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WO2020167892A1 - Procédés d'administration pulmonaire non irritante de cannabinoïdes à l'aide d'inhalateurs de brume douce - Google Patents

Procédés d'administration pulmonaire non irritante de cannabinoïdes à l'aide d'inhalateurs de brume douce Download PDF

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Publication number
WO2020167892A1
WO2020167892A1 PCT/US2020/017840 US2020017840W WO2020167892A1 WO 2020167892 A1 WO2020167892 A1 WO 2020167892A1 US 2020017840 W US2020017840 W US 2020017840W WO 2020167892 A1 WO2020167892 A1 WO 2020167892A1
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WIPO (PCT)
Prior art keywords
thc
cannabinoid
hydroxy
tetrahydrocannabinol
formulation
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PCT/US2020/017840
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English (en)
Inventor
Nicholas J. BOYLAN
Tuna Yucel
Scott S. FINNANCE
Stephen E. Zale
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Molecular Infusions LLC
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Molecular Infusions LLC
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    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators

Definitions

  • Cannabinoids are a class of active compounds derived from the Cannabis sativa, Cannabis indica, or Cannabis hybrid plant commonly known as marijuana.
  • the most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis.
  • THC phytocannabinoid tetrahydrocannabinol
  • Delta-9-tetrahydrocannabinol (A9-THC) and delta-8- tetrahydrocannabinol (A8-THC) mimic the actions of anandamide and 2- arachidonoylglycerol neurotransmitters produced naturally in the body.
  • These cannabinoids produce the effects associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.
  • Cannabidiol is another major constituent of the cannabis plant.
  • Other cannabinoids include Cannabigerol (CBG), Cannabichromene (CBC), Cannabicyclol (CBL), Cannabivarin (CBV), Tetrahydrocannabivarin (THCV), Cannabidivarin (CBDV),
  • Cannabichromevarin CBCV
  • Cannabigerovarin CBGV
  • Cannabigerol Monomethyl Ether CBGM
  • Tetrahydrocannabinobc acid THCA
  • cannabinol CBN
  • Cannabidiobc Acid CBDA
  • the present invention is directed to the administration of a cannabinoid aerosol formulation using a soft mist inhaler.
  • the aerosol formulation is a solution comprising ethanol and the present invention is based on the discovery that the use of glycerol in the ethanol-based formulation of a cannabinoid reduces coughing and irritation as compared to the formulation in the absence of glycerol.
  • the present invention encompasses a method for pulmonary administration of an aerosol formulation comprising a cannabinoid, the method comprising administering the aerosol formulation to a subject by oral inhalation using a soft mist inhaler,
  • aerosol formulation comprises the cannabinoid in a solution comprising ethanol, and wherein the formulation further comprises glycerol,
  • the administration of the aerosol formulation induces less coughing, less throat irritation, and/or less respiratory tract irritation than the administration of an identical formulation in the absence of the glycerol.
  • the present invention also relates to a method of reducing irritation (e.g., throat and respiratory tract irritation) and/or cough caused by cannabinoid administration (e.g., cannabinoid-related irritation) comprising adding an irritation reducing amount of glycerol to an aerosol formulation comprising ethanol and cannabinoid and loading or filling a soft mist inhaler with the aerosol formulation.
  • irritation e.g., throat and respiratory tract irritation
  • cannabinoid administration e.g., cannabinoid-related irritation
  • the present invention also includes an aerosol formulation for pulmonary
  • a cannabinoid by oral inhalation using a soft mist inhaler, wherein the aerosol formulation comprises the cannabinoid in a solution comprising ethanol, and wherein the formulation further comprises glycerol, and wherein the administration of the aerosol formulation comprising the cannabinoid induces less coughing, less throat irritation, and/or less respiratory tract irritation than the administration of an identical formulation in the absence of the glycerol.
  • the soft mist inhaler is the RESPIMAT® Soft Mist
  • the fine particle fraction (FPF) of the total emitted dose is at least about 70%, at least about 75%, or at least about 80%.
  • the amount of glycerol is about 10% w/w or less.
  • FIG. 1 is a plot of viscosity (cP) as a function of the percentage (%) w/w of A9-THC distillate, or CBD isolate in 200 proof ethanol.
  • FIG. 2A and 2B are plots of percent dose of A9-THC in the fine particle fraction (FPF) as a function of viscosity (cP) (FIG. 2A) and emitted dose (mg) (FIG. 2B).
  • FIG. 3 is a plot of the percentage of emitted dose that is the FPF as a function of the amount of glycerol (% w/w) in a 3.5% A9-THC distillate solution in ethanol.
  • the words“a” and“an” are meant to include one or more unless otherwise specified.
  • the term“a cannabinoid” encompasses both a single cannabinoid and a combination of two or more cannabinoids.
  • lower respiratory tract refers to the trachea, main bronchi, lobar bronchi, segmental bronchi, subsegmental bronchi, conducting bronchioles, terminal bronchioles, and lungs, which include the, respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli.
  • treatment means to alleviate, reduce or abrogate one or more symptoms or characteristics of a disease, disorder or event, cause a desired biological effect, and/or may be curative, palliative, prophylactic or slow the progression of the disease or disorder.
  • treatment can include reducing or eliminating irritation in the throat or respiratory tract of an individual and/or reducing, avoiding or eliminating cough. Additionally, treatment can include achieving a psychoactive effect in an individual.
  • the term“effective amount” means an amount of active ingredient(s) that will result in a desired effect or result.
  • the term“therapeutically effective amount” means an amount of active ingredient(s) that will elicit a desired biological or pharmacological response, e.g., effective to prevent, alleviate, or ameliorate symptoms (e.g., reducing or eliminating irritation and/or coughing and/or respiratory tract irritation), treat a disease or disorder (e.g., nausea); or cause a psychoactive effect in the individual.
  • the term“patient” or“subject” means an animal, including mammals, non-human animals, and especially humans.
  • the patient or subject is a human.
  • the patient or subject is a human male.
  • the patient or subject is a human female.
  • the patient can be a healthy individual or an individual in need of medical treatment.
  • the term“patient” is intended to include individuals that can medically benefit from the administration of a cannabinoid as well as individuals who can benefit recreationally.
  • surfactant refers to synthetic and naturally occurring amphiphilic molecules that have hydrophobic portion(s) and hydrophilic portion(s). Due to their amphiphilic (amphipathic) nature, surfactants typically can reduce the surface tension between two immiscible liquids, for example, the oil and water phases in an emulsion, stabilizing the emulsion. Surfactants can be characterized based on their relative hydrophobicity and/or hydrophilicity. For example, relatively lipophilic surfactants are more soluble in fats, oils and waxes, and typically have HLB values less than or about 10, while relatively hydrophilic surfactants are more soluble in aqueous compositions, for example, water, and typically have HLB values greater than or about 10. Relatively amphiphilic surfactants are soluble in oil- and water-based liquids and typically have HLB values close to 10 or about 10.
  • Total emitted dose or delivered dose is the mass of drug emitted per actuation that is available for inhalation at the mouth.
  • the total emitted dose can be measured using a dose uniformity sampling apparatus.
  • Fine particle dose is the mass of particles less than 5 microns in size within the total emitted dose.
  • Fine particle fraction is the fine particle dose divided by the total emitted dose.
  • Coarse particle fraction is the proportion of particles in the total emitted dose that are greater than 5 microns in size.
  • “Pharmaceutically acceptable salts,” or“salts,” include the salt of a cannabinoid (including, for example, a cannabinoid prodrug or a cannabinoid synthetic analog that includes a basic group) suitable for administration to a mammal, including those prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic,
  • a cannabinoid including, for example, a cannabinoid prodrug or a cannabinoid synthetic analog that includes a basic group
  • suitable for administration to a mammal including those prepared from formic, acetic, propionic, succinic,
  • the present invention is directed to the improved administration of a cannabinoid to a subject using a soft mist inhaler (SMI), such as SMIs comprising micron-sized nozzles and/or that generate an aerosol (or monodisperse droplets) by Rayleigh break up, as well as methods of reducing cough and/or respiratory tract irritation induced by pulmonary administration of a cannabinoid.
  • SMI soft mist inhaler
  • Soft mist inhalers generate a‘soft mist’ or liquid aerosol by mechanical, thermo-mechanical or electrochemical means and enable the use of propellant-free drug solutions.
  • the soft mist inhaler generates a soft mist or liquid aerosol by mechanical means.
  • soft mist describes both the mechanism of aerosol generation and the characteristics of the aerosol formed (Anderson, 2006. International Journal of COPD 1(3): 251-259).
  • pMDI pressurized meter dose inhaler
  • dry powder inhalers the emitted aerosol of a soft mist inhaler is lower velocity and has a longer spray duration which results in higher percentage of emitted dose being deposited in the lungs.
  • a non-limiting example of a soft mist inhaler is the
  • MEDSPRAY® Inhaler device which consists of an outer housing, reservoir/cannister, internal pump and spray nozzle chip that contains approximately 100 micron-size nozzles.
  • the liquid aerosol formulation is dispersed into droplets by forcing the drug solution through an array of nozzles with mechanical means which results in generation of Rayleigh jets that break-up into micron size particles (jet break up due to capillary instability).
  • Incorporation of an air-mixing chamber allows the micron size particles to mix with the air stream during the patient’s inhalation maneuver.
  • Such devices are described, for example, in de Boer et al. (2008), Pharmaceutical Research 25(5): 1186-1192; Wissink et al. (2002), Respiratory Drug Delivery available at
  • the soft mist inhaler is a soft mist inhaler comprising micron-sized nozzles and/or that generate aerosol (or monodisperse droplets) by Rayleigh break up.
  • the AERxTM aerosol delivery system is also an example of a soft mist inhaler.
  • This device utilizes a blister package containing a single unit dose reservoir and an array of 2.5 micron size nozzles. During actuation, the reservoir is pressurized and a seal is ruptured allowing formulation to flow to the nozzles. As the drug formulation exits the nozzles, a liquid jet is formed which spontaneously breaks up into liquid droplets which exit the devices in the form of an aerosol. See e.g., U.S. Pat. No. 5,622,162A and U.S. Pat. No. 5,522,385, incorporated by reference in their entireties.
  • the inhaler is a soft mist inhaler comprising micron-sized nozzles and/or that generate an aerosol (or monodisperse droplets) by Rayleigh break up.
  • specific examples of such inhalers that comprise micron-sized nozzles are the
  • MEDSPRAY® Inhaler device and the AERxTM aerosol delivery system described above.
  • An example of a device that comprises micron-sized nozzles and generates an aerosol by Rayleigh break up is the MEDSPRAY® Inhaler device.
  • the MEDSPRAY (MIST Beta) inhaler device was designed to provide an airflow resistance of -2 kPa at a flow rate of 15 L/min. Utilizing inhaler devices with decreased airflow resistance (at a fixed inhalation flow rate) can under certain circumstances enable users to inhale at higher inspiratory flow rates with less overall effort and result in improved user experience.
  • the inhaler device used according to the methods described herein has an Airflow Resistance at a flow rate of 15 L/min of about -2 kPa or less, about -1.5 kPa or less, about -1 kPa or less, or about -0.5 kPa or less.
  • the inhaler device used according to the methods described herein has an Airflow Resistance less than about -2 kPa at a flow rate of 15 L/min. Airflow Resistance value is useful for assessing the inspiratory effort required by users to achieve a desired inhalation flow rate through a medical inhaler. Airflow Resistance measurements can be performed using a custom experimental set-up consisting of a Copley Scientific’s Dry Powder Inhaler dose uniformity sampling apparatus (DUS A) connected to a TPK 2000 critical flow control and in-line DFM 2000 flow meter followed by LCP5 Diaphragm vacuum pump. Devices can be attached to the DUSA inlet via silicone mouthpiece adapter and airflow can be initiated by turning on LCP5 pump.
  • DUS A Dry Powder Inhaler dose uniformity sampling apparatus
  • the flow rates achieved by human users can be measured by attaching a flow meter to mouthpiece body via rubber stopper adapter. Users inhale through the device with minimal, moderate, and high effort and the peak inspiratory flow rates achieved for the inhaler device can be recorded.
  • the MEDSPRAY (MIST Beta) inhaler device was designed to provide a flow rate of about 15 L/min with moderate effort.
  • an inhaler device used in the methods described herein achieve a peak inhalation flow rate under moderate effort of at least about 15 L/min.
  • the inhaler device used in the methods described herein achieve a peak inhalation flow rate under moderate effort of greater than about 15 L/min. In yet additional aspects, the inhaler device used in the methods described herein achieve a peak inhalation flow rate under moderate effort of at least about 20 L/min, at least about 25 L/min, at least about 30 L/min, at least about 35 L/min, or at least about 40 L per min. In yet further aspects, the inhaler device used in the methods described herein achieve a peak inhalation flow rate under moderate effort of between about 15 and about 40 L/min, between about 20 and about 40 L/min, or between about 30 and 40 L/min.
  • the inclusion of a propellant in the formulation can, under certain circumstances, be advantageous.
  • the inclusion of a propellant may result in reduced aerosol droplet size due to evaporation of the propellant. Therefore, in some embodiments, the formulation can include a propellant.
  • the formulation described herein is propellant-free.
  • the aim of pulmonary administration is to deliver aerosol particles comprising the active ingredient to the lungs.
  • Higher lung deposition translates to higher systemic absorption.
  • aerosols with high lung deposition exhibit less deposition in the throat and/or upper airways, this results in less coughing and irritation.
  • Particles that are 5 microns or smaller are most likely to deposited in the lungs.
  • the proportion of particles in an aerosol that are less than 5 microns in size is referred to as the fine particle fraction (FPF) whereas the term fine particle dose (FPD) is the absolute mass of drug particles that are less than 5 microns. Aerosols with higher FPFs have higher likelihood of depositing in the lungs and are associated with reduced irritation of the respiratory tract as opposed to the upper airway.
  • the FPF of the aerosol produced by the RESPIMAT inhaler can be at least twice that of most pMDIs and DPIs.
  • the FPF is higher for ethanol-based formulations as compared to aqueous formulations (Anderson 2006).
  • the higher FPF of an SMI aerosol translates in a higher proportion of the emitted dose delivered to the lungs as opposed to the oropharynx (Anderson 2006).
  • the present invention is directed to improved methods and compositions for pulmonary administration of cannabinoids.
  • pulmonary administration has a further advantage of avoiding hepatic first-pass metabolism.
  • Advantages of the pulmonary administration also include a faster onset of action (the time it takes an active ingredient to reach a minimum effective concentration after the active ingredient is administered), greater stability, greater bioavailability, and/or or reduced individual variability of bioavailabibty, or, in the case of THC, a more intense psychotropic effect as compared to oral formulations such as MARINOL® and may be formulated for immediate release.
  • cannabinoids such as A9-THC, A8-THC, and CBD
  • the aerosol formulation described herein is delivered using a soft mist inhaler.
  • Cannabinoids as well as terpenes have good solubility in ethanol and thus a formulation for the soft mist inhaler can comprise a cannabinoid in a solution comprising ethanol.
  • ethanol itself can irritate the mucosal membranes of the respiratory tract in a concentration and dose-dependent manner.
  • evaporation of ethanol may result in aerosol particle size reduction and concentration of the cannabinoid in the droplet which may further exacerbate the throat and respiratory tract irritation experienced by the user.
  • the present invention is based on the discovery that glycerol can be added to a formulation comprising a cannabinoid in an ethanol solution and that the inclusion of glycerol results in less cough and respiratory tract irritation than that observed using the ethanol solution in the absence of glycerol.
  • the invention encompasses a method for pulmonary administration of an aerosol formulation comprising a cannabinoid, wherein the method comprises administering the formulation to a subject in an aerosol formulation by oral inhalation, wherein the aerosol formulation comprises the cannabinoid in a solution comprising ethanol, wherein the formulation further comprises glycerol; and wherein the administration of the aerosol formulation induces less coughing, less throat irritation, and/or less respiratory tract irritation than the administration of an identical formulation in the absence of the glycerol.
  • the invention also includes method of reducing cough and/or throat and/or respiratory tract irritation) caused by pulmonary administration of a cannabinoid administration (e.g., cannabinoid-related irritation) comprising adding an irritation reducing amount of glycerol to an aerosol formulation comprising ethanol and cannabinoid and loading or filling a soft mist inhaler with the aerosol formulation.
  • a cannabinoid administration e.g., cannabinoid-related irritation
  • Irritation of airways and coughing can, for example, be measured by visual analog scales (VAS) with 0 cm (0%) on the 10-cm VAS scale standing for“not at all” and 10 cm (100%) for“very strong” as described in Meyer et al. (2016), Human Pharmacokinetics and Adverse Effects of Pulmonary and Intravenous THC-CBD Formulations.
  • VAS visual analog scales
  • Med Cannabis Cannabinoids 1 36-43, the contents of which are expressly incorporated by reference herein.
  • the glycerol can be included in the formulation in an amount effective to reduce cough and/or irritation (or an irritation reducing amount) as compared to the identical formulation in the absence of glycerol.
  • the amount of glycerol is about 10% (w/w) or less, about 9% (w/w) or less, about 8.5% (w/w) or less, or about 8% (w/w) or less.
  • the amount of glycerol is between about 8 and about 10% w/w.
  • the amount of glycerol can be between about 0.1 and about 10% (w/w), between about 0.1 and 9% (w/w), between about 1 and about 10% (w/w), between about 1 and about 9% (w/w), between about 5% and about 10% (w/w), and between about 5% and 9% (w/w).
  • the FPF of the emitted dose of the formulation (comprising a cannabinoid in an ethanol solution comprising ethanol, and further comprising glycerol) is at least about 70%, or at least about 80%.
  • the particles in the fine particle fraction have an aerodynamic diameter between 1 and 5 microns.
  • Aerodynamic diameter can be determined by impactor studies such as those using multi-stage impactors and fast screening impactors. Using multi-stage cascade impactors, such as the Anderson cascade impactor and next generation impactor, the diameter is commonly reported as the mass median aerodynamic diameter (MMAD) and geometric Standard Deviation (GSD) which describe the particle size and size distribution, respectively. Multi-stage impactors commonly have 8 stages which allow fractionation of the aerosol based on particle size and subsequent determination of MMAD.
  • MMAD mass median aerodynamic diameter
  • GSD geometric Standard Deviation
  • Multi-stage impactors commonly have 8 stages which allow fractionation of the aerosol based on particle size and subsequent determination of MMAD.
  • an abbreviated impactor set-up, Copley Scientific’s‘Fast Screening Impactor’ (FSI) can be used to determine the FPF within liquid aerosols (Mitchell et al. AAPS PharmSciTech.
  • the FSI consists of the universal induction port (UIP), course fraction collector (pre-separator and insert with a 5 pm diameter cut-off at a specified flow rate, e.g. 28.3 L/min), and fine particle fraction collector consisting of a holder and glass fiber filter.
  • UIP universal induction port
  • course fraction collector pre-separator and insert with a 5 pm diameter cut-off at a specified flow rate, e.g. 28.3 L/min
  • fine particle fraction collector consisting of a holder and glass fiber filter.
  • the system can be assembled along with a Copley LC5 pump.
  • the flow rate is set by attaching a flow meter to the inlet of the induction port and adjusting the flow control valve on the LC5 vacuum pump until the desired flow rate is achieved (e.g., 28.3 L/min +/- 5%). Measurements are performed under ambient laboratory conditions (-60% RH, 72°F).
  • the SMI or Respimat device is primed and attached to the UIP using a mouthpiece adapter. With the vacuum pump running, the device is actuated followed by a 30 second hold before turning off the vacuum pump. The SMI or Respimat device is re-primed and another dose was collected in the FSI. To determine the amount of cannabinoids deposited in each stage, the FSI is dismantled and each stage is extracted with 10 ml of methanol. Samples are diluted and HPLC performed to quantify the mass of cannabinoids deposited in the USP throat, coarse fraction collector, and fine particle fraction collector.
  • the ethanol concentration in the formulation or the solution comprising ethanol is at least an amount that is sufficient to solubilize the cannabinoid in the formulation.
  • the ethanol in the formulation is at least 140 proof, or at least 180 proof.
  • the ethanol is 200 proof.
  • the ethanol solution comprises water in an amount of 40% (w/w), or 30% (w/w), or less.
  • the formulation comprises A9-THC and the solution comprises 30% w/w or less water.
  • the formulation comprises CBD and the solution comprises water in an amount of 40% w/w or less.
  • the formulation comprises A9-THC and CBD and the ethanol solution comprises water in an amount of 30% w/w or less.
  • the aerosol particle size is related to the viscosity of the solution, the surface tension of the solution, and the volatility of the solvent (for example, the volatility of ethanol).
  • the viscosity of the formulation described herein is 2 cP or less.
  • the formulation of the present invention has a Tmax that is about 3 to about 15 minutes. In some embodiments, the composition of the present invention has a Tmax that is about 1 to about 10 minutes. In a further embodiment, the Tmax is about 10 to about 60 minutes. In a further embodiment, the Tmax is about 1 to about 2 hours.
  • the maximum amount of the cannabinoid in the formulation that can be administered without inducing moderate or severe coughing and/or throat and/or respiratory tract irritation is at least about 1.2, about 1.5 times, or 2.0 times more than the maximum amount of the cannabinoid that can be dosed in the formulation without glycerol without causing moderate or severe coughing and/or throat and/or respiratory tract irritation.
  • A9-THC cannabidiol
  • CBD cannabinol
  • CBDV cannabidivarin
  • CBDV cannabigerol
  • THCV tetrahydrocannabivarin
  • CBL cannabicyclol
  • CBC cannabichromene
  • CBV cannabivarin
  • CBDV cannabigerovarin
  • CBCV cannabichromevarin
  • CBDV cannabigerol monomethyl ether
  • Certain cannabinoids like A9-THC. can have three fused rings and these rings are referred to in the literature as the A-ring, B-ring and C-ring.
  • Formula (a) below shows the structure of THC, where the dashed line represents either a double bound between 8-9 (A8-THC) or between 9-10 (A9-THC).
  • certain cannabinoids lack one or two of rings A, B, or C, e.g., CBC (Formula (b)), CBL (Formula (c)) or CBD
  • Cannabinoids that can be used in the methods and formulations of the present invention include, but are not limited, to: tetrahydrocannabinol (THC), D9- tetrahydrocannabinol (A9-THC), A8-tetrahydrocannabinol (A8-THC), tetrahydrocannabinolic acid (THCA), cannabinolic acid (CBNA), A8-tetrahydrocannabinol-dimethylheptyl, D9- tetrahydrocannabinol-dimethylheptyl, A9-tetrahydrocannabinol propyl analogue (THCV), 11- nor-9-carboxy -tetrahydrocannabinol, 5'-azido-A8-tetrahydrocannabinol, AMG-1, AMG-3, AM411, AM855, nabilone, HU-210, dexanabinol
  • CBCV cannabigerol monomethyl ether
  • CBD cannabinol
  • CBC cannabichromene
  • CBCA cannabichromene acid
  • CBL cannabicyclol
  • CT-3 levonantradol
  • CP 50556-1 19,19-Dimethylheptyl-D-8-tetrahydrocannabinol-l l-oic acid
  • CT-3 levonantradol
  • 9-carboxy-l l-norcannabinol l'-oxocannabinol
  • l l-nor-A8-THC-9-carboxylic acid 2'-carboxy-3',4',5'-trinor-A9-THC, 5'-carboxy-A9-THC
  • 9-carboxy-l l-nor-A9-THC 9- carboxy-1 l-nor-A8-THC
  • the cannabinoid is selected from the group consisting of THC, THCA, THCV, CBD, CBDA, CBDV, CBDL, CBC, CBCA, CBCV, CBCN, CBV, CBG, CBGA, CBGV, CBN, CBL, and CBE, or a combination of any of thereof.
  • the cannabinoid is selected from the group consisting of CBG, THCV, CBN, THC, CBC, CBD, and CBDV.
  • the cannabinoid is selected from the group consisting of THC, CBD, THCA, and CBDA, or a combination of any of thereof.
  • the cannabinoid is THC or CBD, or a combination thereof.
  • the THC is A9-THC or A8-THC, or a combination thereof.
  • the THC is A9-THC.
  • the cannabinoid is CBD.
  • the formulation comprises a combination of A9-THC and CBD.
  • the cannabinoid is a naturally occurring cannabinoid.
  • Naturally occurring cannabinoids include cannabinoids that can be extracted from or isolated from the Cannabis sativa, Cannabis indica, or cannabis hybrid plants.
  • Cannabinoids and terpenes can be purchased, or synthesized using well-known techniques. Cannabinoids can be extracted from a plant using well-known methods.
  • cannabinoids and terpenes can be extracted from a plant of the Cannabis genus, e.g., Cannabis sativa, Cannabis indica, or Cannabis hybrid. Terpenes can also be extracted from a plant that is not a member of the Cannabis genus. Phytocannabinoids and terpenes may be extracted as terpene blends or, in the case of a Cannabis species, as a cannabinoid or cannabinoid/terpene blend. The blends may be used directly or can be separated into individual or fewer components using distillation (e.g., short-path rotary distillation) or other techniques.
  • distillation e.g., short-path rotary distillation
  • each principal phytocannabinoid and/or terpene in the plant extract e.g., cannabis extract
  • extracts comprising terpenes e.g., extracts essentially free of cannabinoids, extracts that contain cannabinoids as a minor constituent, or extracts from a plant that is not a species of Cannabis (e.g., Cannabis sativa, Cannabis indica, Cannabis hybrid, or other), i.e., a non -Cannabis species, may be used individually or combined with one or more other active ingredients, e.g., cannabinoids or cannabinoid extracts.
  • Cannabinoids and/or terpenes can be obtained by separating resins from leaves or leaves and flowers of cannabis plants by solvent extraction. Extracts derived from cannabis plants include primary extracts prepared by such processes as, for example, maceration, percolation, and solvent extraction. Solvent extraction can be carried out using a solvent that dissolves cannabinoids/cannabinoid acids, such as for example Cl to C5 alcohols (e.g.
  • cannabinoid/terpenes from the plant matter resulting in a transparent, amber oil.
  • Primary extracts obtained by supercritical fluid extraction (SFE) may undergo an ethanolic precipitation step in order to remove less polar, plant derived impurities (e.g., lipids).
  • the extracts obtained by supercritical fluid extraction (SFE) may undergo a secondary extraction, e.g. an ethanolic precipitation, to remove non-cannabinoid/terpene materials.
  • light petroleum gas extraction using a LHBES (light hydrocarbon butane extraction system) 1300/C from ExtractionTek Solutions is used to extract cannabinoids from cannabis plant material.
  • LHBES light hydrocarbon butane extraction system
  • a modified extraction process consists of decarboxylating the starting concentrate at 300° F until fully converted and the bubbling stops. Once the oil is decarboxylated, it is run through the VTA-VKL 70-5 short path rotary distillation plant twice. The first run separates the heavy terpenes and lighter terpenes from the cannabinoids and waste material. The cannabinoids and waste are run through again with a higher vacuum and higher temperature to separate the cannabinoids from the remaining waste. The waste is collected and run again in a larger batch to extract all cannabinoids and terpenes.
  • the VTA-VKL 70-5 short path rotary distillation plant uses a top stirring rotary column to wipe incoming product into a thin film for better heat distribution and evaporation.
  • the inner condensing column is set to condense the cannabinoids into liquids.
  • the waste and cannabinoids are diverted into the two dispensing arms for collection into receiving vessels.
  • the light terpenes are collected in a receiving flask attached to the inline chiller on the plant.
  • the system (except for feed vessel) are under vacuum during the operation.
  • the vacuum for the first run should be between 0.5 - 0.7 mbar.
  • pressure should be between 0.5 - 0.07 mbar.
  • the cannabinoid is in the form of an extract from a cannabis plant comprising a cannabinoid, i.e., a“cannabinoid extract”.
  • the formulation can further comprise a terpene.
  • the terpene is in the form of an extract from cannabis or other plant comprising a terpene, i.e., a“terpene extract”.
  • the cannabinoid or terpene extract is from a cannabis plant selected from Cannabis sativa, Cannabis indica, or Cannabis hybrid.
  • the cannabinoid or terpene extract is an extract of Cannabis sativa.
  • the cannabinoid or terpene extract is an extract of Cannabis indica. In another embodiment, the cannabinoid or terpene extract is an extract of Cannabis hybrid. In another embodiment, the cannabinoid or terpene extract is a distillate. In a further embodiment, the cannabinoid distillate is the product of short path distillation of a cannabinoid extract. In a further embodiment, the cannabinoid or terpene is synthetic.
  • the cannabinoid extract comprises total cannabinoid(s) in an amount selected from: 50-75 wt%, 50-99 wt%, 75-99 wt%, 75-95 wt%, 80-99 wt%, 85-99 wt%, 90-99 wt%, 85-95 wt%, 90-95 wt%, or >99 wt% total cannabinoid(s).
  • the total concentration of cannabinoid(s) in a composition of the present invention is 1-200 mg/mL.
  • the total concentration of cannabinoid(s) in a composition of the present invention is selected from: 1-5 mg/mL, 1-10 mg/mL, 1-50 mg/mL, 1-100 mg/mL, 5-50 mg/mL, 10-50 mg/mL, 10-100 mg/mL, 5-10 mg/mL, 10-15 mg/mL, 15-20 mg/mL, 20-30 mg/mL, 30-40 mg/mL, 40-50 mg/mL, 50-75 mg/mL, 75-100 mg/mL, 100-150 mg/mL, or 150-200 mg/mL.
  • the total concentration of cannabinoid(s) in a composition of the present invention is ⁇ 0.001 mg/mL, 0.001-0.01 mg/mL, or 0.01-lmg/mL.
  • the composition comprises at least one terpene.
  • the terpene is found in Cannabis sativa, Cannabis indica, or Cannabis hybrid.
  • the terpene is extracted from a plant species, preferably a species of Cannabis (e.g., Cannabis sativa, Cannabis indica, Cannabis hybrid or other).
  • the terpene is synthetic.
  • the terpene is selected from any, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more of the group consisting of: alpha-bisabolol, alpha-phellandrene, alpha-pinene, alpha-terpinene, alpha-terpineol, beta- caryophyllene, beta-pinene, bomeol, cadinene, camphene, camphor, carvacrol, caryophyllene acetate, caryophyllene oxide, cedrane, citral, citronellol, dextro carvone, dextro fenchone, eucalyptol (1,8-cineole), eugenol, famesene, gama-3-carene, gamma-terpinene, geraniol, geranyl
  • the composition further comprises at least one terpene.
  • the at least one terpene is any one, two, three, four, five, six, or all six terpenes selected from the group consisting of beta-caryophyllene, linalool, limonene, alpha- pinene, eucalyptol, and myrcene.
  • the at least one terpene is any one, two, three, four, or all five selected from beta-caryophyllene, linalool, limonene, alpha- pinene, or eucalyptol.
  • the cannabinoid is A9-THC and the dose of the A9-THC administered to the subject is effective to induce a psychoactive effect.
  • the cannabinoid is A9-THC. and the amount of the cannabinoid is a therapeutically effective amount.
  • the cannabinoid is CBD and the amount of the CBD is a therapeutically effective amount.
  • the formulation comprises a D9- THC and CBD, wherein the A9-THC and CBD are each present in an effective amount or a therapeutically effective amount.
  • the dose of cannabinoid emitted by the device is related to the concentration of the cannabinoid in the formulation (for example, % w/w) and the density of the solution.
  • the dose of the cannabinoid administered is greater than about 0.2 mg, greater than about 0.35 mg, greater than about 0.5 mg.
  • the dose of cannabinoid can be administered by one puff or actuation of the device, or more than one puff or actuation.
  • the desired dose can be administered with a single actuation or a plurality of actuations.
  • the composition, e.g., cannabinoid composition, of the present invention has an onset of action within 15 minutes, 15-20 minutes, 20 minutes, 25 minutes, 30 minutes, or within 45 minutes post administration.
  • the composition e.g., cannabinoid composition
  • the composition has a peak time within 90 minutes, within 80 minutes, within 70 minutes, within 60-70 minutes, within 60 minutes, within 50 minutes, within 45-60 minutes, within 45 minutes, within 40 minutes, or within 30 minutes post administration.
  • an SMI formulation comprising a cannabinoid in an ethanol solution that further comprises glycerol is compared to an identical formulation in the absence of glycerol, it is to be understood that all other conditions of the administration are identical (including, for example, the dose of the cannabinoid, the device, the inhalation technique, etc.).
  • the formulation or composition does not include any additional ingredients that would decrease coughing and/or irritation. In other aspects, the formulation or composition does not include any additional ingredients that would decrease the coughing and/or irritation in an amount sufficient to reduce said coughing and/or irritation. In certain aspects, the formulation or composition is free of a medium chain triglyceride, a propylene glycol diester, a human TAS2R bitter taste receptor agonist(s), a local anesthetic(s), and/or a cough suppressant.
  • the formulation or composition does not include medium chain triglyceride, a propylene glycol diester, a human TAS2R bitter taste receptor agonist(s), a local anesthetic(s), and/or a cough suppressant in an amount sufficient to reduce said coughing and/or irritation.
  • the formulation or composition includes a medium chain triglyceride, a propylene glycol diester, a human TAS2R bitter taste receptor agonist(s), a local anesthetic(s), and/or a cough suppressant but the formulation comprising glycerol induces less coughing and/or less throat irritation and/or less upper or lower respiratory irritation than an identical composition in the absence of glycerol.
  • the formulation does not include a local anesthetic.
  • the formulation does not comprise a local anesthetic in an amount effective to decrease the coughing and/or irritation in an amount sufficient to reduce said coughing and/or irritation.
  • the formulation does not include a local anesthetic that is an aminoamide or an aminoester, for example, anesthetic selected from the group consisting of lidocaine, articaine, mepivicaine, etidocaine, prilocaine, bupivacaine, procaine, tetracaine, benzocaine and chloroprocaine (includes the free base of the local anaesthetic and pharmaceutical acceptable salts thereof).
  • the invention also includes a soft mist inhaler device comprising a reservoir or cannister or inhaler body for storing the cannabinoid formulation, and wherein said reservoir or cannister is at least partially filled with the cannabinoid formulation.
  • the inhaler is a portable soft mist inhaler for propellant-free metered nebulization of a cannabinoid formulation, comprising:
  • a mechanical pressure generator for pressurizing a supply of the cannabinoid formulation located in the inhaler body
  • an expulsion nozzle for receiving the formulation and for delivering the received dose of the nebulized medicament preparation as an aerosol
  • the cannabinoid formulation comprises a cannabinoid in a solution comprising ethanol, and wherein the formulation further comprises glycerol,
  • administration of the aerosol formulation induces less coughing, less throat irritation, and/or less respiratory tract irritation than the administration of an identical formulation in the absence of the glycerol.
  • the cannabinoid formulation is stored as a solution in the drug cartridge or inhaler body which can, for example, be an aluminum cylinder containing a double-walled, plastic, collapsible bag that contracts as the solution is used.
  • the number of actuations per device can be, for example, about 50, about 60 about 100, about 120, or more than about 100.
  • the formulation described herein comprises at least two active ingredients, wherein at least one of the active ingredients is the cannabinoid.
  • the composition may contain, e.g., one or more additional cannabinoids, terpenes, or other additional non-cannabinoid active ingredient(s).
  • At least one of the other additional active ingredients is selected from one or more cannabinoid, cannabinoid extract, terpene, terpene extract, anti insomnia, anti-tussive, opioid analgesic, decongestant, non-opioid analgesic/ anti - inflammatory drug, anti-migraine drug, anti-emetic, anti-histamine, proton pump inhibitor, Th antagonist/Th blocker, tranquilizer, anticonvulsant, hypnotic, muscle relaxant, anti-psychotic, anti-diarrheal, Attention Deficit and Hyperactivity Disorder (ADHD) drug, anti-Parkinson disease drug, benzodiazepine, benzodiazepine antagonist, barbiturate, barbiturate antagonist, stimulant, stimulant antagonist, antidepressant, nutraceutical, nicotine, BCS Class II active ingredient, BCS Class IV active ingredient, or a combination thereof.
  • cannabinoid cannabinoid extract, terpene, terpene extract, anti insomnia
  • the additional active ingredient(s) comprises an anti-insomnia drug.
  • the anti-insomnia drug is selected from any one or more of: melatonin, trazodone, zolpidem, temazepam, elprazolam, amitriptyline, halcion, lorazepam, clonazepam, Intermezzo, eszopiclone, diphenhydramine, doxepin, mirtazapine, gabapentin, doxylamine, quetiapine, flurazepam, estazolam, olanzapine, Seconal, triazolam, zaleplon, secobarbital, chloral hydrate, oxazepam, quazepam, ramelteon, suvorexant, butabarbital, pentobarbital, phenobarbital, phenyltoloxamine, amobarbital, diphenhydramine,
  • dimenhydrinate diphenhydramine / magnesium salicylate, diphenhydramine / naproxen, diphenhydramine / aspirin, diphenhydramine / paracetamol, diphenhydramine / ibuprofen, or tasimelteon.
  • the additional active ingredient(s) comprise an anti-tussive.
  • the anti-tussive is selected from any one or more of: benzonatate, caramiphen edisylate, chlophedianol, codeine, dextromethorphan hydrobromide,
  • hydrocodone levopropoxyphene, morphine, codeine, ethylmorphine, dihydrocodeine, benzylmorphine, laudanum, dihydroisocodeine, nicocodeine, nicodicodeine, hydrocodone, hydromorphone, acetyldihydrocodeine, thebacon, diamorphine (heroin), acetylmorphone, noscapine, or pholcodine.
  • the additional active ingredient(s) comprise an opioid analgesic.
  • the opioid analgesic is selected from any one or more of: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,
  • dimepheptanol dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol,
  • the additional active ingredient(s) comprise a
  • the decongestant is selected from any one or more of: pseudoephedrine hydrochloride, phenylephrine bitartrate, phenylephrine hydrochloride or pseudoephedrine sulfate.
  • the additional active ingredient(s) comprise a non opioid analgesic/anti-inflammatory drug.
  • the non-opioid analgesic/ anti-inflammatory is selected from any one or more of: acetaminophen or a non-steroidal anti-inflammatory agent selected from the group consisting of aspirin, celecoxib, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin,
  • the additional active ingredient(s) comprise an anti-migraine drug.
  • the anti-migraine drug is selected from any one or more of: 2- bromo-LSD, acetaminophen/dichloralphenazone/isometheptene mucate, almotriptin, alni ditan, amidrine, avitriptan, caffeine/ergotamine, calcitonin gene-related peptide receptor antagonist, clonidine, dasolampanel, dihydroergotamine, dimetotiazine, donitriptan, dotarizine, eletriptan, ergotamine, ergotamine/chlorcyclizine/caffeine, flumedroxone acetate, iprazochrome, lasmiditan, lisuride, lomerizine, methysergide, migraleve, naratriptan, naproxen, naproxen/sumatripta, olcegepant
  • the additional active ingredient(s) comprise an anti-emetic.
  • the anti-emetic is selected from any one or more of: dolasetron, granisetron, ondansetron, tropisetron, palonosetron, mirtazapine, metoclopramide, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, or hydroxyzine.
  • the additional active ingredient(s) comprise an anti histamine.
  • the anti-histamine is selected from any one or more of: diphenhydramine, loratadine, desloratadine, meclizine, fexofenadine, pheniramine, cetirizine, promethazine, brompheniramine, clemastine fumarate or chlorpheniramine.
  • the additional active ingredient(s) comprise a proton pump inhibitors (PPI).
  • PPI proton pump inhibitors
  • omeprazole esomeprazole
  • pantoprazole lansoprazole
  • rabeprazole rabeprazole
  • the additional active ingredient(s) comprise a 3 ⁇ 4 antagonist/ ⁇ blocker.
  • the fk antagonist/ ⁇ blocker is selected from any one or more of: cimetidine, ranitidine, or famotidine.
  • the additional active ingredient(s) comprise a tranquilizer.
  • the tranquilizer is selected from any one or more of: amobarbital, pentobarbital, secobarbital, phenobarbital, clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlordiazepoxide, or alprazolam.
  • the additional active ingredient(s) comprise an anticonvulsant.
  • the anti-convulsant is selected from any one or more of: elbamate, carbamazepine, oxcarbazepine, vigabatrin, progabide, tiagabine, topiramate, gabapentin, pregabalin, ethotoin, phenytoin, valproic acid, or lamotrigine.
  • the additional active ingredient(s) comprise a hypnotic.
  • the hypnotic is selected from any one or more of: zolpidem, zaleplon, zopiclone, or eszopiclone.
  • the additional active ingredient(s) comprise a muscle relaxant.
  • the muscle relaxant is selected from any one or more of:
  • methocarbamol carisoprodol, chlorzoxazone, cyclobenzaprine, gabapentin, metaxalone, or orphenadrine.
  • the additional active ingredient(s) comprise an anti-psychotic.
  • the anti-psychotic is selected from any one or more of: haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine,
  • methotrimeprazine pimozide, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, or paliperidone.
  • the additional active ingredient(s) comprise an anti-diarrheal.
  • the anti-diarrheal is bismuth subsalicylate or loperamide.
  • the additional active ingredient(s) comprise an Attention Deficit and Hyperactivity Disorder (ADHD) drug.
  • ADHD drug is selected from any one or more of: methylphenidate, dextroamphetamine sulfate, amphetamine, or atomoxetine hydrochloride.
  • the additional active ingredient(s) comprise an anti-Parkinsons disease drug.
  • the anti-Parkinson disease drug is selected from any one or more of: amantadine, Apokyn, apomorphine, bromocriptine, carbidopa/levodopa, Cycloset, Duopa, entacapone/levodopa/carbidopa, Gocovri, levodopa, Mirapex, Mirapex ER, Neupro, Parlodel, pramipexole, Requip, Requip XL, ropinirole, rotigotine, Rytary, Sinemet, Sinemet CR, or Stalevo.
  • the additional active ingredient(s) comprise a benzodiazepine.
  • the benzodiazepine is selected from any one or more of: alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam.
  • the additional active ingredient(s) comprise is a
  • the benzodiazepine antagonist is flumazenil.
  • the additional active ingredient(s) comprise a barbiturate.
  • the barbiturate is selected from any one or more of: amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital,
  • the additional active ingredient(s) comprise a barbiturate antagonist.
  • the barbiturate antagonist is an amphetamine.
  • the additional active ingredient(s) comprise a stimulant.
  • the stimulant is selected from caffeine or an amphetamine, such as amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, or methylphenidate.
  • the additional active ingredient(s) comprise a stimulant antagonist.
  • the stimulant antagonist is a benzodiazepine.
  • the additional active ingredient(s) comprise an antidepressant.
  • the antidepressant is selected from any one or more of: agomelatine, Allegron (see nortriptyline), amitriptyline, Anafranil (see clomipramine), Brintelbx (see vortioxetine), Cipralex (see escitalopram), Cipramil (see citalopram), citalopram, clomipramine, Cymbalta (see duloxetine), Depefex XL (see venlafaxine), dosulepin, doxepin, duloxetine, Edronax (see reboxetine), Efexor XL (see venlafaxine), escitalopram, Faverin (see fluvoxamine), fluoxetine, fluvoxamine, Foraven XL (see venlafaxine), imipramine, isocarboxazid, lofepramine, Lomont (see l), Faverin (see
  • the antidepressant is selected from any one or more of: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), venlafaxine (Effexor), reboxetine (Edronax), teniloxazine (Lucelan, Metatone), or viloxazine (Vivalan).
  • the additional active ingredient(s) comprise a nutraceutical.
  • the nutraceutical is selected from any one or more of: 5- methyltetrahydrofolic acid, ademetionine, adenine, adenosine monophosphate, alfacalcidol, alpha-linolenic acid, ATP, beta carotene, biotin, calcidiol, calcitriol, castor oil,
  • John's Wort succinic acid, taurine, tetrahydrofolic acid, thiamine, tretinoin, tyramine, ubidecarenone, ubiquinol, vitamin A, vitamin C, vitamin D, vitamin E, or vitamin K.
  • the additional active ingredient(s) comprise nicotine.
  • the additional active ingredient(s) comprise a BCS Class II active ingredient.
  • the BCS Class II active ingredient is selected from any one or more of following: aceclofenac, albendazole, amiodarone, atorvastatin, azithromycin, bicalutamide, bisacodyl, cabergoline, candesartancilexetil, carbamazepine, carvedilol, cefditoren, celecoxib, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, clarithromycin, clofazimine, clopidogrel, clozapine, cyclosporine, cyproterone, danazol, dapsone, diazepam, diclofenac, diflunisal, digoxin, diloxanide, ebastine, efavirenz, epalrestat, eprosartan,
  • tosufloxacin triflusal, ursodeoxychobcacid, valproicacid, valsartan, verapamil, warfarin, or zaltoprofen.
  • At least one additional active ingredient is a BCS Class IV active ingredient.
  • the BCS Class IV active ingredient is selected from any one or more of following: acetaminophen (paracetamol), acetazolamide, acetylsabcybc acid, acyclovir, allopurinol, aluminium hydroxide, amoxicillin, azathioprine, cefdinir, cefixime, cefotiam, cefpodoxime, cefuroxime axetil, dapsone, dexamethasone, doxycycbne, famotidine, folic acid, hydrochlorothiazide, 1-carbocysteine, levodopa, bnezobd, mesalamine, methylphenidate, metronidazole, modafmil, nalidixic acid, nitrofurantoin, nystatin, oxcarbazepine,
  • the aerosol formulation can further comprise additional physiologically or pharmaceutically acceptable excipients.
  • Excipients can include, for example, solvents, flavoring agents, surfactants, preservatives, chelating agents, pH modifiers, humectants, valve lubricants, anti-oxidants, anti-aggregating agents, and fatty acids.
  • Flavor modifying excipients that may be added to the composition include peppermint oil, menthol, saccharin and saccharin sodium.
  • the flavor modifying excipient is a solid, preferably it is micronized. The concentration will depend on the individual composition and the flavor modifying excipient.
  • the composition further comprises: an amount of flavor modifying excipient selected from 0.01-0.025 wt%, 0.025- 0.05 wt%, 0.05-0.1 wt%, 0.1-0.25 wt%, 0.25-0.5 wt%, 0.5-1 wt%, 1-2 wt%, 1-2.5 wt%, 1-5 wt%, 2-3 wt%, 3-4 wt%, 4-5 wt%, 5-7.5 wt%, 5-10 wt%, 10-12.5 wt%, 10-15 wt%, 10-20 wt%, 15-20 wt%, or 20-25 wt%, 25-30 wt%, or 25-50% wt%.
  • an amount of flavor modifying excipient selected from 0.01-0.025 wt%, 0.025- 0.05 wt%, 0.05-0.1 wt%, 0.1-0.25 wt%, 0.25-0.5 wt%, 0.5-1 wt%, 1-2 wt%,
  • the composition further comprises: an amount of sweetener selected from 0.01-0.025 wt%, 0.025-0.05 wt%, 0.05-0.1 wt%, 0.1-0.25 wt%, 0.25-0.5 wt%, 0.5-1 wt%, 1-2 wt%, 2-3 wt%, 2.5-5%, 3-4 wt%, 4-5 wt%, 5-6 wt%, 5-7.5 wt%, 7.5-10 wt%, or 5-10 wt%.
  • an amount of sweetener selected from 0.01-0.025 wt%, 0.025-0.05 wt%, 0.05-0.1 wt%, 0.1-0.25 wt%, 0.25-0.5 wt%, 0.5-1 wt%, 1-2 wt%, 2-3 wt%, 2.5-5%, 3-4 wt%, 4-5 wt%, 5-6 wt%, 5-7.5 wt%, 7.5-10 wt%, or 5-10 wt%
  • flavoring may represent a single species of flavor molecule (e.g., limonene) or a mixture of flavor molecule species (e.g., limonene, linalool, citral, citronellol, geranyl acetate and perillal) combined to produce a certain flavor.
  • limonene a single species of flavor molecule
  • mixture of flavor molecule species e.g., limonene, linalool, citral, citronellol, geranyl acetate and perillal
  • the composition comprises a surfactant that has an HLB value greater than 9, 10, 11, 12, 13, 14, 15, 16, or greater than 16.
  • the surfactant has an HLB value between 9-17, 9-16.7, 9-16, 9-15, 9-14, 10-17, 10-16.7, 10-16, 10-15, 12-14, 12-16, 14-16, 14-17, 15-17, and between 10-14.
  • the surfactant is selected from: PEG 15 hydroxystearate (Solutol HS15), polyoxyl-10-Oleyl Ether (BRIJ® 97), polyethylene glycol 25 hydrogenated castor oil, polyethylene glycol (PEG) 40 hydrogenated castor oil (Kolliphor RH40,
  • Cremophor RH40 polyethylene-polypropylene glycol (poloxamer 124), PEG 8
  • caprylic/capric glycerides (Labrasol), PEG 300 oleic glycerides (Labrafil M 1944), diethylene glycol monoethyl ether (Transcutol), lauroyl macrogol 32 glycerides (GELUCIRE® 44/14), polyethylene glycol 400 (PEG 400), propylene glycol laurate (Lauroglycol FCC), D-a- Tocopherol polyethylene glycol 1000 succinate (TPGS), polyethylene-polypropylene glycol (poloxamer 188), polyethylene-polypropylene glycol (poloxamer 407), polyvinyl pyrrolidone (e.g., Mw 28-34 kDa, Mw 44-54kDa (e.g., Kollidon 30), or 1-1.5M kDa (e.g., Kollidon 90), Iota Carrageenan, Xanthan gum, locust Bean gum, Kelcogel LT100, acacia
  • the surfactant is selected from: polyoxyl-10-Oleyl Ether (BRIJ® 97), polyethylene glycol 25 hydrogenated castor oil, polyethylene glycol (PEG) 40 hydrogenated castor oil (Kolbphor REMO, Cremophor REMO), polyethylene-polypropylene glycol (poloxamer 124), PEG 8 caprybc/capric glycerides (Labrasol), PEG 300 oleic glycerides (Labrafil M 1944), di ethylene glycol monoethyl ether (Transcutol), sorbitane monooleate (Span 80), Lauroyl macrogol 32 glycerides (GELUCIRE® 44/14), polyethylene glycol 400 (PEG 400), propylene glycol laurate (Lauroglycol FCC), polysorbate 20
  • TWEEN® 20 polysorbate 40 (TWEEN® 40), polysorbate 60 (TWEEN® 60), polysorbate 80 (TWEEN® 80), D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS), polyethylene-polypropylene glycol (poloxamer 188), polyethylene-polypropylene glycol (poloxamer 407), polyvinyl pyrrolidone (Kollidon 30), polyvinyl pyrrolidone (Kollidon 90), Iota Carrageenan, Xanthan gum, locust Bean gum, Kelcogel LT100, acacia gum, guar gum, gamma-Cyclodextrin, Tracacanth gum, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), microcrystalline cellulose (MC), lecithin, or a combination thereof.
  • HPMC hydroxypropyl methylcellulose
  • CMC carboxymethyl cellulose
  • MCC microcrystalline cellulose
  • the composition comprises at least one fatty acid, at least one monoglyceride, at least one diglyceride, or at least one triglyceride, or a combination thereof.
  • the fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof is an oil.
  • the oil is selected from anise oil, apricot kernel oil PEG-6 esters, apricot kernel oil, beeswax, borage oil, canola oil, castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 castor oil, polyoxyl 60 hydrogenated castor oil, hydrogenated castor oil, polyoxyl 60 castor oil, cinnamon oil, clove oil, coconut oil fractioned, coconut oil, coconut oil-lecithin, coriander oil, com oil PEG-6 esters, com oil PEG-8 esters, com oil, cottonseed oil hydrogenated, cottonseed oil, cottonseed oil, hydrogenated soybean oil, hydrogenated vegetable oils, kernel oil PEG-6 esters, kernel oil, lemon oil, mineral oil (light), mineral oil, neutral oil, nutmeg oil, olive oil PEG-6 esters, olive oil, orange oil, palm kernel oil PEG-6 esters, palm kernel oil, palm kernel oil/ palm kernel oil hydrogenated, palm fruit oil, peanut
  • the fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof is a fat.
  • the fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof is exogenously added fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof.
  • exogenously added means other than any fatty acids, monoglycerides, diglycerides, triglycerides, or combinations thereof, that were originally present in a cannabis plant, or other plant extract, and remains in the extract, e.g., a cannabinoid extract, after the extraction/distillation process.
  • pressed cannabis/hemp seed oil added to a composition of the present invention is exogenously added.
  • the only exogenously added fatty acid, monoglyceride, diglyceride, triglyceride, or a combination thereof is a flavoring oil, e.g., flavor compounds diluted with and MCT or other oil.
  • the flavoring oil is an essential oil.
  • the essential oil is produced by distillation (e.g., steam distillation), solvent extraction (example, a hydrocarbon such as hexane or supercritical carbon dioxide), or by expression.
  • the monoglyceride, diglyceride, or triglyceride is a medium chain monoglyceride, diglyceride, or triglyceride and/or a long chain monoglyceride, diglyceride triglyceride.
  • the triglyceride is a medium chain triglyceride (MCT).
  • the triglyceride is a long chain triglyceride (LCT).
  • the medium chain triglycerides (MCT) of the present invention are triglycerides whose fatty acids have an aliphatic tail of 6-12 carbon atoms.
  • the MCT may be a single MCT or a mix of MCT.
  • the MCT is formed from fatty acids having from C6 to C8, C8 to CIO, CIO to C12, or C8 to C12 carbon atoms.
  • the fatty acids of the MCT may be saturated, mono-unsaturated, and/or poly-unsaturated fatty acids. In one embodiment 80 to 100% of the medium chain fatty acids are saturated, 0 to 10% are monounsaturated, and 0 to 5% are polyunsaturated.
  • Preferred medium chain fatty acids include caproic acid, caprylic acid, capric acid, and mixtures thereof.
  • An oil comprising MCT may comprise at least 5 wt% medium chain triglycerides, e.g., coconut oil, or palm kernel oil.
  • the oil comprising an MCT is coconut oil.
  • MCT may be in the form of oil that is enriched or fractionated to increase the concentration of medium chain triglycerides.
  • the MCT is fractionated coconut oil (e.g., glyceryl tricaprylate or NATURE’S OIL MCT).
  • Medium chain triglycerides may also be formed by esterifying glycerol with mixtures of C6-C12 fatty acids, e.g., C8-C10 fatty acids such as caprylic (C:8) and capric (C: 10) fatty acids fractionated from coconut or palm kernel oils.
  • C6-C12 fatty acids e.g., C8-C10 fatty acids such as caprylic (C:8) and capric (C: 10) fatty acids fractionated from coconut or palm kernel oils.
  • the long chain triglycerides (LCT) of the present invention are triglycerides whose fatty acids have an aliphatic tail of 13-24 carbon atoms.
  • the LCT may be a single LCT or a mix of MCT.
  • the LCT is formed from long chain fatty having from C14 to C16, C16 to C18, C18 to C20, C14 to C20, or C20 to C24 carbon atoms.
  • the fatty acids of the LCT may be saturated, mono-unsaturated, and poly-unsaturated fatty acids. In one embodiment 5 to 25 % of the long chain fatty acids are saturated, 15 to 80 % are
  • the oil comprising an LCT may comprise at least 5 wt% long chain triglycerides, e.g., olive oil, poppy seed, safflower, sunflower, com, and soybean oils, sesame oil, or castor oil.
  • LCT may be in the form of oil that is enriched or fractionated to increase the concentration of long chain triglycerides. In one embodiment, the LCT is olive oil.
  • the oil comprising an MCT and/or LCT may be selected from the group consisting of borage oil, castor oil, coconut oil, cottonseed oil, soybean oil, safflower oil, sunflower oil, castor oil, com oil, olive oil, palm oil, peanut oil, poppy seed oil, canola oil, hydrogenated soybean oil, hydrogenated vegetable oils, sesame oil, triolein, trilinolein, and trilinolenin.
  • compositions may include one or more antioxidant.
  • Preferred antioxidants include ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxy toluene, propyl gallate, a-tocopherol, g-tocopherol, and mixed tocopherols.
  • the composition of the present invention further comprises an antioxidant(s) in the range of about 0.01% w/v to about 0.1% w/v.
  • the composition further comprises an antioxidant(s) in the range of 0.1-0.25 wt%, 0.25-0.5 wt%, 0.5-1 wt%, 1-2 wt%, 2-3 wt%, 2.5-5%, 3-4 wt%, or 4-5 wt%.
  • a composition may comprise chelating agents in a final range of about 0.01% to about 0.5% w/v.
  • chelating agents include ethylenediaminetetraacetic acid (EDTA), phosphoric acid, polyphosphates, polysaccharides, citric acid and combinations thereof.
  • a composition may also additionally comprise inactive ingredients selected from a group consisting of co-solvents, dispersing agents, emulsifiers, flavors, humectants, lubricants, preservatives, propellants, sorbents, suspension aids, sweeteners, tonicity modifiers, and combinations thereof.
  • inactive ingredients selected from a group consisting of co-solvents, dispersing agents, emulsifiers, flavors, humectants, lubricants, preservatives, propellants, sorbents, suspension aids, sweeteners, tonicity modifiers, and combinations thereof.
  • a composition may further comprise a pH adjusting agent, e.g., disodium hydrogen phosphate, sodium acetate, sodium bicarbonate, sodium hydroxide, sodium phosphate tribasic, dipotassium hydrogen phosphate, phosphoric acid, acetic acid, lactic acid, fumaric acid, adipic acid, malic acid, tartaric acid, citric acid, hydrochloric acid, sulfuric acid, salts thereof, and combinations thereof.
  • the composition pH is in the range of about 5.0 to about 6.5.
  • the composition pH is in the range of about 6.5 to about 7.5.
  • the composition pH is in the range of about 7.0 to about 7.5.
  • the composition pH is in the range of about 6.5 to about 7.0.
  • a composition may additionally comprise an osmotic agent, e.g., glycerin, glucose, sucrose, sorbitol, sodium phosphate and combinations thereof.
  • an osmotic agent e.g., glycerin, glucose, sucrose, sorbitol, sodium phosphate and combinations thereof.
  • a composition may further comprise a sweetener, flavoring and/or taste-masking agent, e.g., glucose, fructose, sucrose, sorbitol, sucralose, saccharin, saccharin sodium, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid, xylitol and combinations thereof.
  • a sweetener e.g., glucose, fructose, sucrose, sorbitol, sucralose, saccharin, saccharin sodium, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid, xylitol and combinations thereof.
  • a sweetener e.g., glucose, fructose, sucrose, sorbitol, sucralose, saccharin, saccharin sodium, aspartame, n
  • the sweetener is selected from one or more of: acesulfame potassium, advantame, aspartame, neotame, saccharin, sodium saccharin, sucralose, stevia, glucose, fructose, sucrose, sorbitol, or xylitol. In one preferred embodiment, the sweetener is sucralose.
  • a composition may also further comprise preservatives, e.g., methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid, acetic acid, propionic acid, sulfites, nitrites, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzonate, potassium benzonate, calcium benzonate, sodium metabi sulfite, propylene glycol, benzaldehyde, butylated hydroxytoluene, butylated hydroxyanisole, formaldehyde donors, essential oils, monoglyceride, benzalkonium chloride and ethylene diamine tetra-acetic acid (EDTA), and combinations thereof.
  • preservatives e.g., methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid,
  • the invention also encompasses methods of treating a subject having a disease or disorder that would benefit from the administration of a cannabinoid, comprising
  • administration of said cannabinoid causes less coughing and/or upper and/or lower respiratory tract irritation than administration of said cannabinoid.
  • the subject is a human.
  • the disease or disorder is selected from: Alzheimer Disease, Amyotrophic Lateral Sclerosis (ALS), pain, anxiety, nausea, vomiting, insomnia, restless leg syndrome (RLS), diabetes mellitus, dystonia, epilepsy, fibromyalgia, gastrointestinal disorders, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, gliomas, cancer, Hepatitis C, Human Immunodeficiency Virus (HIV) Huntington Disease, hypertension, incontinence, methicillin-resistant Staphyloccus aureus (MRSA), multiple sclerosis, osteoporosis, pruritus, rheumatoid arthritis, insomnia, sleep apnea, or Tourette Syndrome.
  • ALS Amyotrophic Lateral Sclerosis
  • RLS restless leg syndrome
  • diabetes mellitus dystonia
  • epilepsy fibromyalgia
  • gastrointestinal disorders inflammatory bowel disease
  • Crohn's disease irritable bowel syndrome
  • gliomas cancer
  • the pain is chronic pain. In another embodiment, the pain is acute pain. In a further embodiment, the acute pain is a migraine. In a further embodiment, the pain is selected from any one or more of the following: post-herpetic neuralgia, trigeminal neuralgia, spinal cord injury pain, carpal tunnel syndrome, phantom limb, ischemic pain, pain resulting from sports injuries, back pain (e.g., low back pain), menstrual pain, gastrointestinal or urethral cramps, skin wounds, bums, or cancer pain. In a preferred embodiment, the pain is cancer pain.
  • the nausea and/or vomiting results from a chemotherapy, e.g., cancer chemotherapy. In another embodiment, the nausea and/or vomiting results from opioid use.
  • a chemotherapy e.g., cancer chemotherapy.
  • the nausea and/or vomiting results from opioid use.
  • the method is for increasing socialization, increasing relaxation, inducing sleep, reducing the time needed to fall asleep, or for inducing a psychotropic effect (commonly known as a“high”).
  • the method is for reducing the amount of opioid(s) used by a subject suffering from pain or used by a subject addicted to an opioid.
  • composition may be administered once, twice, three, or four times a day, or as needed.
  • the invention provides a method of reducing the intensity or duration of pain in a subject (i.e., a subject, e.g., human), in need thereof, comprising the step of administering to the subject an effective amount of a cannabinoid composition of the present invention.
  • the method decreases pain intensity in the subject.
  • the method decreases pain duration in the subject.
  • the pain is acute pain.
  • the pain is chronic pain.
  • the subject has reduced pain intensity for at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours, or at least 24 hours post administration.
  • the cannabinoid composition of the present invention has a maximum pain- relieving effect between 1-4 hours or between 1.5-2.5 hours post administration. In another embodiment, the cannabinoid composition of the present invention has an onset of pain- relieving effect within 15 minutes, 20 minutes, 25 minutes, 30 minutes, or within 45 minutes post administration.
  • the invention provides a method of reducing or preventing nausea or vomiting in a subject in need thereof, comprising administering to the subject an effective amount of a cannabinoid composition of the present invention.
  • the nausea or vomiting is opioid induced nausea or vomiting.
  • the opioid inducing the nausea or vomiting may be an opioid analgesic such as hydrocodone, oxycodone, oripavine, dihydromorphine, hydromorphinol, ni comorphine, dipropanoylmorphine,
  • the cannabinoid composition is administered 0-30 minutes, 30-60 minutes prior to administration of the opioid. In another embodiment, the cannabinoid composition is administered 60 minutes prior to administration of the opioid. In another embodiment, the cannabinoid composition is administered concurrently with the administration of the opioid.
  • the nausea or vomiting occurs after surgery and results from anesthesia.
  • the subject has reduced intensity of nausea in the 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, or 24 hours following initial administration of the cannabinoid containing composition.
  • the subject has reduced vomiting in the 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, or 24 hours following initial administration of the cannabinoid composition.
  • the cannabinoid composition of the present invention has a maximum nausea or vomiting reducing effect between 1-4 hours, 1-3 hours, 2-4 hours, or between 1.5-2.5 hours post administration.
  • the cannabinoid composition of the present invention has an onset of nausea or vomiting reducing effect within 15 minutes, 20 minutes, 25 minutes, 30 minutes, or within 45 minutes post administration.
  • the method of reducing nausea or vomiting in a subject includes reducing the occurrence of nausea or vomiting.
  • Example 1 Viscosity and FPF characterization of ethanol-based THC and CBD formulations Preparation of Ethanol-based Formulations
  • D9-THC distillate was heated in a 60°C oven for 30 minutes. Subsequently, 10.2 g of distillate and 16.4 g of 200 proof ethanol were transferred via pouring to a clean, dry 2-ounce jar. The jar was sealed and mixed at room temperature using a Multi-Tube Vortexer (VWR DVX-2500). Upon fully dissolving, the resulting distillate-ethanol tincture had a distillate concentration of 38%w/w. Serial dilutions of 19, 9.6, 4.8, 2.4, and 1.2%w/w distillate in 200 proof ethanol were prepared by diluting 10 g of formulation with 10 g of 200 proof ethanol. Samples were stored at 4°C until use.
  • the flow rate was set by attaching a flow meter to the inlet of the induction port and adjusting the flow control valve on the LC5 vacuum pump until the flow rate through the system was 28.3 L/min +/- 5%. Measurements were performed under ambient laboratory conditions (-60% RH, 72°F).
  • the Respimat device was primed and attached to the UIP using a mouthpiece adapter. With the vacuum pump running, the device was actuated followed by a 30 second hold before turning off the vacuum pump. The Respimat device was re-primed and another dose was collected in the FSI. To determine the amount of cannabinoids deposited in each stage, the FSI was dismantled and each stage was extracted with 10 ml of methanol. Samples were diluted and HPLC performed to quantify the mass of cannabinoids deposited in the USP throat, coarse fraction collector, and fine particle fraction collector.
  • FIG. 1 shows a plot of viscosity (cP) as a function of the percentage (%) w/w of A9-THC distillate, CBD isolate in 200 proof ethanol.
  • FIG. 2A and 2B are plots of percent dose of A9-THC in the fine particle fraction (FPF) as a function of viscosity (cP) (FIG. 2A) and emitted dose (mg) (FIG. 2B). As shown in these figures, formulations with viscosity less than 2 cP and/or less than 2 mg emitted dose delivered about 80% of the dose in FPF.
  • Example 2 Observation feedback of the tolerability of A9-THC distillate in ethanol delivered via RESPIMAT®
  • the irritation was caused by cannabinoid deposition at mucosal membranes in the throat and upper airways.
  • the lung deposition profile is affected by multiple factor including FPF as well as user inhalation technique. For example, it has been shown that the timing of inhalation and actuation as well as the posture of the user’s head can have an impact on lung deposition. It is also important to note that in vitro impactor studies commonly underestimate dose deposition in the throat and overestimate the dose deposited in the lungs (Wei et al. (2016), Journal of Aerosol Medicine and Pulmonary Drug Delivery 31(0): 1-14.
  • Example 3 Effect of glycerol inclusion in cannabinoid aerosol formulation
  • Glycerol is non-volatile and is a humectant. Glycerol in amounts up to 29% (w/w) were added to a solution of 3.5% A9-THC distillate in ethanol and viscosity was measured as shown in Table 3 below:
  • FIG. 3 shows the effect of the percentage of the doe in the FPF as a function of the amount of glycerol (% w/w) in the formulation (3.5% A9-THC distillate in ethanol). As shown, in the figure, the FPF of formulations comprising glycerol in an amount of 8.6% (w/w) or less was more than about 70%.

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Abstract

La présente invention concerne l'administration d'une formulation d'aérosol cannabinoïde à l'aide d'un inhalateur de brume douce avec une toux et une irritation réduites. L'invention concerne des formulations d'aérosol et leurs procédés d'utilisation, la formulation comprenant un cannabinoïde dans une solution d'éthanol, et la formulation comprenant en outre du glycérol.
PCT/US2020/017840 2019-02-13 2020-02-12 Procédés d'administration pulmonaire non irritante de cannabinoïdes à l'aide d'inhalateurs de brume douce Ceased WO2020167892A1 (fr)

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