[go: up one dir, main page]

WO2020257333A1 - Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes - Google Patents

Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes Download PDF

Info

Publication number
WO2020257333A1
WO2020257333A1 PCT/US2020/038211 US2020038211W WO2020257333A1 WO 2020257333 A1 WO2020257333 A1 WO 2020257333A1 US 2020038211 W US2020038211 W US 2020038211W WO 2020257333 A1 WO2020257333 A1 WO 2020257333A1
Authority
WO
WIPO (PCT)
Prior art keywords
concentrate
drinabant
polymorph
salt
cannabinoid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2020/038211
Other languages
English (en)
Inventor
Phil Skolnick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Opiant Pharmaceuticals Inc
Original Assignee
Opiant Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/704,699 external-priority patent/US20200179271A1/en
Application filed by Opiant Pharmaceuticals Inc filed Critical Opiant Pharmaceuticals Inc
Priority to EP20827604.8A priority Critical patent/EP3986396A4/fr
Priority to AU2020295410A priority patent/AU2020295410A1/en
Publication of WO2020257333A1 publication Critical patent/WO2020257333A1/fr
Priority to IL289066A priority patent/IL289066A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • Acute cannabinoid overdose (also referred to as acute cannabinoid intoxication/poisoning] is most often linked to the consumption of“edibles” (sold as brownies, cookies, and candies) containing large quantities of D9-tetrahydrocannabinol (THC).
  • SBA cannabinoid
  • CB cannabinoid receptors
  • Symptoms of ACO produced by both edibles and SCs include panic and anxiety, feelings of paranoia, agitation, visual and auditory hallucinations, and nausea. There are no FDA approved medications to treat ACO. Treatment is supportive and symptom driven, requiring emergency medical attention and in some instances, hospitalization.
  • Cannabinoid use can also produce a syndrome which includes incapacitating, cyclic bouts of nausea and vomiting.
  • the severe nausea and vomiting that is associated with chronic cannabinoid use is commonly referred to as cannabinoid hyperemesis syndrome (CHS).
  • CHS can be viewed as paradoxical, since a synthetic form of A 9 -tetrahydrocannabinol (THC), the principal psychoactive compound present in cannabis, has been approved by the U.S. FDA (and regulatory authorities in other countries) for the treatment of chemotherapy- induced nausea and vomiting.
  • THC A 9 -tetrahydrocannabinol
  • the interval from cessation of cannabis use to complete resolution of symptoms may be as along as 1-4 weeks.
  • Patients treated for CHS in the emergency department often require admission to better manage both the emesis and the ensuing dehydration, electrolyte imbalance, and esophagitis that result from the frequent and severe vomiting.
  • authorities consider CHS distinct from acute cannabinoid overdose (also known as acute cannabinoid poisoning or intoxication) because of distinct symptoms and temporal patterning.
  • Phase II studies were conducted in dyslipidemia, mild-to-moderate Alzheimer’s disease, and in schizophrenia (as an add-on medication to treat cognitive impairment).
  • Drinabant was safe and well tolerated in these studies, with a preponderance of GI related (nausea, vomiting, and diarrhea) adverse events.
  • Tmax > 3 h the slow onset of oral drinabant
  • a parenteral fluid concentrate comprising:
  • parenteral fluid comprising a parenteral fluid concentrate described herein diluted with a pharmaceutically acceptable aqueous carrier.
  • Also provided is a method of treating, reversing, or reducing one or more symptoms of acute cannabinoid overdose comprising parenterally administering a parenteral fluid described herein to a subject in need thereof.
  • This range may be integral or continuous between and including the end values.
  • the range“from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units.
  • the range“from 1 to 3 mL (milliliters),” which is intended to include 1 mL, 3 mL, and everything in between to any number of significant figures (e.g. , 1.255 mL, 2.1 mL, 2.9999 mL, etc.).
  • the term“about” is intended to qualify the numerical values which it modifies, denoting such a value as variable within a range.
  • the term“about” should be understood to mean the greater of the range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, considering significant figures, and the range which would encompass the recited value plus or minus 20%.
  • reversal of symptom(s) of acute cannabinoid overdose is “apparent” when, in the judgment of a trained healthcare giver (e.g., physician, nurse practitioner, nurse, paramedic, or emergency medical technician), the symptom(s) have abated to a noticeable degree.
  • a trained healthcare giver e.g., physician, nurse practitioner, nurse, paramedic, or emergency medical technician
  • Such a caregiver may use any appropriate measure to quantify the reversal of symptom(s), e.g., a visual analog scale for self-reporting, a heart rate monitor for tachycardia, etc.“Apparent” reversal of symptom(s) includes, but need not extend to, complete reversal.
  • cannabinoid is synonymous with“cannabinoid receptor agonist” and refers to a compound which binds to and activates a cannabinoid receptor.
  • the term includes both natural and synthetic compounds.
  • SC synthetic cannabinoid
  • cannabinoids While not synthetic analogues of THC and other naturally occurring cannabinoids, SCs share many common features with THC. Most are lipid-soluble, non polar, small molecules (usually about 20-26 carbon atoms) that are fairly volatile, and often have a side-chain of 5-9 saturated carbon atoms which is associated with psychotropic activity from binding CB1 receptors. There are at least five major structural categories for synthetic cannabinoids: classical cannabinoids, non-classical cannabinoids, hybrid cannabinoids, aminoalkylindoles (and their analogues), and eicosanoids.
  • Classical cannabinoids are analogs of THC that are based on a dibenzopyran ring; examples include and Compounds such as HU-210 (the (-)-l,l-dimethylheptyl analog of 11-hydroxy- D8- tetrahydrocannabinol (HU-210)) are synthetic analogs of THC.
  • aminoakylindoles including naphthoylindoles such as l-pentyl-3-(l-naphthoyl)indole (JWH-018), phenylacetylindoles such as l-pentyl-3-(2-methoxyphenylacetyl)indole (JWH- 250), and benzoylindoles such as l-[(N-methylpiperidin-2-yl)methyl]-3-(2- iodobenzoyl)indole (AM-2233); they are the most common SCs found in SC blends due to relative ease of synthesis.
  • Other compounds structurally similar to aminoalkylindoles include naphthoy lpyrroles , naphthy lmethylindenes , phenylacetylindoles/benzoylindoles ,
  • Eicosanoid SCs are analogs of endocannabinoids such as anandamide.
  • cannabinoid receptor antagonist refers to a compound which binds to and blocks or dampens the normal biological function of the receptor and its signaling, especially in the presence of an agonist or partial agonist.
  • the term includes cannabinoid receptor antagonists that are selective or nonselective for the CB 1 receptor subtype, i.e., a“CB1 antagonist.”
  • CHS cannabinoid hyperemesis syndrome
  • C max refers to the maximum observed plasma concentration.
  • IM intramuscular
  • Suitable muscles include the deltoid (upper arm), the thigh (esp. the anterolateral aspect of the thigh; particularly useful if via an autoinjector), the gluteus maximus (typically only adults and children > 3 years old), and hip.
  • the IM injection may be via a classical syringe or an autoinjector device.
  • IV intravenous
  • IV administration can be by injection (in a relatively small volume and at relatively high concentration) by injection via a syringe or into a previously-inserted IV catheter, or by intravenous infusion (“IVN,” in a relatively larger and more dilute volume). IV administration, particularly injection, can be done in one or more pushes.
  • non- ionic solubilizer and/or“emulsifying agent” and/or“solubilizing agent” are generally interchangeable as used herein, and include agents that result in formation of a micellar solution or a true solution of the agent being solubilized and a typically immiscible partner (for example, drinabant, which has a high logP, and water, which has a negative logP).
  • Solubilizing agents include cationic and nonionic surfactants, and in certain circumstances may also act as absorption or permeation enhancers.
  • Kolliphor HS 15 / Solutol HS 15 e.g., macrogol 15 hydroxys tearate, CAS No. 70142-34-6 or 61909-81-7, polyoxyl 15 hydroxystearate, polyglycol mono- and di-esters of 12-hydroxystearic acid with about 30% polyethylene glycol.
  • the terms“overdose,”“intoxication,” and“poisoning” are synonymous and may be used interchangeably, and refer to the condition of having taken into the body of a subject, e.g. by inhalation or ingestion, an excess of a physiologically active and and/or psychoactive substance, such that the normal functioning of the body or one of its functions or parts is perturbed and the subject is at risk of harm.
  • the term“parenteral” means administered by means other than oral, nasal (i.e., bypassing mucous membranes) or rectal intake, particularly intravenously or by injection elsewhere, e.g., intramuscular or subcutaneous injection.
  • the term“push” in the context of an intravenous (IV) push is the rapid administration of a small volume of medication into a patient's vein, typically via a previously inserted IV catheter. Multiple pushes make be used to comprise a single IV dose.
  • the term“subcutaneous” means“under the skin,” i.e., administered into the subcutis, the layer of skin directly below the dermis and epidermis (collectively referred to as the cutis), above muscle.
  • a“symptom” of intoxication or overdose is a physical or mental feature that is regarded as is a departure from normal function or feeling.
  • Common symptoms of cannabinoid intoxication or overdose include dry mouth, increased appetite, nystagmus, slurred speech, and conjunctival injection (red eye), as well as generalized psychomotor impairment, including impaired attention, reduced alertness (drowsiness), impaired concentration, slowed reaction time, impaired short-term memory, impaired executive functioning, and confusion.
  • More serious symptoms may include postural/orthostatic hypotension, hypertension, tachycardia, nausea, delirium, agitation, anxiety, panic attacks, myoclonic jerking, sedation, paranoia, and hallucination. Severe effects may include seizures, hyperthermia, rhabdomyolysis, renal failure, angina, and myocardial infarction. Symptoms may present differently in children, and are known in the art. Symptoms of cannabinoid intoxication or overdose may be divided into cardiovascular symptom(s), neuropsychiatric symptom(s), and gastrointestinal symptom(s), with some overlap (e.g., a panic attack has both physical and neuropsychiatric components).
  • the term“in need of treatment” and the term“in need thereof’ when referring to treatment are used interchangeably and refer to a judgment made by a health caregiver (e.g. physician, nurse, nurse practitioner, that a patient will benefit from treatment.
  • the term“subject” is intended to be synonymous with“patient,” and refers to any mammal (preferably human) who is intoxicated or overdosed with a cannabinoid.
  • a parenteral fluid concentrate comprising: an amount of drinabant or a salt or polymorph thereof effective to i) treat, reverse, or reduce acute cannabinoid overdose or one or more symptoms thereof in a subject in need thereof, and/or ii) treat, reverse, or reduce cannabinoid hyperemesis syndrome (CHS) or one or more symptoms thereof in a subject in need thereof; and
  • At least one agent that acts as a non-ionic solubilizer and/or emulsifying agent at least one agent that acts as a non-ionic solubilizer and/or emulsifying agent.
  • the amount of drinabant or a salt or polymorph thereof is effective to reverse acute cannabinoid overdose or one or more symptoms thereof in a subject in need thereof, and/or ii) reverse cannabinoid hyperemesis syndrome (CHS) or one or more symptoms thereof in a subject in need thereof.
  • the amount of drinabant or a salt or polymorph thereof is effective to reverse acute cannabinoid overdose or one or more symptoms thereof in a subject in need thereof.
  • the amount of drinabant or a salt or polymorph thereof is effective to reverse cannabinoid hyperemesis syndrome (CHS) or one or more symptoms thereof in a subject in need thereof.
  • the at least one agent that acts as a non-ionic solubilizer and/or emulsifying agent is chosen from polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polysorbate 80; macrogol 15 hydroxystearate, and polyoxamers.
  • the at least one agent that acts as a non-ionic solubilizer and/or emulsifying agent is chosen from polysorbate 80 and macrogol 15 hydroxystearate.
  • the at least one agent that acts as a non-ionic solubilizer and/or emulsifying agent is macrogol 15 hydroxystearate.
  • the concentrate further comprises at least one hydrophilic solvent.
  • the at least one hydrophilic solvent is chosen from ethanol, PEG 400, and propylene glycol.
  • the concentrate comprises an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject and macrogol 15 hydroxystearate.
  • the concentrate consists essentially of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject; and macrogol 15 hydroxystearate.
  • the concentrate consists of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject; and macrogol 15 hydroxystearate.
  • the concentrate comprises an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, macrogol 15 hydroxystearate, and at least 20% ethanol.
  • the concentrate consists essentially of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, macrogol 15 hydroxystearate, and at least 20% ethanol. In some embodiments, the concentrate consists of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, macrogol 15 hydroxystearate, and at least 20% ethanol.
  • the concentrate comprises an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, and a mixture of 80 macrogol 15 hydroxystearate and 20% ethanol.
  • the concentrate consists essentially of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, and a mixture of 80% macrogol 15 hydroxystearate and 20% ethanol.
  • the concentrate consists of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, and a mixture of 80% macrogol 15 hydroxystearate and 20% ethanol.
  • the concentrate comprises an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, macrogol 15 hydroxystearate, and at least 30% propylene glycol.
  • the concentrate consists essentially of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, macrogol 15 hydroxystearate, and at least 30% propylene glycol.
  • the concentrate consists of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, macrogo! 15 hydroxystearate, and at least 30% propylene glycol.
  • the concentrate comprises an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, and a mixture of 70% macrogol 13 hydroxystearate and 30% propylene glycol.
  • the concentrate consists essentially of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, and a mixture of 70% macrogol 15 hydroxystearate and 30% propylene glycol.
  • the concentrate consists of an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject, and a mixture of 70% macrogol 15 hydroxystearate and 30% propylene glycol.
  • the concentrate comprises between about 2 and about 50 mg/g with drinabant or a salt or polymorph thereof.
  • die concentrate comprises between about 2 and about 40 mg/g with drinabant or a salt or polymorph thereof.
  • the concentrate comprises about 10 mg/g drinabant or a salt or polymorph thereof.
  • the concentrate comprises about 20 mg/g drinabant or a salt or polymorph thereof.
  • the concentrate comprises about 30 mg/g drinabant or a salt or polymorph thereof.
  • the concentrate comprises about 40 mg/g drinabant or a salt or polymorph thereof.
  • the concentrate is stable for one week at room temperature.
  • the concentrate further comprises at least one
  • the at least one phospholipid is chosen from lecithins of natural origin, phospholipids of natural origin, synthetic phospholipids, and a mixture thereof.
  • the concentrate further comprises Miglyol 812 (medium chain triglycerides), a pharmaceutical oil, or a mixture thereof.
  • the pharmaceutical oil is chosen from soybean oil, olive oil, sesame oil, and hydrogenated vegetable oil.
  • the concentrate further comprises at least one antioxidant.
  • the at least one antioxidant is chosen from ascorbic acid,
  • the concentrate further comprises at least one isotonic agent.
  • the at least one isotonic agent is chosen from polyethylene glycol, glycerol, saline, and glucose.
  • parenteral fluid comprising a concentrate described herein diluted with a pharmaceutically acceptable aqueous carrier.
  • the pharmaceutically acceptable aqueous carrier is chosen from sterile water, aqueous dextrose, saline, aqueous saline/dextrose, and aqueous glucose.
  • the pharmaceutically acceptable aqueous carrier is glucose 5% solution.
  • the parenteral fluid comprises about 1 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 1.5 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 2 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 2.5 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 3 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 3.5 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 4 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 4.5 mg/mL drinabant or a salt or polymorph thereof.
  • the parenteral fluid comprises about 5 mg/mL drinabant or a salt or polymorph thereof.
  • the concentrate or parenteral fluid comprises one or more antimicrobials (sometimes referred to as preservatives).
  • the antimicrobial(s) may be present in a bacteriostatic, fungistatic, bacteriocidal, or fungicidal amount, and should avoid toxicity to the subject receiving the formulation.
  • the one or more antimicrobials may be present in a bacteriostatic, fungistatic, bacteriocidal, or fungicidal amount, and should avoid toxicity to the subject receiving the formulation.
  • the one or more antimicrobials may be present in a bacteriostatic, fungistatic, bacteriocidal, or fungicidal amount, and should avoid toxicity to the subject receiving the formulation.
  • the one or more antimicrobials may be present in a bacteriostatic, fungistatic, bacteriocidal, or fungicidal amount, and should avoid toxicity to the subject receiving the formulation.
  • the one or more antimicrobials may be present in a bacteriostatic,
  • preservative(s) is/are chosen from benzyl alcohol, phenol, p-hydroxybenzoic acid (PHBA), o- hydroxybenzoic acid (salicylic acid), one or more parabens or a mixture thereof (e.g., methylparaben, ethylparaben, n-propylparaben, isopropylparaben, butylparaben, and nipastat), a methylphenol ( o -, m-, or -hydroxy toluene) or a derivative thereof, benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylmercuric nitrate, and thimerosal.
  • benzyl alcohol e.g., methylparaben, ethylparaben, n-propylparaben, isopropylparaben, butylparaben, and nipastat
  • the concentrate or parenteral fluid comprises one or more stabilizing agents (sometimes also referred to as preservatives or antioxidants).
  • the one or more stabilizing agent(s) is/are chosen from
  • ethylenediaminetetraacetic acid or a salt thereof (ETDA, disodium EDTA), ascorbic acid, sodium bisulfite, and a sulfurous acid salt.
  • the concentrate or parenteral fluid comprises one or more pH-adjusting agents, e.g. an acid (e.g., a strong such as HC1, or a weak acid such as citric acid) or a base (such as NaOH).
  • an acid e.g., a strong such as HC1, or a weak acid such as citric acid
  • a base such as NaOH
  • Also provided is a method of treating, reversing, or reducing one or more symptoms of acute cannabinoid overdose comprising parenterally administering a parenteral fluid described herein to a subject in need thereof.
  • the symptom(s) of acute cannabinoid overdose is/are chosen from cardiovascular symptom(s), neuropsychiatric symptom(s), and gastrointestinal symptom(s).
  • the cardiovascular symptom(s) is/are chosen from hypertension and tachycardia.
  • the neuropsychiatric symptom(s) is/are chosen from agitation, confusion, drowsiness/lack of alertness, hallucinations, and feeling“high.”
  • the gastrointestinal symptom(s) is/are chosen from nausea and vomiting.
  • the onset of reversal of symptom(s) of acute cannabinoid overdose are apparent within 5-30 minutes following intravenous injection of drinabant, or a salt or polymorph thereof. In some embodiments, the onset of reversal of symptom(s) of acute cannabinoid overdose are apparent within 15-45 min following intramuscular administration of drinabant, or a salt or polymorph thereof.
  • a second dose may be administered. In some embodiments, if no response is observed within 30-45 minutes of a first administration of drinabant, and the presence of cannabinoids is confirmed or strongly suspected, a second dose may be administered.
  • a method of treating, reversing, or reducing cannabinoid hyperemesis syndrome or one or more symptoms thereof comprising parenterally administering a parenteral fluid described herein to a subject in need thereof.
  • the symptom(s) of CHS is/are chosen from nausea, vomiting, and/or abdominal pain.
  • the onset of reversal of symptom(s) of CHS are apparent within 5-30 minutes following intravenous injection of drinabant, or a salt or polymorph thereof. In some embodiments, the onset of reversal of symptom(s) of CHS are apparent within 15-45 min following intramuscular administration of drinabant, or a salt or polymorph thereof.
  • the parenteral route of administration is chosen from among intravenous (IV), intramuscular (IM), and subcutaneous (SC).
  • the parenteral route of administration is IV.
  • the plasma concentrations achieved by parenteral administration of drinabant or salt or polymorph thereof is 200 to about 730 ng/ml.
  • the administration of the drinabant, or a salt or polymorph thereof provides a C max of 500 ng/ml.
  • the amount of drinabant, or a salt or polymorph thereof is between about 1 mg and about 60 mg per intravenous dose. In some embodiments, the amount of drinabant, or a salt or polymorph thereof is between about 30 and about 60 mg per intravenous dose.
  • the IV dose is delivered by IV injection.
  • the IV dose is delivered in a liquid volume of between about 1 and about 20 mL.
  • the IV dose is delivered by IV infusion.
  • the IV infusion is delivered in a liquid volume of between about 125 to about 500 mL.
  • the IV infusion is delivered over a period of about 1 hour to about 2 hours. In some embodiments, the IV infusion is delivered at a rate of about 0.5 mL/min to about 2 mL/min.
  • the parenteral route of administration is IM or SC.
  • the amount of drinabant, or a salt or polymorph thereof is between about 5 and about 60 mg per IM or SC dose. In some embodiments, the amount of drinabant, or a salt or polymorph thereof is between about 5 and about 30 mg per IM or SC dose .
  • the intramuscular dose is delivered in a liquid volume of up to about 2.5 ml. In some embodiments, the intramuscular dose is delivered in a liquid volume of about 1 to about 2.5 ml.
  • the SC dose is delivered in a liquid volume of up to about 1.5 ml. In some embodiments, the SC dose is delivered in a liquid volume of about 1 mL to about 1.5 ml.
  • Plasma concentrations of CB 1 antagonists useful in treating, reversing, or reducing acute cannabinoid overdose or one or more symptoms thereof will vary based on several factors, including the identity of the antagonist. For example, plasma concentrations of drinabant useful in treating, reversing, or reducing acute cannabinoid overdose or one or more symptoms thereof range from about 200 ng/mL to about 730 ng/mL. Additionally, it is understood by those skilled in the art that the because drinabant has been characterized as a competitive CB 1 receptor antagonist, effective (therapeutic) plasma concentrations are dependent upon the dose and type of cannabinoid (a SC, THC, or a combination thereof) responsible for the overdose.
  • a SC cannabinoid
  • Both the onset and degree of symptom relief may vary, and some symptoms (e.g. cardiovascular symptoms such as tachycardia) may be more sensitive to reversal than others (e.g., alertness, as measured by a clinician’s impression and/or assessment through a visual analog scale (VAS)).
  • Onset of symptom relief should be apparent within about 5 min to about 30 min following intravenous administration and about 15 min to about 45 min following intramuscular or subcutaneous administration, respectively.
  • intravenous doses of drinabant of between about 1 mg and about 150 mg, about 1 mg and about 100 mg, or between about 1 mg and about 60 mg, or between about 15 mg and about 60 mg, or between about 30 mg and about 60 mg, or between about 1 mg and about 30 mg, or between about 15 mg and about 30 mg, or between about 50 mg and about 100 mg may be administered.
  • Intravenous doses can be injected in volumes of about 1 to about 20 mL (lower volumes are preferred in certain circumstances).
  • intramuscular or subcutaneous doses of drinabant of between about 1 mg and about 150 mg, about 5 mg and about 100 mg, or between about 5 mg and about 60 mg, or between about 15 mg and about 60 mg, or between about 30 mg and about 60 mg, or between about 15 mg and about 30 mg, or between about 50 mg and about 100 mg, or between about 5 mg and about 50 mg, or between about 5 mg and about 30 mg.
  • Intramuscular or subcutaneous doses can be injected in a volume of up to about 2.5 mL for IM and about 1.5 mL for SC. Intramuscular injections are typically into a deltoid or gluteal muscle.
  • Table 1 below discloses several examples of compositions which can be formulated for parenteral administration (i.e., as liquid preparations) comprising an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject.
  • Table 2 below discloses several examples of compositions which can be formulated for parenteral administration as an IV infusion, comprising an amount of drinabant or a salt or polymorph thereof effective to reverse acute cannabinoid overdose or one or more symptoms thereof or reverse cannabinoid hyperemesis syndrome or one or more symptoms thereof in a subject.
  • the drinabant is delivered, e.g., over the given time interval (period, in minutes) below.
  • venous blood may be collected in, e.g., heparinized polypropylene tubes (lithium heparin) of 4 mL. Blood samples may be taken at baseline and (by way of example only) 2.5, 5, 10, 15, 20, 30, and/or 45 min and 1, 1.5, 2, 3, 4, 5, 6, 12 and 24 h after oral administration of drinabant or matching placebo. After blood collection, the tubes are centrifuged within 30 min for 15 min at 2000 g at 4 °C. Plasma samples may be stored at a temperature of -20 °C.
  • Turbulent Flow Chromatography-Mass Spectrometry/Mass Spectrometry is a validated method to analyze plasma drinabant concentrations. See, e.g., Zuurman, et al., 2010. Validation of this method included evaluation of selectivity for drinabant. In each run, standards (known amount of drinabant) man be included periodically (e.g., after every 10 samples). The limit of quantification has been reported in the art 0.2 ng/mL; the intra-assay coefficient of variation between 1.0 and 5.4%; the inter-assay coefficient of variation between 2.0 and 6.5%. Preferably, all blood samples are handled and analyzed according to GCP/GLP. Drinabant plasma pharmacokinetic parameters (including tmax, Cmax, AUCo-24, AUCinf, t 1 ⁇ 2 ) may be determined using non-compartmental analysis from individual plasma concentration-time profiles.
  • Plasma concentrations of cannabinoids may be assessed by methods known in the art, e.g. as disclosed in Sprensen LK and Hasselstrpm JB, Sensitive Determination of Cannabinoids in Whole Blood by LC-MS-MS After Rapid Removal of Phospholipids by Filtration, J Anal Toxicol 2017 Jun 1;41(5):382-391.
  • Pharmacodynamics Pharmacodynamic endpoints of the efficacy of various formulations and doses of cannabinoid antagonists such as drinabant in treating, reversing, or reducing cannabinoid overdose or one or more symptoms thereof can be measured using a variety of measures, including both objectively observable and subject-reported phenomena.
  • Cannabinoids tend to increase postural instability, and a cannabinoid antagonist such as drinabant would be expected to reverse this effect. Drinabant is expected to reduce postural instability in a subject intoxicated or overdosed with one or more cannabinoids.
  • VASs visual analogue scales
  • Drinabant may be added to a fixed volume of aqueous solution with and without various amounts of water soluble carriers such as Solutol HS 15 in screw capped bottles. Samples are shaken (alternatively, stirred) for a length of time (e.g., 48 hours) at room temperature, pH optionally adjusted, and any suspensions filtered through, e.g., a Whatman filter paper no 1. Filtered solutions are then analyzed for drinabant concentration using an appropriate method such as UV/visible spectrophotometry at an appropriate wavelength (nm) or by HPLC. It is expected that at low concentrations of solubilizing agent (e.g., 1, 5, or 10%), improvement in solubility will increase linearly, but that at higher concentrations this trend may deviate.
  • solubilizing agent e.g., 1, 5, or 10%
  • Solutol HS15 was thus retained for further screening in combination with one or two (co)solvents.
  • the solvent will have a double role: to decrease the Solutol total content in the formulation (issue of toxicity for all the surfactants after iv injection) and to maintain the formulation liquid at Room Temperature, by decreasing the melting point. No contribution of the solvent in the solubilization of drinabant is expected. On the contrary, a reduced solubilization was anticipated for mixtures with PG or Ethanol, since the solubility of drinabant in those solvents was much lower than in Solutol HS15 ( ⁇ 10 mg/g).
  • Adlve 266 Active 2.52 NTU NTU
  • a Solutol-based solution for iv administration has been successfully developed.
  • a Solutol concentrate is diluted in glucose 5% solution before administration and exhibits the following physico-chemical stability depending on drinabant loading:
  • the concentrate was composed of Solutol-Ethanol 80:20 in order to avoid a melting step before dilution in the infusion bag.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des formulations et des méthodes pour traiter, inverser ou réduire le surdosage aigu aux cannabinoïdes, le syndrome d'hyperémèse cannabinoïde, ou un ou plusieurs symptôme de ceux-ci, comprenant l'administration parentérale d'un antagoniste CB1 en quantité suffisante pour inverser le surdosage aigu aux cannabinoïdes, le syndrome d'hyperémèse cannabinoïde ou un ou plusieurs symptômes de ceux-ci.
PCT/US2020/038211 2019-06-18 2020-06-17 Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes Ceased WO2020257333A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP20827604.8A EP3986396A4 (fr) 2019-06-18 2020-06-17 Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes
AU2020295410A AU2020295410A1 (en) 2019-06-18 2020-06-17 Compositions and methods for treating acute cannabinoid overdose with a cannabinoid receptor antagonist
IL289066A IL289066A (en) 2019-06-18 2021-12-16 Preparations and methods for treating acute cannabinoid overdose using a cannabinoid receptor antagonist

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US201962862832P 2019-06-18 2019-06-18
US201962862830P 2019-06-18 2019-06-18
US62/862,830 2019-06-18
US62/862,832 2019-06-18
US16/704,699 US20200179271A1 (en) 2018-12-07 2019-12-05 Compositions and methods for treating acute cannabinoid overdose with a cannabinoid receptor antagonist
US16/704,699 2019-12-05
US202063037351P 2020-06-10 2020-06-10
US63/037,351 2020-06-10

Publications (1)

Publication Number Publication Date
WO2020257333A1 true WO2020257333A1 (fr) 2020-12-24

Family

ID=74040920

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/038211 Ceased WO2020257333A1 (fr) 2019-06-18 2020-06-17 Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes

Country Status (4)

Country Link
EP (1) EP3986396A4 (fr)
AU (1) AU2020295410A1 (fr)
IL (1) IL289066A (fr)
WO (1) WO2020257333A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11471437B2 (en) 2019-06-18 2022-10-18 Opiant Pharmaceuticals, Inc. Compositions and methods for treating cannabinoid hyperemesis syndrome with a cannabinoid receptor antagonist

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010018856A1 (fr) * 2008-08-13 2010-02-18 持田製薬株式会社 Agent prophylactique/d’amélioration ou thérapeutique destiné aux maladies associées au récepteur des cannabinoïdes
WO2013068371A1 (fr) * 2011-11-08 2013-05-16 Intervet International B.V. Compositions à forme posologique douce à mâcher d'antagonistes des récepteurs de cannabinoïdes de type 1 (cb-1)
US20160008364A1 (en) * 2014-07-09 2016-01-14 Eip Pharma, Llc Methods for treating neurologic disorders
WO2018002636A1 (fr) * 2016-07-01 2018-01-04 GW Research Limited Formulations parentérales
US20180311205A1 (en) * 2012-12-18 2018-11-01 Kotzker Consulting Llc Use of cannabinoids and terpenes for treatment of organophosphate and carbamate toxicity
US20200179271A1 (en) * 2018-12-07 2020-06-11 Opiant Pharmaceuticals, Inc. Compositions and methods for treating acute cannabinoid overdose with a cannabinoid receptor antagonist

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010018856A1 (fr) * 2008-08-13 2010-02-18 持田製薬株式会社 Agent prophylactique/d’amélioration ou thérapeutique destiné aux maladies associées au récepteur des cannabinoïdes
WO2013068371A1 (fr) * 2011-11-08 2013-05-16 Intervet International B.V. Compositions à forme posologique douce à mâcher d'antagonistes des récepteurs de cannabinoïdes de type 1 (cb-1)
US20180311205A1 (en) * 2012-12-18 2018-11-01 Kotzker Consulting Llc Use of cannabinoids and terpenes for treatment of organophosphate and carbamate toxicity
US20160008364A1 (en) * 2014-07-09 2016-01-14 Eip Pharma, Llc Methods for treating neurologic disorders
WO2018002636A1 (fr) * 2016-07-01 2018-01-04 GW Research Limited Formulations parentérales
US20200179271A1 (en) * 2018-12-07 2020-06-11 Opiant Pharmaceuticals, Inc. Compositions and methods for treating acute cannabinoid overdose with a cannabinoid receptor antagonist

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
OPIANT: "Development Stage Specialty Pharma Company focused on Addiction and Drug Overdose", OPIANT - COMPANY PRESENTATION, March 2019 (2019-03-01), XP055776366, Retrieved from the Internet <URL:https://ir.opiant.com/static-files/3b108da1-329b-486e-9ed7-e93b4146f8cd> [retrieved on 20200831] *
See also references of EP3986396A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11471437B2 (en) 2019-06-18 2022-10-18 Opiant Pharmaceuticals, Inc. Compositions and methods for treating cannabinoid hyperemesis syndrome with a cannabinoid receptor antagonist

Also Published As

Publication number Publication date
IL289066A (en) 2022-02-01
AU2020295410A1 (en) 2022-01-20
EP3986396A4 (fr) 2023-08-02
EP3986396A1 (fr) 2022-04-27

Similar Documents

Publication Publication Date Title
EP2244783B1 (fr) Compositions d&#39;anesthésique volatil et procédés d&#39;utilisation
BR112018005423B1 (pt) Composição farmacêutica oral compreendendo canabinóide, processo para sua preparação e seu uso
JP7754799B2 (ja) てんかん重積状態の治療に使用するためのガナキソロン
WO2018200024A1 (fr) Formulations de cannabinoïdes stables
KR102550376B1 (ko) 에다라본의 경구 또는 위 투여를 포함하는 치료
US20200397749A1 (en) Compositions and methods for treating acute cannabinoid overdose with a cannabinoid receptor antagonist
AU2023202752A1 (en) Compositions and methods for treating acute cannabinoid overdose with a cannabinoid receptor antagonist
JP5860468B2 (ja) シクロスポリンエマルジョン
TW201521786A (zh) 胺碘酮類似物（ｂｕｄｉｏｄａｒｏｎｅ）調配物
WO2020257333A1 (fr) Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes
Tsagogiorgas et al. Evaluation of pharmacokinetic properties and anaesthetic effects of propofol in a new perfluorohexyloctane (F6H8) emulsion in rats–a comparative study
WO2025054397A1 (fr) Formulations parentérales pour n, n-diméthyltryptamine (dmt) et analogues de dmt, leurs méthodes de fabrication et leurs méthodes d&#39;utilisation
US20230364030A1 (en) Parenteral treatments involving aminoadamantane derivatives
EP4590277A1 (fr) Compositions pharmaceutiques
EP3986856A1 (fr) Compositions et méthodes de traitement du syndrome de l&#39;hyperémésie cannabinoïde avec un antagoniste du récepteur des cannabinoïdes
JP2008508257A (ja) 禁煙のための組成物および方法
US20190117634A1 (en) Treatment of Vulvodynia
WO2025049544A1 (fr) Formulations parentérales d&#39;inhibiteurs de cb1 et procédés d&#39;utilisation
RU2684330C1 (ru) Композиции фулвестранта
TW202440106A (zh) 用於治療勃起障礙之化合物
WO2025229641A1 (fr) Procédés de réduction de la dépendance à la nicotine et à la marijuana par administration de cannabinoïdes
WO2010102991A2 (fr) Émulsions de riluzole liquides
EP2519261A1 (fr) Composition pharmaceutique liquide orale de nifédipine
BR112019011914A2 (pt) formulação líquida parenteral, composição injetável, e, método para preparar uma formulação líquida parenteral.
BR112013007373B1 (pt) Emulsão de ciclosporina, e, uso de uma emulsão de ciclosporina

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20827604

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020295410

Country of ref document: AU

Date of ref document: 20200617

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020827604

Country of ref document: EP

Effective date: 20220118

WWW Wipo information: withdrawn in national office

Ref document number: 289066

Country of ref document: IL