polymers also include various natural polymers.
  • natural polymers include polypeptides including those modified non-peptide components, such as saccharide chains and lipids; nucleotides; sugar-based biopolymers such as polysaccharides; cellulose; carbohydrates and starches; dextrans; lignins; polyamino acids; adhesion proteins; lipids and phospholipids (e.g., phosphorylcholine).
  • the polymer is a cellulose derivative such as hydroxypropyl methylcellulose polymers. Hydroxypropyl methyl cellulose (HPMC) is a non-ionic cellulose ether made through a series of chemical processes, with the natural polymer cellulose as the raw material.
  • HPMC Hydroxypropyl methyl cellulose
  • the product is a non-ionic cellulose ether in the shape of white powder, odorless and tasteless.
  • HPMC is also known as hypromellose, is a methylcellulose modified with a small amount of propylene glycol ether groups attached to the anhydroglucose of the cellulose.
  • Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymorph of Compound 1.
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • solubilizing agents are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
  • solubilizing agents comprise poloxamers, Solutol HS 10, Cremophor EL, or other solubilizing agent.
  • solubilizing agents are described in Strickley, Robert G. "Solubilizing excipients in oral and injectable formulations.” Pharmaceutical research 21 (2004): 201-230, which is incorporated by reference.
  • useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
  • Pharmaceutical Compositions for Parenteral Delivery [0084] In some embodiments, Compound 1 is formulated into an injectable composition.
  • the injectable composition comprises (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, or the pharmaceutical composition described herein, an opioid antagonist, and a benzodiazepine antagonist.
  • the benzodiazepine antagonist is flumazenil.
  • the opioid antagonist is naloxone or naltrexone.
  • the opioid antagonist is samidorphan.
  • the opioid antagonist is naltrexone.
  • the injectable composition is formulated in a single dose injectable device.
  • parenteral formulations comprise a compound having the structure: .
  • parenteral formulations comprise a compound having the structure: and at least one excipient.
  • parenteral formulations comprise a nanosuspension, oil and water emulsion, liposome, or micelles.
  • Parenteral formulations in some instances are administered by intravenous (IV), intramuscular (IM), or subcutaneous (SC) methods.
  • IV intravenous
  • IM intramuscular
  • SC subcutaneous
  • Oil in water emulsions may comprise an oil and water emulsion.
  • the at least one excipient comprises an oil.
  • the excipient comprises soybean oil (SBO), Miglyol 812, olive oil, coconut oil, or a mixture thereof.
  • the pharmaceutical composition comprises soybean oil and at least one of coconut oil, olive oil, or Miglyol 812.
  • the pharmaceutical composition comprises a 10:1 to 1:10, 5:1 to 1:5, 3:1 to 1:3, 2:1 to 1:2: or 1.5:1 to 1:5 mixture of soybean oil to any one of coconut oil, olive oil, or Miglyol 812.
  • the compound is present at 1-20, 2-20, 3-20, 5-20, 8-20, 10-20, 15-20, or 20-50 mg/mL. In some instances, the compound is present at less than 3, 2, 1.5, 1, or 0.5 mg/mL.
  • Parenteral formulations may comprise micelles.
  • the parenteral formulation comprises micelles.
  • the parenteral formulation comprises a mixed micelle formulation.
  • a parenteral formulation comprises a phospholipid and at least one bile salt.
  • a bile salt comprises sodium deoxycholate or sodium glycocholate.
  • the parenteral formulation comprises a phospholipid.
  • the excipient comprises Miglycol 812, Lipoid E80, saline, or a combination thereof.
  • the pharmaceutical composition comprises 0.1-5%, 0.2-5%, 0.5-3%, 0.8-3%, 0.5- 1.5%, 1-3%, 1.5-3%, or 2-3%, Lipoid E80.
  • the compound is present at 1-20, 2- 20, 3-20, 5-20, 8-20, 10-20, 15-20, or 20-50 mg/mL. In some instances, the compound is present at less than 3, 2, 1.5, 1, or 0.5 mg/mL.
  • Parenteral formulations may comprise liposomes.
  • a liposome can have a similar structure, but is usually formed from a double layer of surfactant or amphiphilic molecules (e.g., a lipid bilayer) ) encapsulating one or more aqueous compartments.
  • a liposome comprises an inner aqueous compartment portion, a middle portion, and an outer shell composed of a phospholipid bilayer.
  • the inner portion is relatively hydrophilic
  • the middle portion e.g., the outer shell of the liposome, formed by the bilayer structure of the surfactant or amphiphilic molecules mainly phospholipids
  • the exterior to the liposome is an aqueous or a hydrophilic environment.
  • the liposomes are dispersed an aqueous or a hydrophilic environment.
  • the inner portion if present within an entity, contains a liquid, and in all cases, the liquid is aqueous. In some cases, the liquid contains saline or a salt solution in water.
  • the liquid can contain a drug or other pharmaceutical agent (e.g., Compound 1).
  • the liquid contains an isotonic solution in water.
  • the liquid contains a sugar solution in water.
  • sugar comprises glucose, sucrose, lactose, trehalose, and maltose, or other sugar.
  • the parenteral formulation comprises a liposome.
  • the at least one excipient comprises a phospholipid.
  • the pharmaceutical composition comprises 10-50, 10-40, 10-30, 20-50, 20-40, 20-30, 25-45, 30-50, or 40-50 mg/mL phospholipid.
  • the at least one excipient comprises Lipoid S100 or dimyristoylphosphatidylglycerol (DMPG). In some instances, the excipient comprises Lipoid S100 and DMPG. In some instances, the excipient comprises soybean phosphatidylcholine and 1,2 dimyristoylphosphatidylglycerol. In some instances, a phosphatidylcholine is sold under the trade name LIPOID E 80 or LIPOID S 100 by Lipoid GmbH.
  • the Compound 1 is present at 0.1-15, 0.5-10, 0.8-10, 0.5-15, 0.5-3, 0.8-3, 0.8-2, 0.8-5, 0.5-3, 5-15, or 10-15 mg/mL in the liposomal formulation. In some instances, the Compound 1 is present about 0.1, 0.2, 0.3, 0.5, 0.8, 1.0, 1.2, 1.5, 1.7, 2.0, 2.2, 2.5, 2.8, 3, 3.1, 3.2, 3.3, or about 3.5 mg/mL in the liposomal formulation.
  • Phospholipids e.g., phosphatidylcholine
  • phospholipids are obtained from hen egg yolk, soybeans, Non-GMO Soybeans, sunflowers, or are synthetically produced.
  • phosphatidylcholine is obtained from hen egg yolk, soybeans, Non-GMO Soybeans, sunflowers, or is synthetically produced.
  • Liposomal formulations may comprise a ratio of compound/drug (e.g., Compound 1) to lipid (e.g., phospholipid). In some embodiments, the ratio of compound to lipid is 1:5 to 1:25, 1:5 to 1:50 (w/w), 1:1 to 1:25, 1:2 to 1:25, 2:1 to 1:25, 1:5 to 1:25, 1:10 to 1:25, or 1:10 to 1:20.
  • the ratio of compound to lipid is about 2:1, 1:1, 1:1.5, 1:2, 1:5, 1:7, 1:10, 1:12, 1:15, 1:17, 1:20, 1:25, or about 1:50.
  • the phospholipids comprise diacyl-phospholipids.
  • the phospholipids comprises phosphatidylcholine, or phosphatidylethanolamine,.
  • Lipoid Gmbh (https://lipoid.com/en/product-finder/) produces a variety of phospholipids products suitable for formulations described herein, which includes but not limited to Lipoid 16:1/18:1, Lipoid S 100, DMPG NA, Lipoid P 75, Lipoid S 80, Lipoid S, Lipoid R, Lipoid E, Lipoid E 100j, and Lipoid E PG/DSPG.
  • Synthetic DA-PLs such as Lipoid PC, Lipoid PE, Lipoid PG, Lipoid PA, Lipoid PS are also in some embodiments used in the liposomal formulations described herein.
  • a liposomal formulation comprises at least 40, 50, 60, 70, 80, 90, 94, 96, 97, or at least 98% of one or more of CAS Reg. Nos.: 8001-17-0, 93685-90-6, 97281-44-2, 97281-50-0, 92347- 24-5, 85187-10-6, 97281-45-3, 8030-76-0, 97281-47-5, 92128-87-5, 97281-48-6, 28319-77-9, 9008-30-4, 97281-49-7, 18194-24-6, 63-89-8, 816-94-4, 4235-95-4, 51779-95-4, 26853-31-6, 67232-80-8, 67232-81-9, 200880-42-8, 67254-28-8, 208070-86-8, 998-07-2, 923-61-5, 1069-79-0, 4004-05-1, 70614-14-1, 169051-60-9, 384835-59-0
  • a phospholipid comprises one or more of lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingomyelin, phosphatidylcholine, hydrogenated, sn-glycero-3- phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3- phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3- phosphocholine, 1.2- dioleoylphosphatidylcholine, 1,2 dierucoyl-sn-glycero-3-phosphocholine, 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycer
  • a parenteral formulation comprises at least one excipient selected from 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-oleoyl-sn-glycero- 3-phosphocholine (POPC), 1-palmitoyl, 2-oleoylphosphatidylglycerol, 1,2 dioleoylphosphatidylserine, phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG), or a salt thereof.
  • DSPG 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol
  • HSPC hydrogenated soybean phosphatidylcholine
  • POPC 1-palmitoyl-2-oleoyl-sn-glycero- 3-phosphocholine
  • DMPG dimyristoylphosphati
  • Liposomal formulations may comprise a combination of two or more excipients (e.g., phospholipids).
  • a parenteral formulation comprises at least two excipients selected from 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG), or a salt thereof.
  • DSPG 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol
  • HSPC hydrogenated soybean phosphatidylcholine
  • POPC 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • DMPG dimyristoylphosphatidylglycerol
  • the ratio of the first excipient to the second excipient is 50:50 to 99:1, 60:40 to 99:1, 70:30 to 99:1, 80:20 to 99:1, 90:10 to 99:1, or 95:99:1.
  • the first excipient comprises HSPC, DMPC, phosphatidylcholine, DOPG, POPC, or a salt thereof.
  • the second excipient comprises DSPG, DMPG, DMPC, or a salt thereof.
  • Parenteral formulations of liposomes may comprise two excipients. In some instances, formulations comprise phospholipids. In some embodiments, formulations comprise two phospholipids.
  • a first lipid and a second lipid are independently selected from POPC (1-palmitoyl, 2-oleoylphosphatidylcholine), DOPC (1.2- dioleoylphosphatidylcholine), DMPC (1.2- dimyristoylphksphatidylcholine), POPG (1-palmitoyl, 2-oleoylphosphatidylglycerol), POPG (1- palmitoyl, 2-oleoylphosphatidylglycerol) ammonium or sodium salt, DOPG (1,2 dioleoylphosphatidylglycerol), DOPG (1,2 dioleoylphosphatidylglycerol), ammonium or sodium salt, DOPS (1,2 dioleoylphosphatidylserine), DOPS (1,2 dioleoylphosphatidylserine) sodium salt, Lipoid S 100, DMPG, egg phosphatidyl, DOPC
  • a first lipid is selected from soybean phosphatidylcholine with at least 96 % PC content (Lipoid S 100), Egg yolk PC with 70 - 100 % PC content (examples LIPOID E 80, Lipoid E 100j, Soybean PC with at least 70 up to 98 % PC content (example Lipoid S 75), POPC (1-palmitoyl, 2-oleoylphosphatidylcholine), DOPC (1.2- dioleoylphosphatidylcholine), or DMPC (1.2-dimyristoylphksphatidylcholine).
  • a second lipid is selected from DMPG (1,2 dimyristoylphosphatidylglycerol) (Lipoid DMPG), Egg phosphatidylglycerol, ammonium or sodium salt, POPG (1-palmitoyl, 2- oleoylphosphatidylglycerol), ammonium or sodium salt, DOPG (1,2 dioleoylphosphatidylglycerol) ammonium or sodium salt, DOPS (1,2 dioleoylphosphatidylserine) sodium salt.
  • the first lipid comprises soybean phosphatidylcholine with at least 96 % PC content (e.g., Lipoid S 100),
  • the second lipid comprises DMPG (1,2 dimyristoylphosphatidylglycerol) (Lipoid DMPG).
  • a phospholipid used herein comprises a natural (e.g. egg yolk, soybean, rapeseed) or synthetic or semi-synthetic phospholipid (described in the catalogue of Avanti Polar Lipid (https://avantilipids.com/product-category/phospholipids).
  • a phospholipid comprises one or more of the following properties (a)-(h): (a) possessing two esterified fatty acids to the glycerol backbone of the phospholipids; (b) wherein the two fatty acids comprise a mixture of different fatty acids or two identical fatty acids, which yield at 37°C a liquid crystalline state of the phospholipid; (c) wherein said fatty acids may be saturated, mono unsaturated or polyunsaturated; (d) wherein said fatty acids have a chain length ranging from C 2 -C 32 ; (e) wherein the polar head group of said un-charged phospholipids is choline (for example, a first lipid) or ethanolamine; (f) wherein said un-charged phospholipids (for example, a first lipid) is a sphingomyelin; (g) wherein the polar head group of the negatively charged phospholipid is selected from the group of inositol, glyce
  • the phospholipids comprise a negative charge. It has been observed that, in some cases, a pharmaceutical composition disclosed herein comprising negatively charged phospholipids exerts a stronger anti-calcium effect than neutral charged phospholipids at pH values of about 7. Thus, in some embodiments, the phospholipids are negatively charged. In some embodiments, the phospholipids is lecithin. In some embodiments, the phospholipids is phosphatidylglycerol. In aqueous medium diacyl-phospholipids normally form liposomes. The participation of surfactant in the formation of vesicles increases the curvature, which results in liposomes with smaller diameter or results in thermodynamically stable micelles.
  • the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable salt thereof, diacyl-phospholipids and at least one surfactant, preferably one surfactant.
  • the at least one surfactant is monoacyl- phospholipids.
  • the at least one surfactant is bile salt.
  • the at least one surfactant is vitamin E TPGS.
  • the pharmaceutical composition comprises diacyl- phospholipids and monoacyl-phospholipids.
  • the molar ratio between monoacyl-phospholipids and diacyl-phospholipids is from at least about 1:20 to up to about 1:4, to up to about 1:3, to up to about 1:2, to up to about 1:1.
  • the pharmaceutical composition comprises diacyl- phospholipids and at least one bile salt, preferably one bile salt.
  • the molar ratio between diacyl-phospholipids and the bile salt is from about 3:1 to about 1:3, from about 2:1 to about 1:2 and more typically about 1:1.
  • the pharmaceutical composition comprises diacyl- phospholipids, monoacyl-phospholipids and at least one bile salt.
  • Suitable bile salts include, but not limited to, sodium cholate, sodium deoxycholate, sodium chenodeoxycholate, sodium lithocholate, sodium ursodeoxycholate, sodium hyodeoxycholate, glycine conjugated sodium glycocholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, sodium glycoursodeoxycholate, taurine conjugated sodium taurocholate, sodium taurodeoxycholate, sodium taurochenodeoxycholate.
  • the bile salt is selected from a group consisting of sodium taurocholate sodium taurodeoxycholate sodium taurochenodeoxycholate sodium glycocholate, sodium glycodeoxycholate and sodium glycochenodeoxycholate.
  • the bile salt is selected from a group consisting of sodium cholate, sodium deoxycholate, sodium glycocholate, sodium taurocholate, and sodium taurodeoxycholate. In some embodiments, the bile salt is sodium taurocholate. In some embodiments, the bile salt is sodium glycocholate.
  • bile salts exist in abundance in gastric intestinal tract, which could interact with the DA-PL released from the composition to form micelles or small sized liposomes even if the composition itself does not comprise bile salt.
  • the phospholipid is soybean phosphatidylcholine or monoacyl-phospholipids.
  • Lipoid LPC 80 contains 70%-80% of monoacyl-phospholipids, while the rest is mainly diacyl-phospholipids.
  • the pharmaceutical composition comprises phospholipids, wherein phospholipids is predominantly lyso-phospholipids. Used in this context, the term “predominantly” is understood that the molar ratio between monoacyl- phospholipids and diacyl-phospholipids is from at least about 1:1 to up to about 2:1, to up to about 3:1, to up to about 4:1, to up to about 5:1. [00101]
  • the pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, phospholipids and at least one co-solvent.
  • Co-solvent is miscible with water and can increase the solubilization of the drug.
  • the co-solvent is pharmaceutically acceptable.
  • Pharmaceutical compositions may comprise a buffer as disclosed herein.
  • the buffer comprises a pH of 6-8, 6-7, 7-8, or 7-9.
  • the buffer is isotonic and isohydric.
  • the buffer comprises a sugar.
  • the buffer is isotonic.
  • the buffer comprises sucrose.
  • the buffer comprises an isotonizing agent.
  • the buffer comprises a sugar.
  • the buffer comprises saline, glucose, sucrose, lactose, trehalose, and maltose, or other sugar.
  • the buffer comprises a phosphate buffer.
  • the buffer comprises sodium phosphate dibasic, potassium phosphate monobasic, or a combination thereof.
  • Pharmaceutical compositions provided herein may comprise liposome particles of defined size. In some instances, particles comprise an average particle size of 100-500, 100-400, 100-300, 100-250, 100-200, 150-500, 150-400, 150-300, 150-250, 150-200, 175-300, 175-250, 175-200, 200-500, 200-400, 200-300, or 300-500 nm.
  • particles comprise an average particle size of no more than 500, 400, 300, 275, 250, 225, 200, 190, 180, 175, 170, 160, 150, or no more than 140 nm.
  • particles comprise a PDI of no more than 0.05, 0.1, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.35, 0.4 or no more than 0.5.
  • liposomes comprise average particle sizes enabling passage through a 0.22 micron pore size filter for sterilization purposes.
  • a parenteral formulations (e.g., liposomal formulation) is frozen. In some instances, a parenteral formulations (e.g., liposomal formulation) is stored as a lyophilized powder. In some instances, a parenteral formulations (e.g., liposomal formulation) is stored as a liquid or solution. In some instances, a parenteral formulations (e.g., liposomal formulation) is stored at a temperature of no more than 30, 25, 20, 15, 10, 5, 4, 0, -5, -10, -15, -20, or no more than -40 degrees C. In some embodiments, parenteral formulations are stored under inert gas or under vacuum.
  • parenteral formulations are stored under nitrogen or argon.
  • Pharmaceutical compositions disclosed herein may comprise advantageous properties for storage.
  • formulations e.g., liposomes
  • formulations e.g., liposomes
  • formulations are stable in terms of average particle size and chemical degradation.
  • pharmaceutical compositions are stable at room temperature for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years.
  • the pharmaceutical composition is stable at 2-8 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is stable at no more than 4 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years.
  • the pharmaceutical composition is stable at no more than 0 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is stable at no more than -10 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years.
  • the pharmaceutical composition is stable at no more than -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is essentially unchanged at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC.
  • the pharmaceutical composition is essentially unchanged at no more than -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC.
  • the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% degradation at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC.
  • the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% Compound 1 degradation at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC.
  • the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% Compound 1 and phospholipid degradation at no more than 20, 4, 0, - 10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC.
  • the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% phospholipid degradation at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC.
  • formulations prevent or reduce crystallization, which may negatively affect parenteral administration.
  • the pharmaceutical composition is substantially free of crystals. In some embodiments, the pharmaceutical composition is substantially free of crystals as measured under light microscopy.
  • the pharmaceutical composition is substantially free of crystals after at least one week, one month, two months, six months, or at least a year. In some embodiments, the pharmaceutical composition is substantially free of crystals after at least 1, 2, 3, 4, 5, 6, or more than 6 freeze-thaw cycles.
  • Pharmaceutical compositions disclosed herein may have a high purity (e.g., purity of Compound 1). In some embodiments, the purity of a pharmaceutical compositions is at least 90, 92, 94, 95, 96, 97, 98, 99, 99.5, 99.8, 99.9, or at least 99.95% pure. In some embodiments, a pharmaceutical compositions is essentially free of solvents or other impurities.
  • a pharmaceutical compositions comprises no more than 10,000, 7500, 5000, 4000, 3000, 2000, 1000, or no more than 500 ppm residual solvent.
  • solvent comprises an alcohol, ether, ketone, aldehyde, amide, amine, alkane, or haloalkane solvent.
  • the solvent comprises methanol, ethanol, or chloroform.
  • Nanosuspensions may comprise a nanosuspension. In some instances, the parenteral formulation comprises a nanosuspension.
  • the at least one excipient comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or Sodium Deoxycholate.
  • the at least one excipient comprises a wetting agent for a nanoparticle formulation.
  • the wetting agent comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or sodium deoxycholate.
  • the pharmaceutical composition comprises 0.1- 5%, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.2-0.6, 0.3-0.5, 0.5-5, 0.5-3, 0.5-2, 0.5-1.5, 1-5, 1-4, 1-3, 1-2, 2-5, or 2-7% poloxamer 188.
  • the pharmaceutical composition comprises 0.01-0.5, 0.02- 0.5, 0.05-0.5, 0.05-0.4, 0.05-0.3, 0.05-0.2, 0.05-0.1, 0.1-0.5, 0.2-0.5 or 0.3-0.5% sodium deoxycholate.
  • the pharmaceutical composition comprises 0.1-3, 0.2-2, 0.3-3, 0.5-3, 1-3, 1.5-3, 2-3, or 0.5-3% PVP K17 or PVP K30.
  • the compound is present at 20-200, 20-150, 20-100, 25-150, 25-100, 50-150, 50-200, 75-200, 75-200, 100-200, or 150-300 mg/mL.
  • Methods of Making Compound 1 and Polymorphic Forms Thereof [00109] In another aspect, the present disclosure provides methods of making Compound 1 or polymorphs thereof: p , or a pharmaceutically acceptable solvate or hydrate thereof. [00110] The preparation and uses of Compound 1 have been previously described (see, Example 81 of US 7,504,522, which is incorporated by reference in its entirety). [00111] The preparation of polymorphs of Compound 1 has been previously described (see, US 11,795,146, which is incorporated by reference in its entirety).
  • Methods provided herein may comprise measurement of one or more metrics followed by treatment with compounds described herein (e.g., Compound 1).
  • compounds described herein e.g., Compound 1
  • parenteral formulations provided herein are uniquely suited to treat subjects that are unable to receive treatment using alternative methods of administration (e.g., oral), or require amelioration of symptoms faster than provided by other routes of administration.
  • the present disclosure provides a method of treating known or suspected acute drug overdose reaction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, or the pharmaceutical composition as described herein.
  • a method of treating a known or suspected acute cannabinoid toxicity in a subject in need thereof comprising: administering to the subject a therapeutically-effective amount of a compound having the structure: .
  • the method comprises parenteral administration.
  • the subject shows signs of an acute cannabinoid overdose.
  • the acute cannabinoid overdose is caused by a compound from the Cannabis genus.
  • the acute cannabinoid overdose is caused by a synthetic cannabinoid.
  • the acute cannabinoid overdose is caused by oral ingestion of cannabinoids or synthetic cannabinoids.
  • the acute cannabinoid overdose is caused by oral ingestion of cannabinoids or synthetic cannabinoids.
  • the synthetic cannabinoid is capable of binding to the Cannabinoid (CB1) receptor.
  • a subject may be unwilling or physically unable to be administered an oral formulation. This could include inability to swallow, unconsciousness, or age limitations.
  • the subject shows signs of cannabinoid hyperemesis syndrome.
  • the subject shows signs of vomiting.
  • parenteral administration is used to treat subjects showing symptoms of cannabinoid hyperemesis syndrome and/or vomiting.
  • parenteral administration is used to treat subjects showing symptoms of nausea, vomiting, coughing, and choking.
  • parenteral administration is used to treat subjects showing symptoms of cannabis toxicity/poisoning (e.g., pediatric patients).
  • parenteral administration is used to treat subjects showing neurologic, cardiovascular, gastrointestinal, ocular, respiratory, or other cannabinoid toxicity symptom. In some instances, parenteral administration is used to treat subjects showing symptoms of cannabis-induced CNS depression. In some instances, parenteral administration is used to treat subjects showing symptoms of CNS depression, respiratory depression, drowsiness/lethargy, ataxia, tachycardia, agitation, confusion tremors, seizures, and coma. In some instances, parenteral administration is used to treat subjects showing symptoms of anaphylactic shock. In some instances, parenteral administration is used to treat subjects experiencing trauma or swelling to the face, mouth, throat, esophagus, or digestive tract.
  • respiratory depression is caused by synthetic cannabinoids.
  • respiratory depression is caused by another drug in the patient’s system, such as an opiate.
  • parenteral administration is used to treat acute cannabis (or cannabinoid)-induced CNS depression.
  • a pediatric patient comprises an adolescent, child, infant, or neonate.
  • the patient is no more than 28 days, 2 years, 12 years, or 21 years old.
  • the patient is 1-28 days old, 29 days to less than 2 years old, 2 years to less than 12 years old, or 12 years to less than 21 years old.
  • the method further comprises monitoring the subject for improvement of cannabinoid overdose symptoms.
  • parenteral administration is used to treat subjects showing neurologic, cardiovascular, gastrointestinal, ocular, respiratory, or other cannabinoid toxicity symptom.
  • neurologic symptoms comprise one or more of ataxia, agitation, confusion, tremor, dizziness/vertigo, seizure, hallucinations/delusions, slurred speech, or headache.
  • cardiovascular symptoms comprise one or more of tachycardia, hypotension, bradycardia, hypertension.
  • gastrointestinal symptoms comprise one or more of vomiting, nausea, and abdominal pain.
  • ocular symptoms comprise one or more of mydriasis, red eye/conjunctivitis, nystagmus, and miosis.
  • respiratory symptoms comprise one or more of respiratory depression and hyperventilation/tachypnea.
  • additional symptoms comprise one or more of pallor, fever/hyperthermia, acidosis, muscle weakness, hypothermia, urinary retention, and electrolyte abnormality.
  • Administration e.g., parenteral with a compound described herein (e.g., Compound 1) to treat cannabinoid intoxication may occur immediately after exposure to cannabis, extract thereof, or synthetic cannabinoid (e.g., first time;), or at a later time (e.g., second time).
  • administration e.g., ingestion of edibles, inhalation, etc.
  • administration of cannabis or other cannabinoid occurs at the same time as administration of a cannabinoid intoxication treatment (e.g., Compound 1).
  • administration e.g., ingestion of edibles, inhalation, etc.
  • cannabis or other cannabinoid occurs prior to treatment.
  • administration e.g., ingestion of edibles, inhalation, etc.
  • administration of cannabis or other cannabinoid occurs 0.1, 0.2, 0.5, 0.7.1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, or about 20 hours prior to treatment (e.g., administration of Compound 1).
  • administration (e.g., ingestion of edibles, inhalation, etc.) of cannabis or other cannabinoid occurs at least 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, or no more than 20 hours prior to treatment (e.g., administration of Compound 1).
  • administration e.g., ingestion of edibles, inhalation, etc.
  • administration of cannabis or other cannabinoid occurs at least 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, or at least 20 hours prior to treatment (e.g., administration of Compound 1).
  • administration e.g., ingestion of edibles, inhalation, etc.
  • administration of cannabis or other cannabinoid occurs at least 0.1-20.0.1-16, 0.1-12, 0.1-10, 0.1- 8, 0.1-6, 0.1-6, 0.1-4, 0.1-1, 0.5-12, 0.5-8, 0.5-6, 0.5-4, 1-8, 1-6, 1-4, 1-2, 2-4, 2-6, 2-8, 4-12, 4-6, 4- 8, 4-12, 6-12, 6-14, or 6-20 hours prior to treatment (e.g., administration of Compound 1).
  • the method further comprising treatment for drug overdose prior to treatment with (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide.
  • the prior treatment comprises one or more of administration of an opiate antagonist, activated charcoal, or emetic.
  • the present disclosure provides a method of using (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, or the pharmaceutical composition as described herein, comprising administering a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide prior to exposure to a cannabinoid.
  • the cannabinoid is tetrahydrocannabinol (THC).
  • the present disclosure provides a method of treating a subject suspected of a drug overdose, comprising administering a therapeutically effective amount of (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide to the subject and monitoring said subject for reduced symptoms associated with overdose.
  • the monitoring comprises monitoring heart rate or respiration.
  • the present disclosure provides a method of treating cannabis use disorder (CUD) in a subject in need thereof, comprising administering a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide, or the pharmaceutical composition as described herein.
  • the subject is addicted to a compound from the Cannabis genus.
  • the subject is addicted to a synthetic cannabinoid.
  • the synthetic cannabinoid is capable of binding to the CB1 receptor.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is Form I.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide is Form II.
  • the method further comprising a diagnostic test prior to treatment with (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide.
  • the diagnostic test is a blood test.
  • the subject has a cannabinoid plasma concentration of at least 25 ⁇ g/L.
  • the diagnostic test is a blood test.
  • the subject has a cannabinoid plasma concentration of at least 50 ⁇ g/L.
  • the subject has a cannabinoid plasma concentration of about 25 ⁇ g/L to 350 ⁇ g/L. In some embodiments, the subject has a cannabinoid plasma concentration of about 50 ⁇ g/L to 350 ⁇ g/L. In some embodiments, the subject has a cannabinoid plasma concentration of about 75 ⁇ g/L to 350 ⁇ g/L. In some embodiments, the subject has a cannabinoid plasma concentration of about 100 ⁇ g/L to 350 ⁇ g/L. In some embodiments, the subject has a cannabinoid plasma concentration of about 150 ⁇ g/L to 350 ⁇ g/L.
  • the subject has a cannabinoid plasma concentration of about 200 ⁇ g/L to 350 ⁇ g/L.
  • the amount of (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 0.1 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 1 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 0.5 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 2 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 5 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 10 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 15 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 20 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 25 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 30 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 35 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 40 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 45 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 50 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 75 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 100 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 125 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 150 mg to about 200 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 175 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 25-500, 25-400, 25-300, 25-250, 25- 200, 25-150, 25-100, or 25-75 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 50-500, 50-400, 50- 300, 50-250, 50-200, 50-150, 50-100, or 50-75 mg.
  • the amount of (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 75- 500, 75-400, 75-300, 75-250, 75-200, 75-150, 75-100, or 75-125 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide is 100-500, 100-400, 100-300, 100-250, 100-200, 100-150, 100-125 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 1-200 mg, 10-50 mg, 10-30 mg, or 20-30 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 5-300 mg, 5-100 mg, or 10-30 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 1-50, 1-30, 1-25, 1-20, 1-15, 1-20, 1- 5, or 1-3 mg.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 50 mg.
  • administration is parenteral.
  • the amount of compound administered parenterally to the subject is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 50 mg.
  • the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 30 minutes.
  • the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 1 hour. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 10 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 15 minutes. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 45 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 20 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 5 minutes.
  • the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 3 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 1 minute. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 1 minute. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 30 seconds. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 10 seconds.
  • the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in 5-60, 5-45, 5-30, 5-25, 5-20, 5-15, 5-10, 10- 60, 10-120, 10-30, 20-60, 20-120, 50-120, 60-120, or 90-120 minutes. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in 5- 60, 5-45, 5-30, 5-25, 5-20, 5-15, 5-10, 10-60, 10-120, 10-30, 20-60, 20-120, 50-120, 60-120, or 90- 120 minutes by parenteral injection.
  • the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in 5-60, 5-45, 5-30, 5-25, 5-20, 5-15, 5- 10, 10-60, 10-120, 10-30, 20-60, 20-120, 50-120, 60-120, or 90-120 seconds by parenteral injection.
  • Compounds described herein e.g., Compound 1 in some instances have desirable PK profiles for treating cannabinoid overdose.
  • concentrations e.g., Cmax, AUC, etc.
  • the amount of (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least about 50 ng/mL, at least about 100 ng/mL or at least about 200 ng/mL within one hour after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 50 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 40 minutes after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 30 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 20 minutes after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 10 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 5 minutes after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 3 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 1 minute after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 30 seconds after parenteral administration.
  • the amount of ®-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 15 seconds after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within 10 seconds after parenteral administration.
  • the amount of (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng/mL within one hour after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 50 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 40 minutes after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 30 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 20 minutes after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 10 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 5 minutes after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 5 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 3 minutes after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 1 minute after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 30 seconds after parenteral administration.
  • the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 15 seconds after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng/mL within 10 seconds after parenteral administration.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is dosed to provide a Tmax of no more than 5, 4, 3, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5, or 0.25 hours.
  • (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is dosed to provide a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 100-200 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at 25-250 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25- 3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 150 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25- 1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 75 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 10-50 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 20-75 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at 15-50 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25- 3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 10-100 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5- 1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr.
  • the dosage is configured for parenteral administration.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100-500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 75 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500I/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 15 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 10 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 5 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 1 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100- 500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 15-50 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50-300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100-500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 20-50 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50- 300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100-500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 10-75 mg provides a Cmax of about 100-500 ng/mL, about 50-1000 ng/mL, about 50-400 ng/mL, about 50- 300 ng/mL, about 50-200 ng/mL, about 50-500 ng/mL, about 75-750 ng/mL, about 100-500 ng/mL, about 100-400 ng/mL, or about 100-300 ng/mL.
  • the dosage is parenteral.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide provides a dosage normalized plasma AUC last of about 25-600 h*ng/mL/mg, about 25-500 h*ng/mL/mg, about 25-450 h*ng/mL/mg, about 50-500 h*ng/mL/mg, about 50-450 h*ng/mL/mg, about 50-400 h*ng/mL/mg, about 50-300 h*ng/mL/mg, about 50-250 h*ng/mg, about 40-300 h*ng/mL/mg, or about 50-200 h*ng/mL/mg.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200-3000 ng/mL.
  • (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 150 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200- 3000 ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200-3000 ng/mL.
  • (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 75 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200- 3000 ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200-3000 ng/mL.
  • (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 40 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200- 3000 ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200-3000 ng/mL.
  • (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200- 3000 ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 15 mg provides a AUClast of about 1000-3500 h*ng/mL, about 1000-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200-3000 ng/mL.
  • (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 10 mg provides a AUClast of about 500-3500 h*ng/mL, about 500-3000 ng/mL, about 1250-3000 ng/mL, about 1500-2800 ng/mL, about 1000-2500 ng/mL, or about 1200- 3000 ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 5 mg provides a AUClast of about 100-3500 h*ng/mL, about 200-3000 ng/mL, about 1250-3000 ng/mL, about 500- 2800 ng/mL, about 300-2500 ng/mL, or about 400-3000 ng/mL.
  • (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 1 mg provides a AUClast of about 100-3500 h*ng/mL, about 100-3000 ng/mL, about 125-3000 ng/mL, about 150-2800 ng/mL, about 200-2500 ng/mL, or about 500-3000 ng/mL. In some instances, the dosage is parenteral.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide provides a dosage normalized plasma AUC 5h of about 5-60 h*ng/mL/mg, about 5-50 h*ng/mL/mg, about 5-45 h*ng/mL/mg, about 5-45 h*ng/mL/mg, about 7-60 h*ng/mL/mg, about 7-50 h*ng/mL/mg, about 7-45 h*ng/mL/mg, about 7- 40 h*ng/mL/mg, about 10-60 h*ng/mL/mg, about 10-50 h/mL/mg, about 10-50 h*ng/mL/mg, or about 10-40 h*ng/mL/mg.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 150 mg provides a AUC 5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at no more than 75 mg provides a AUC 5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 40 mg provides a AUC 5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at no more than 25 mg provides a AUC 5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 15 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 10 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at no more than 5 mg provides a AUC5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 1 mg provides a AUC 5h of about 200-2000 h*ng/mL, about 200-1500 h*ng/mL, about 200-1200 h*ng/mL, about 300-2500 h*ng/mL, about 300-2000 h*ng/mL, about 300-1750 h*ng/mL, about 300-1500 h*ng/mL, about 400-3000 h*ng/mL, about 400-2000 h*ng/mL, about 400-1500 h*ng/mL, about 400-1200 h*ng/mL, or about 400-1000 h*ng/mL.
  • the dosage is parenteral.
  • the method reduces the subject’s ability to experience euphoria after inhaling or consuming Cannabis or a synthetic cannabinoid.
  • Compositions and formulations described herein may be administered as single or multiple doses.
  • described herein are methods of using the (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide as a single dose, one- time treatment for overdose THC or SC, or both.
  • the overdose can also be from consumption of cannabis, synthetic cannabinoid, or any compound that is an agonist of the CB1 receptor.
  • methods described herein include treatment to children who inadvertently consume cannabis or cannabinoid edibles.
  • any suspected overdose patient that presents a mentally disoriented or psychotic or cannot articulate the nature of their condition or the substances that have been ingested or administered can be treated with (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide.
  • the methods described herein include pre-exposure prophylaxis treatments.
  • CB1 antagonism which in some instances includes anhedonia, potentially makes them unsuitable for chronic use.
  • a CB1 antagonist such as (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, before encountering a situation where they may likely be exposed to or tempted to ingest THC or SCs or both.
  • (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide is used to prevent effects from secondhand smoke from marijuana.
  • the method of using (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in some instances includes use by a subject who wishes to gain acceptance to a situation or group by smoking marijuana or SCs, but also wants to remain mentally alert, such as during an undercover police or law enforcement investigation.
  • a method comprises one or more steps of: preparing an organic phase; mixing the organic phase with an aqueous phase to generate a mixture; shearing the mixture; extruding the mixture; concentrating the mixture; removing the solvent and sterile- filtering the mixture.
  • methods comprise preparing parenteral formulations of liposomes.
  • methods comprise preparing parenteral formulations of liposomes having a concentration of at least 1, 2, 3, or at least 4 mg/mL of Compound 1.
  • preparing the organic phase comprises generating liposomes.
  • preparing the organic phase comprises: mixing the compound with a first excipient in a first solvent to generate a first solution; mixing a second excipient in a second solvent to generate a second solution; and combining the first solution and the second solution.
  • the first solution is mixed at about room temperature.
  • the first solution is mixed at 15-25 degrees C.
  • the second solution is mixed at 30-80, 30-60, 40-50, 40-60, 50-60 or 50-80 degrees C.
  • combining the first solution and the second solution occurs at about room temperature.
  • the first solution or the second solution independently comprises an alcohol, ether, ketone, aldehyde, amide, amine, alkane, or haloalkane solvent or mixture thereof. In some embodiments, the first solution or the second solution independently comprises methanol, ethanol, or chloroform or mixture thereof.
  • the aqueous phase may comprise a buffer as described herein. In some embodiments, the buffer comprises one or more of a salt, a solvent, and a stabilizer. In some embodiments, the buffer comprises a pH of 6-8, 6-7, 7-8, or 7-9. In some embodiments, the buffer is isotonic and isohydric. In some embodiments, the buffer comprises a sugar.
  • the buffer is isotonic. In some embodiments, the buffer comprises glucose, sucrose, lactose, trehalose, maltose, or other sugar. In some embodiments, the buffer comprises a phosphate buffer. In some embodiments, the buffer comprises sodium phosphate dibasic, potassium phosphate monobasic, or a combination thereof. [00140] Shearing (or homogenization) may be used to form the liposomes by mixing the organic phase containing the liposome components with an excess of an aqueous phase and simultaneously decrease and control the size of the liposome particles. Shearing (or homogenization) may be used to decrease the size of the liposome particles.
  • shearing comprises mixing at 2000-7000, 2000-6000, 2000-5000, 2000-400, 3000-4000, 3000-5000, 3000-6000, 4000-5000, 4000-6000, or 5000-6000 RPM.
  • sheering comprises use of a square mixing screen.
  • the organic phase is added to the aqueous phase during shearing. In some instances, the organic phase is added over at least 3, 4, 5, 6, 7, 8, 9, or at least 10 minutes. In some instances, the phases are sheared for at least 2, 4, 5, 6, 8, 10, 12, 15, or at least 20 minutes.
  • the mixing and shearing results in an average particle size of 100-500, 100-400, 100-300, 100-250, 100-200, 150-500, 150-400, 150-300, 150-250, 150-200, 175-300, 175-250, 175-200, 200-500, 200-400, 200-300, or 300-500 nm.
  • shearing results in an average particle size of no more than 500, 400, 300, 275, 250, 225, 200, 190, 180, 175, 170, 160, 150, or no more than 140 nm.
  • Extrusion may be used to further modulate particle sizes in a mixture.
  • extrusion comprises 1, 2, 3, 4, or more than 4 passes through a filter.
  • the filter comprises a 500, 450, 400, 350, 300, 250, 200, 150, 100 nm or smaller filter.
  • Extrusion in some embodiments is conducted at a temperature of 5-10, 5-25, 5-50, 5-80, 10- 80, 25-80, 30-80, 30-60, 40-50, 40-60, 50-60 or 50-80 degrees C. Extrusion in some embodiments is conducted at a pressure of at least 5, 10, 25, 50, 60, 70, 80, 90, 100, 120, or at least 150 bar. Multiple extruder heads may also be utilized. In some instance, extrusion results in an average particle size of no more than 500, 400, 300, 275, 250, 225, 200, 190, 180, 175, 170, 160, 150, or no more than 140 nm.
  • extrusion results in particles having a PDI of no more than 0.05, 0.1, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.35, 0.4 or no more than 0.5. In some instance, extrusion results in a decrease of at least 20, 15, 10, 5, or at least 3 percent in average particle size relative to pre-extrusion. In some instances, a first filter is used for a first pass extrusion, and a second filter is used for a second pass extrusion. In some instances, each subsequent extrusion uses a smaller filter size. [00142] Mixtures may be manipulated to concentrate particles and/or to or reduce the level of residual solvents. In some embodiments, concentrating comprises filtration.
  • concentrating comprises tangential flow filtration. In some embodiments, concentrating comprises dialysis.
  • the method comprises sterilizing a formulation. In some embodiments, mixtures are filtered through a 800, 700, 600, 500, 450, 400, 300, 250, 200, 150, 100 nm or smaller filter for sterilization. In some instances, more than one sterile filtration is used. In some embodiments, mixtures are first filtered through an about 220 nm filter. In some embodiments, mixtures are first filtered through an about 220 nm filter, followed by about a 450 nm filter. In some embodiments, mixtures are first filtered through no more than a 220 nm filter.
  • mixtures are first filtered through no more than a 220 nm filter, followed by no more than a 450 nm filter.
  • a first filter is used for a first pass sterilization
  • a second filter is used for a second pass sterilization.
  • each subsequent sterilization uses a smaller filter size.
  • the method comprises freezing after sterilization.
  • the method comprises lyophilizing after sterilization.
  • aqueous and organic phases are mixed using continuous controlled in-line T mixing.
  • in-line mixing the product is subjected to tangential flow filtration.
  • in-line mixing the product is subjected to tangential flow filtration followed by sterile filtration.
  • active agent is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pharmaceutical utility.
  • an active agent may be an anti-cancer therapeutic.
  • modulation refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity.
  • the change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity.
  • the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.
  • “therapeutically effective amount” of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.
  • “Treating” or “treatment” encompasses administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and/or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer.
  • a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, carbonate, phosphate, hydrogenphosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, Tris (hydroxymethyl-aminomethane), p-toluenesulfonate, propionate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, oxalate, pamoate, and alkanoate such as acetate, HOOC-(CH 2 ) n -COOH where n is 0-4, and like salts.
  • inorganic acids such as hydrochlorate, carbonate, phosphate,
  • salts include sulfate, methanesulfonate, bromide, trifluoroacetate, picrate, sorbate, benzilate, salicylate, nitrate, phthalate or morpholine.
  • Pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to treat the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • acid addition salts may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • “subject” refers to a mammal that has been or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.
  • Prodrugs described herein include any compound that becomes Compound 1 when administered to a subject, e.g., upon metabolic processing of the prodrug.
  • pharmaceutically acceptable salts includes “prodrugs” of pharmaceutically acceptable salts.
  • Examples of prodrugs include derivatives of functional groups, such as a carboxylic acid group, in Compound 1.
  • Exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters.
  • exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.
  • exemplary prodrugs include amides of carboxylic acids.
  • a “solvate” is formed by the interaction of a solvent and a compound.
  • the term “compound” is intended to include solvates of compounds.
  • “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates. Also included are solvates formed with the one or more crystallization solvents.
  • Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • a “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points.
  • a “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term “compound”.
  • pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts.
  • a pharmaceutical composition configured for parenteral administration comprising a compound having the structure: and at least one excipient.
  • Embodiment 2. The pharmaceutical composit ion of embodiment 1 wherein the parenteral formulation is selected from a nanosuspension, oil and water emulsion, liposome, or micelle.
  • Embodiment 3. The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises an oil and water emulsion.
  • the pharmaceutical composition of embodiment 3, wherein the at least one excipient comprises an oil.
  • the pharmaceutical composition of embodiment 3, wherein the excipient comprises soybean oil (SBO), Miglycol 812, olive oil, coconut oil, or a mixture thereof.
  • Embodiment 8. The pharmaceutical composition of embodiment 3, wherein the compound is present at 5-20 mg/mL.
  • Embodiment 9 The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises micelles.
  • Embodiment 10 The pharmaceutical composition of embodiment 9, wherein the parenteral formulation comprises a phospholipid.
  • the pharmaceutical composition of embodiment 9, wherein the excipient comprises Miglyol 812, Lipoid E80, saline, or a combination thereof.
  • Embodiment 12. The pharmaceutical composition of embodiment 9, wherein the pharmaceutical composition comprises 0.5-3% Lipoid E80.
  • Embodiment 13 The pharmaceutical composition of embodiment 9, wherein the compound is present at 5-20 mg/mL.
  • Embodiment 14. The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises a liposome.
  • Embodiment 15 The pharmaceutical composition of embodiment 14, wherein the at least one excipient comprises a phospholipid.
  • Embodiment 16 The pharmaceutical composition of embodiment 15, wherein the pharmaceutical composition comprises 10-50 mg/mL phospholipid.
  • the pharmaceutical composition of embodiment 14, wherein the at least one excipient comprises Lipoid S100 or dimyristoylphosphatidylglycerol (DMPG).
  • Embodiment 18 The pharmaceutical composition of embodiment 14, wherein the compound is present a 0.5-10 mg/mL.
  • Embodiment 19 The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises a nanosuspension.
  • Embodiment 20 The pharmaceutical composition of embodiment 19, wherein the at least one excipient comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or Sodium Deoxycholate.
  • Embodiment 21 The pharmaceutical composition of 19, wherein the pharmaceutical composition comprises 0.1-5% poloxamer 188.
  • Embodiment 22 The pharmaceutical composition of 19, wherein the pharmaceutical composition comprises 0.1-5% poloxamer 188.
  • the pharmaceutical composition of embodiment 19, wherein the pharmaceutical composition comprises 0.05-05% sodium deoxycholate.
  • Embodiment 23. The pharmaceutical composition of embodiment 19, wherein the pharmaceutical composition comprises 0.2-2% PVP K17 or PVP K30.
  • Embodiment 24. The pharmaceutical composition of embodiment 19, wherein the compound is present at 50-200 mg/mL.
  • Embodiment 25. A method of treating a known or suspected acute cannabinoid intoxication in a subject in need thereof, the method comprising: administering to the subject a therapeutically-effective amount of a parenteral formulation of a compound having the structure , wherein treating improves one or more metrics associated with acute cannabinoid intoxication.
  • Embodiment 27 The method of embodiment 1, wherein the metric is measured by a healthcare provider or emergency responder.
  • Embodiment 28 The method of any one of embodiments 25-27, wherein the amount of compound administered to the subject is 1-200 mg, 1-10 mg, 1-25 mg, 5-20 mg, 10-50 mg, 10-30 mg, or 20-30 mg.
  • Embodiment 29 The method of any one of embodiments 25-27, wherein the method further comprises administering 5- 300 mg, 5-100 mg, or 10-30 mg of delta-9-tetrahydrocannabinol (THC) to the subject.
  • Embodiment 30 The method of any one of embodiments 25-27, wherein the method further comprises administering 5- 300 mg, 5-100 mg, or 10-30 mg of delta-9-tetrahydrocannabinol (THC) to the subject.
  • THC delta-9-tetrahydrocannabinol
  • ANEB-001 was soluble in Miglyol at 20 mg/mL and even >100 mg/mL.
  • Miglyol is an oil excipient which can be used in parenteral emulsions.
  • Example 2 – Evaluation of Parenteral Formulations of Compound 1 [00167] ANEB-001 was evaluated in oil-in-water emulsions formed by a mixture of Miglyol and phospholipids. ANEB-001 was dissolved in Miglyol to form 6 mg/mL or 60 mg/mL solutions. The phospholipid Lipoid E80 (1.2% w/v) was added and heated at 50C for 3 hours to solubilize ingredients.
  • the solutions were diluted 1:10 with saline [0.9% w/v] to provide an oil in water emulsion of ANEB-001 [10 mg/ml ].
  • the stability of the 10% ANEB-001 emulsion was evaluated at either 50C or 2-8 C.
  • the solutions were stable at the two temperatures and the two concentrations for at least 14 days. See FIGS.1-8.
  • Oil-in water emulsions with 10 or 20% oil phase and particle size of approximately 250 nm were prepared enabling the IV, IM, or SC administration of a large range of ANEB-001 concentrations/doses. In addition, no crystallization of the drug substance was observed after dilution of this emulsion in saline for 16 h at ambient temperature.
  • Example 3 Evaluation of Liposomal Formulations of Compound 1 [00169]
  • a screening of various drug to lipid ratios and short-term stability testing were performed.
  • ANEB-001, Lipoid S100 and DMPG-Na were loaded in 100 mL flask.
  • the mixture was dissolved in MeOH: Chloroform: Water (65:55:4). Once dissolved, the mixture was dried with a rotary evaporator and vacuum overnight.
  • the solid was re-constituted in PBS pH 6.8 [10 ml] and extruded twice through a 200 nm filter and once through a 100 nm filter.
  • ANEB-001 A formulation with 2 mg ANEB-001/mL and 30 mg lipid/mL and 1 : 15 drug to lipid mass ratio, enabling the IV, IM or SC administration of ANEB-001, appeared to have acceptable chemical and physical stability properties.
  • Example 4 Evaluation of Nanoparticle Suspension Formulations of Compound 1 [00171]
  • ANEB-001 was evaluated in nanoparticles including a mixture of excipients, such as polyvinylpyrrolidone [PVP], nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene [poloxamer], PBS and sodium deoxycholate. See Table 3.
  • ANEB-001 concentrations ranged from 40 to 100 mg/mL.
  • a liquid nanosuspension with crystalline ANEB-001 was achieved with high drug loading ( ⁇ 100 mg/mL ANEB-001).
  • Formulation E [10% ANEB-001 with 1% PVP K17 and 0.15% Na Deoxy] was selected for nanomilling and stability analysis.
  • the particle size distribution analysis ⁇ PSD ⁇ after a week at either 5C or 25C is shown in FIGS.9-10.
  • 5C a bimodal PSD curve was observed with peaks at 1.4 and 4 um.
  • 25C a bimodal PSD curve was observed with peaks at 1.5 and 9 um.
  • Formulation F [10% ANEB-001 with 1% PVP K17 and 0.20% Na Deoxy] at either 40 mg/mL or 100 mg/mL loads was also selected for nanomilling and stability analysis.
  • the particle size distribution analysis ⁇ PSD ⁇ after a week at either 5C or 25C is shown in FIGS.11-14.
  • a PSD curve was observed with peak at 4 um.
  • a PSD curve was observed with a peak at um.
  • a monomodal PSD curve was observed with the tail on right side with particles as big as 5.5 ⁇ m.
  • a monomodal PSD curve was observed with the tail on right side with particles as big as 7 ⁇ m.
  • the liposome was administered intravenously at a concentration of 1.35mL/kg [2.00 mg/kg (3% liposome)], 1.20 mL/kg [1.67mg/kg (3% liposome)] for intravenous infusion, 1.00 mL/kg [3.33 mg/kg (5% liposome) or 1.50 mg/kg (3% liposome)] for subcutaneous administration or intramuscularly at 0.25 mL/kg [0.50 mg/kg (3% liposome)].
  • the nanosuspension was administered subcutaneously at a concentration of 0.20 mL/kg.
  • Each formulation was administered as a single dose to 6 male beagle dogs by intravenous, intramuscular, and subcutaneous dosing, with a 2 week washout between doses.
  • Plasma samples were taken at the following schedule: Pre dose then 2, 5, 10, 15 and 30 minutes then 1, 2, 4, 6, 8, 12, and 24 hours post dose.
  • plasma samples were taken Pre dose then 5 (during infusion), 15 (end of infusion) and then 17, 20, 30 minutes then 1, 2, 4, 6, 8, 12, and 24 hours post dose.
  • Table 4 [00175] The amount of compound was analyzed by quantitative bioanalysis by LC-MS/MS of dog (male Beagle) plasma samples.
  • the intravenous liposome formulation appears to have the greatest potential to provide high exposure to Compound 1 and a rapid onset of action, suitable for a human IV product for ACI.
  • a Cmax after IM administration of about 115 ng/mL was observed.
  • a Tmax of 12 minutes was observed for IM dosing (FIG.17)
  • the relative bioavailability for IM administration was about 66%.
  • Liposomal PK Data SC 1.5 mg/kg
  • Example 6 Liposomal formulations of Compound 1 [00178] A phospholipid mixture and Compound 1 were dissolved in the respective organic solvents and then dried in rotary evaporator followed by overnight storage under high vacuum (freeze-drier), to ensure complete drying. The initial target was for the final solution to have a concentration of 1mg/mL of Compound 1 loaded into 3% w/v multi-lamellar vesicles in saline. In some instances, Compound 1 and one or more components were pre-dissolved in one solvent or solvent mixture, and then later mixed with additional components.
  • a control was prepared by dissolving Compound 1 in ethanol at a concentration of 20 mg/mL and diluting that with 20mL of the 0.9% w/v NaCl in WFI. Table 9.
  • Liposomes Example 7 – Preparation of a Liposomal Formulation of Compound 1
  • Compound 1 was formulated in a liposomal dosage form comprising 2 to 3 mg Compound 1/ml and 1:15 drug to lipid weight ratio and 97:3 soybean phosphatidylcholine (sold as Lipoid S100, Lipoid Gmbh)/DMPG sodium weight ratio as lipid components and an isotonic sucrose buffer.
  • the buffer comprises phosphate buffer, pH 7.4: (279.4 mM Sucrose, 8.26 mM Phosphate (7 mM sodium phosphate dibasic and 1.26 mM potassium phosphate monobasic)).
  • Step 1 Preparation of organic phase.
  • Step 2 The organic phase is mixed until addition to aqueous phase sucrose/phosphate buffer. Addition occurs within 30 minutes to prevent precipitation of the DMPG, to a target concentration of 2mg/mL Compound 1).
  • Step 3 High shear mixing for 10 minutes at 3000-5000rpm with a square mixing screen is conducted.
  • Step 4. Mixture is extruded for 1-2 passes through 200nm PCTE filter, with a target average particle size to below 200nm with narrow PDI. [00184] Step 5.
  • Tangential Flow Filtration is used to reduce ethanol content to below 5000ppm (target NMT 1500ppm, see Table 11), and Compound 1 to a target concentration of 2-3mg/mL.
  • Step 6. Filling. Mixture is sterile filtered through 0.2 micron PES filter under nitrogen into clear glass vials (pharma grade).
  • Step 7. Vials are frozen at -20°C. Vials may also be lyophilized for storage. [00187] After three freeze/thaw cycles, formulations were evaluated by light microscopy under polarized light to check for the presence of crystals (Table 10). No degradation of samples was observed by HPLC after about 1-2 weeks from manufacture.
  • Conditions for crystallization were obtained using (1) pre-extrusion samples of 2 mg/mL compound 1 in buffer sodium phosphate/sucrose only (2 month old sample); or (2) pre-extrusion samples of 3 mg/mL compound 1 in buffer sodium chloride/sodium+potassium phosphate/sucrose, pH 7.4 (both 0.1L scale). With other process conditions no crystallization or precipitation of Compound 1 was observed.
  • Table 10 Homogenization Evaluation, 3mg/mL (4L scale) Key: * Buffer 8.3mM phosphate components and 280 mM sucrose; + Buffer 8.3mM phosphate components and 190 mM sucrose Particle Size: A: 150-175; B: 176-200; C: >200 PDI: A: 0.1-0.15; B: 0.16-0.2; C: >0.2 n.d.
  • the bile salts that were used were sodium glycocholate and sodium deoxycholate, and the phospholipids used were Lipoid S100 (Soybean Phosphatidylcholine) and DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) (provided by Lipoid). Two different molar ratios of bile salt to phospholipid were tested, 1:1 and 2:1. The protocol followed was to first prepare a concentrated solution of mixed micelles at 30% w/v in 0.9% w/v NaCl in milli-Q water and load the micelles with 10mg/ml Compound 1. The final dilution of the Compound 1 was performed to achieve an expected mixed micelle concentration of 3-10% w/v.
  • Table 13 DLS analysis of mixed micelle blank solutions with LipoidS100 [00191] Then, the mixed micelle solutions were loaded with Compound 1 (10mg/mL) and were left shaking for a total of 24 hours at 37°C and an extra 24 hours at 50°C. Compound 1 did not solubilize fully; as the drug did not solubilize fully, the experiments were then centrifuged at 10,000 rpm for 10 minutes and the supernatant was collected and analyzed via HPLC to obtain an assay value and microscopy to check for any signs of precipitation. The assay values obtained via the HPLC are presented in Table 14 below. Table 14. HPLC assay of mixed micellar solutions supernatant upon centrifugation at 10,000rpm for 10 minutes.
  • Example 10 Manufacture of Parenteral Formulation using in-line mixing [00197] The general methods of Example 7 were followed with modification: continuous controlled in-line T mixing was used to mix aqueous and organic phases. The product was also subjected to tangential flow filtration followed by sterile filtration.
  • Example 11 Treatment of a Pediatric Patient with a Parenteral Formulation
  • a six-year old child suspected of consuming cannabinoid-containing edibles is admitted to the emergency room.
  • the child is administered a parenteral formulation of any one of Examples 1- 10 by I.V. and monitored for amelioration of symptoms (if present) or change in condition.
  • Example 12 Treatment of a Patient with a Respiratory Depression
  • a patient suspected of smoking synthetic cannabinoids is admitted to the emergency room.
  • the patient is suffering from respiratory depression, and is administered a parenteral formulation of any one of Examples 1-10 by I.V. and monitored for amelioration of symptoms.

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Abstract

L'invention concerne des procédés de traitement de la toxicité induite par des cannabinoïdes. L'invention concerne en outre des compositions injectables pour traiter une surdose de cannabinoïde aiguë, un empoisonnement ou une dépression aiguë du SNC induite par des cannabinoïdes. L'invention concerne en outre des méthodes de traitement de la toxicité induite par les cannabinoïdes chez des patients pédiatriques.
PCT/US2024/044144 2023-08-29 2024-08-28 Formulations parentérales d'inhibiteurs de cb1 et procédés d'utilisation Pending WO2025049544A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220151990A1 (en) * 2020-11-18 2022-05-19 Anebulo Pharmaceuticals, Inc. Formulations and methods for treating acute cannabinoid overdose
US20220233495A1 (en) * 2019-05-31 2022-07-28 GW Research Limited Cannabinoid formulations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220233495A1 (en) * 2019-05-31 2022-07-28 GW Research Limited Cannabinoid formulations
US20220151990A1 (en) * 2020-11-18 2022-05-19 Anebulo Pharmaceuticals, Inc. Formulations and methods for treating acute cannabinoid overdose

Non-Patent Citations (1)

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Title
PINAR SILA GÜLBAĞ, OKTAY AYŞE NUR, KARAKÜÇÜK ALPTUĞ EREN, ÇELEBI NEVIN: "Formulation Strategies of Nanosuspensions for Various Administration Routes", PHARMACEUTICS, MDPI AG, SWITZERLAND, vol. 15, no. 5, Switzerland, pages 1520 - 1520-28, XP093289174, ISSN: 1999-4923, DOI: 10.3390/pharmaceutics15051520 *

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