WO2021071967A1 - Compositions permettant l'administration par voie pulmonaire de cannabinoïdes, méthodes et systèmes associés - Google Patents

Compositions permettant l'administration par voie pulmonaire de cannabinoïdes, méthodes et systèmes associés Download PDF

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Publication number
WO2021071967A1
WO2021071967A1 PCT/US2020/054609 US2020054609W WO2021071967A1 WO 2021071967 A1 WO2021071967 A1 WO 2021071967A1 US 2020054609 W US2020054609 W US 2020054609W WO 2021071967 A1 WO2021071967 A1 WO 2021071967A1
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Prior art keywords
icp
pharmaceutically acceptable
cannabinoid
suspension
total mass
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PCT/US2020/054609
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English (en)
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Michael S. Hartman
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Island Breeze Systems Ca, Llc
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Publication of WO2021071967A1 publication Critical patent/WO2021071967A1/fr

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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
    • A61K31/658—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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids

Definitions

  • the present disclosure relates generally to pharmaceutical formulations and methods for delivery of cannabinoids via a metered dose inhaler to the respiratory tract.
  • Inhaler systems include dry powder inhalers, nebulizers and metered dose inhalers (MDIs).
  • the active agent to be delivered by a suspension MDI is typically provided as a fine particulate dispersed within a propellant or a propellant system that includes a combination of two or more propellants. In order to form the fine particulates, the active agent is typically micronized.
  • a pharmaceutical composition deliverable from a metered dose inhaler including: a suspension medium substantially free of co-solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of inhalable cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of a cannabinoid selected from the group consisting of delta-9-tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), delta- 8-tetrahydrocannabinol (D8THC), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), tetrahydrocannabinovarin (THCV), tetrahydrocannabinovarinic acid (THCV A), cannabidivarin (CBDV), cannabidi
  • THC delta-9-t
  • a cannabinoid composition can include naturally-occurring cannabinoid compounds that are produced via synthetic chemistry means, synthetic analogs and derivatives of naturally-occurring cannabinoids, and various combinations of natural and synthetic cannabinoids and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprise, for example, a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP that ranges from above 0.05:1 up to 200:1.
  • ICP inhalable carrier particles
  • Some aspects relate to a method for treating a neurological disorder, cancer or pain in a patient, the method including: providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising: a suspension medium substantially free of cosolvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of inhalable cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprise a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP that ranges from above 0.05:1 up to 200:1; and administering the co-suspension to the patient
  • a method for respiratory delivery of a cannabinoids active agent to a patient comprising: providing metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium substantially free of co-solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprise a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP that ranges from above 0.05:1 up to 200:1; and actuating the metered dose inhaler at least
  • the CP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 1 pg and about 10 mg, between about 0.5 pg and about 400 pg, between about 2 mg and 50 mg, between about 2 mg and about 10 mg, between about 5 mg and about 10 mg, or between 3 mg and about 30 mg per actuation of the metered dose inhaler.
  • the CP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from up to about 30 mg, up to about 10 mg, up to about 400 pg, up to about 2.5 pg, up to about 2 pg, or up to about 1.5 pg per actuation of the metered dose inhaler.
  • the CP are included in the co-suspension in an amount sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 0.01 mg/ml and about 10 mg/ml, between about 0.01 mg/ml and about 2 mg/ml, or between about 0.03 mg/ml and about 0.4 mg/ml.
  • At least 90% of the CP by volume exhibit an optical diameter of 5 mem or less.
  • At least 50% of the CP by volume exhibit an optical diameter of 3 mem or less.
  • the ICP comprise perforated microstructures.
  • the perforated microstructures are prepared using a spray drying process.
  • the perforated microstructures comprise 1,2- disteroyl-sn-glycero-3-phosphocholine and calcium chloride.
  • the ICP exhibit a mass median aerodynamic diameter (MMAD) selected from between about 10 mem and about 500 nm, between about 5 mem and about 750 nm, or between about 1 mem and about 3 mem.
  • MMAD mass median aerodynamic diameter
  • the ICP exhibit a volume median optical diameter selected from between about 0.2 mem and about 50 mem, between about 0.5 mem and about 15 mem, between about 1.5 mem and about 10 mem, or between about 2 mem and about 5 mem.
  • the method includes providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising an amount of CP sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) within the co-suspension selected from between about 0.01 mg/ml and about 10 mg/ml, between about 0.01 mg/ml and about 3 mg/ml, or between about 0.03 mg/ml and about 0.4 mg/ml.
  • administering the pharmaceutically acceptable co-suspension includes administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 1 pg and about 50 pg, between about 1 pg and about 30 pg, between about 2 pg and 5 pg, between about 2 pg and about 10 pg, between about 5 pg and about 10 pg, or between 3 pg and about 30 pg per actuation.
  • administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer or solvate of cannabinoids selected from up to about 5 mg, up to about 1 mg, up to about 100 pg, up to about 5 pg, up to about 2 pg, or up to about 1 pg per actuation.
  • administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount resulting in a clinically significant decrease in pain, tumor size or anxiety.
  • actuating the metered dose inhaler to provide respiratory delivery of cannabinoid(s) active agent includes delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids to the patient at a delivered dose uniformity (DDU) selected from a DDU of ⁇ 30%, or better, a DDU of ⁇ 25%, or better, or a DDU of ⁇ 20%, or better, throughout emptying of the canister.
  • DDU delivered dose uniformity
  • actuating the metered dose inhaler to provide delivery of the cannabinoid(s) active agent includes delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction.
  • the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction.
  • the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 0.05:1 up to 200:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 0.0:1 up to 60:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 10:1 up to 200:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 15:1 up to 60:1.
  • the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid comprises a cannabinoid salt selected from the group consisting of delta-9-tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), delta- 8-tetrahydrocannabinol (D8THC), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), tetrahydrocannabinovarin (THCV), tetrahydrocannabinovarinic acid (THCV A), cannabidivarin (CBDV), cannabidivarin acid (CBDVA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabinodiol
  • THC delta-9-t
  • a cannabinoid composition can include naturally-occurring cannabinoid compounds that are produced via synthetic chemistry means, synthetic analogs and derivatives of naturally-occurring cannabinoids, and various combinations of natural and synthetic cannabinoids.
  • Some embodiments relate to a co-suspension composition deliverable from a metered dose inhaler for pulmonary administration of a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s), the suspension composition prepared by a process including: providing a pharmaceutically acceptable propellant substantially free of cosolvents and solubilizing agents; providing inhalable cannabinoid particles (CP) comprising the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) in crystalline form; providing inhalable carrier particles (ICP), wherein the ICP are formed using a dry particulate phospholipid material that is substantially insoluble in the propellant and are free of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s); and dispersing the CP and the ICP within the pharmaceutically acceptable propellant to form a co-suspension composition wherein the ICP are included in the suspension medium at a weight ratio of total mass of
  • the weight ratio of total mass of the ICP to total mass of the CP ranges from 10:1 up to 200:1.
  • the pharmaceutically acceptable propellant comprises a hydrofluoroalkane propellant.
  • compositions including:
  • the cannabinoid is selected from the group consisting of Cannabidiol, Tetrahydrocannabinol, Tetrahydrocannabinolic acid, Cannabidiolic acid, Cannabidivarin and Cannabidivaric acid.
  • the phospholipid has a gel to liquid crystal phase transition of greater than about 40°C.
  • the phospholipid is a C16-C22 saturated lipid.
  • the phospholipid is selected from the group consisting of a phosphoglyceride, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerol, a short-chain phosphatidylcholines, a long-chain saturated phosphatidylethanolamine, long-chain saturated phosphatidylserine, long-chain saturated phosphatidylglycerol, and long-chain saturated phosphatidylinositol.
  • a phosphoglyceride dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerol, a short-chain phosphatidylcholines,
  • the pharmaceutically acceptable propellant includes a hydrofluoroalkane propellant.
  • the plurality of inhalable carrier particles include a fat.
  • the fat is a phospholipid.
  • the plurality of inhalable carrier particles (ICP) include a sugar.
  • the plurality of inhalable carrier particles (ICP) are part of an emulsion.
  • the plurality of inhalable carrier particles (ICP) include a surfactant.
  • a pharmaceutical composition contained within a metered dose inhaler including: a) a suspension medium substantially free of co-solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; b) a plurality of inhalable cannabinoid particles (CP) including: a pharmaceutically acceptable salt, ester, isomer, or solvate of a cannabinoid selected from the group consisting of Cannabidiol, Tetrahydrocannabinol, Tetrahydrocannabinolic acid, Cannabidiolic acid, Cannabidivarin, Cannabinol and Cannabidivaric acid; wherein an amount of the CP is sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) from between about 0.03 mg/ml and about 0.4 mg/ml, wherein the CP is in crystalline form; c) a plurality of
  • compositions that can be delivered by a metered dose inhaler and their methods of use.
  • fine particle dose refers to the dose, either in total mass or fraction of the nominal dose or metered dose, that is within a inhalable range.
  • the dose that is within the inhalable range is measured in vitro to be the dose that deposits beyond the throat stage of a cascade impactor, e.g., the sum of dose delivered at stages 3 through filter in a Next Generation Impactor operated at a flow rate of 301/min.
  • fine particle fraction refers to the proportion of the delivered material relative to the delivered dose (i.e., the amount that exits the actuator of a delivery device, such as an MDI) that is within a inhalable range.
  • the amount of delivered material within the inhalable range is measured in vitro as the amount of material that deposits beyond the throat stage of a cascade impactor, e.g., the sum of the material delivered at stages 3 through filter in a Next Generation Impactor operated at a flow rate of 301/min.
  • the term “inhibit” refers to a measurable lessening of the tendency of a phenomenon, symptom or condition to occur or the degree to which that phenomenon, symptom or condition occurs.
  • the term “inhibit” or any form thereof, is used in its broadest sense and includes minimize, prevent, reduce, repress, suppress, curb, constrain, restrict, slow progress of and the like.
  • Mass median aerodynamic diameter refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol consists of particles with an aerodynamic diameter smaller than the MMAD, with the MMAD being calculated according to monograph 601 of the United States Pharmacopeia (“USP”).
  • USP United States Pharmacopeia
  • the term “optical diameter” indicates the size of a particle as measured by the Fraunhofer diffraction mode using a laser diffraction particle size analyzer equipped with a dry powder dispenser (e.g., Sympatec GmbH, Clausthal-Zellerfeld, Germany).
  • solution mediated transformation refers to the phenomenon in which a more soluble form of a solid material (i.e., particles with small radius of curvature (a driving force for Ostwald ripening), or amorphous material) dissolves and recrystallizes into the more stable crystal form that can coexist in equilibrium with its saturated propellant solution.
  • a more soluble form of a solid material i.e., particles with small radius of curvature (a driving force for Ostwald ripening), or amorphous material
  • a “patient” or “subject” refers to an animal in which cannabinoids will have a therapeutic effect.
  • the patient is a human being.
  • Perforated microstructures refer to carrier particles that include a structural matrix that exhibits, defines or comprises voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations or holes that allow the surrounding suspension medium to permeate, fill or pervade the microstructure, such as those materials and preparations described in U.S. Pat. No. 6,309,623 to Weers, et al.
  • the primary form of the perforated microstructure is, generally, not essential, and any overall configuration that provides the desired formulation characteristics is contemplated herein. Accordingly, in one embodiment, the perforated microstructures may comprise approximately spherical shapes, such as hollow, suspending, spray-dried microspheres. However, collapsed, corrugated, deformed or fractured particulates of any primary form or aspect ratio may also be compatible.
  • perforated microstructures may be formed of any biocompatible material that does not substantially degrade or dissolve in the selected suspension medium. While a wide variety of materials may be used to form the particles, in some embodiments, the structural matrix is associated with, or includes, a surfactant such as, a phospholipid or fluorinated surfactant. Although not required, the incorporation of a compatible surfactant in the perforated microstructure or, more generally, the carrier particles, can improve the stability of the respiratory dispersions, increase pulmonary deposition and facilitate the preparation of the suspension.
  • a surfactant such as, a phospholipid or fluorinated surfactant
  • the term “suspension medium” as uses herein refers to a substance providing a continuous phase within which active agent particles and carrier particles can be dispersed to provide a co-suspension formulation.
  • the suspension medium used in co- suspension formulations described herein includes propellant.
  • the term “propellant” refers to one or more pharmacologically inert substances which exert a sufficiently high vapor pressure at normal room temperature to propel a medicament from the canister of an MDI to a patient on actuation of the MDI's metering valve. Therefore, the term “propellant” refers to both a single propellant and to a combination of two or more different propellants forming a “propellant system.”
  • respirable generally refers to particles, aggregates, drops, etc. sized such that they can be inhaled and reach the airways of the lung.
  • the terms “physical stability” and “physically stable” refer to a composition that is resistant to one or more of aggregation, flocculation, and particle size changes due to solution mediated transformations and is capable of substantially maintaining the MMAD of carrier particles and the fine particle dose.
  • physical stability may be evaluated through subjecting compositions to accelerated degradation conditions, such as by temperature cycling as described herein.
  • suspension stability and “stable suspension” refer to suspension formulations capable of maintaining the properties of a co-suspension of active agent particles and carrier particles over a period of time.
  • suspension stability may be measured through delivered dose uniformity achieved by co suspension compositions described herein.
  • substantially insoluble means that a composition is either totally insoluble in a particular solvent or it is poorly soluble in that particular solvent.
  • the term “substantially insoluble” means that a particular solute has a solubility of less than one part per 100 parts solvent.
  • the term “substantially insoluble” includes the definitions of “slightly soluble” (from 100 to 1000 parts solvent per 1 part solute), “very slightly soluble” (from 1000 to 10,000 parts solvent per 1 part solute) and “practically insoluble” (more than 10,000 parts solvent per 1 part solute) as given in Table 16-1 of Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott, Williams & Wilkins, 2006, p. 212.
  • surfactant refers to any agent which preferentially adsorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water/air interface or organic solvent/air interface.
  • Surfactants generally possess a hydrophilic moiety and a lipophilic moiety, such that, upon adsorbing to microparticles, they tend to present moieties to the continuous phase that do not attract similarly-coated particles, thus reducing particle agglomeration.
  • surfactants may also promote adsorption of a drug and increase bioavailability of the drug.
  • a “therapeutically effective amount” is the amount of compound which achieves a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of a disease or disorder.
  • a therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease or disorder in a patient; returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder; and/or reduces the likelihood of the onset of the disease of disorder.
  • chemically stable and “chemical stability” refer to co suspension formulations wherein the individual degradation products of active agent remain below the limits specified by regulatory requirements during the shelf life of the product for human use (e.g., 1% of total chromatographic peak area per ICH guidance Q3B(R2)) and there is acceptable mass balance (e.g., as defined in ICH guidance Q1E) between active agent assay and total degradation products.
  • cannabinoid denotes a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain.
  • the class includes endocannabinoids, phytocannabinoids, and synthetic cannabinoids.
  • Examples include cannabis-derived cannabindoids, delta-nine-tetrahydrocannabinol (THC) and cannabidiol (CBD), Cannabigerol-type, Cannabichromene-type, Tetrahydrocannabinol- and Cannabinol-type, Cannabielsoin-type, iso-Tetrahydrocannabinol-type, Cannabicyclol-type, and Cannabicitran-type.
  • THC delta-nine-tetrahydrocannabinol
  • CBD cannabidiol
  • Cannabigerol-type Cannabichromene-type
  • Tetrahydrocannabinol- and Cannabinol-type Cannabielsoin-type
  • iso-Tetrahydrocannabinol-type Cannabicyclol-type
  • Cannabicitran-type examples include cannabis-derived cannabindoids, delta-nine-tetrahydro
  • cannabinoid includes: CBG (Cannabigerol), CBC (Cannabichromene), CBL (Cannabicyclol), CBV (Cannabivarin), THCV (Tetrahydrocannabivarin), CBDV (Cannabidivarin), CBCV (Cannabichromevarin), CBGV (Cannabigerovarin), and/or CBGM (Cannabigerol Monomethyl Ether).
  • the at least one cannabinoid can be at least one of tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), and tetrahydrocannabinovarinic acid (THCV A).
  • THCA tetrahydrocannabinolic acid
  • CBD cannabidiol
  • THCV A tetrahydrocannabinovarinic acid
  • the at least one cannabinoid comprises both THCA and CBD.
  • the at least one cannabinoid can comprise a biosynthetic cannabinoid, for example a cannabinoid from yeast or artificial sources.
  • the amount of the at least one cannabinoid is sufficient for the desired purpose (for example achieving great subject comfort). In some embodiments, the amount of the at least one cannabinoid is at least 0.2 mg/mL and less than 350 mg/mL, for example 0.5 to 300 mg/mL, 1 to 200 mg/mL, 10 to 100, or 30 to 60 mg/mL.
  • the formulation can further (or instead) comprise at least one terpene.
  • any type of terpene can be employed.
  • the amount of the terpene is at least 3mcg/mL and less than 100 mg/mL.
  • the terpene is selected from the group of at least one of: Pinene, Limonene, Myrcene, Phellandrene, Carene, Terpinene, Linalool, Fenchol, Borneol, Terpineol, Geraniol, Humulene, Caryophyllene, Bisabolol or Phytol.
  • the terpene is selected from the group of at least one of: Pinene, Limonene, Myrcene, Phellandrene, Carene, Terpinene, Linalool, Fenchol, Bomeol, Terpineol, Geraniol, Humulene, Caryophyllene, Caryophyllene Oxide, Bisabolol, Citronellol, Menthol, Ocimene, Camphene or Phytol.
  • the amount of the at least one cannabinoid is sufficient for the desired purpose (for example achieving great subject comfort). In some embodiments, the amount of the at least one cannabinoid is at least 0.2 mg/mL and less than 350 mg/mL, for example 0.5 to 300 mg/mL, 1 to 200 mg/mL, 10 to 100, or 30 to 60 mg/mL.
  • the cannabinoid employed can be 100% activated. In some embodiments, less than 100% of the cannabinoid present is activated, for example, less than 100%, 99, 98, 95, 90, 80, 70, 50, 40, 30, 20, 10, or 5% or less of the cannabinoid present can be activated. In some embodiments, at least 50% of the cannabinoid is activated, for example, at least 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99 percent of the cannabinoid is activated. In some embodiments, none of the cannabinoid is activated. In some embodiments the at least one cannabinoid comprises at least one activated cannabinoid, such as 2, or more different cannabinoids are activated and/or at least partially activated.
  • cannabinoid denotes a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain.
  • the class includes endocannabinoids, phytocannabinoids, and synthetic cannabinoids.
  • Examples include cannabis-derived cannabindoids, delta-nine-tetrahydrocannabinol (THC) and cannabidiol (CBD), Cannabigerol-type, Cannabichromene-type, Tetrahydrocannabinol- and Cannabinol-type, Cannabielsoin-type, /.voTetrahydrocannabinol-type, Cannabicyclol-type, and Cannabicitran-type.
  • THC delta-nine-tetrahydrocannabinol
  • CBD cannabidiol
  • Cannabigerol-type Cannabichromene-type
  • Tetrahydrocannabinol- and Cannabinol-type Cannabielsoin-type
  • /.voTetrahydrocannabinol-type Cannabicyclol-type
  • Cannabicitran-type examples include cannabis-derived cannabindoids, delta-nine-tetra
  • cannabinoid includes: CBG (Cannabigerol), CBC (Cannabichromene), CBL (Cannabicyclol), CBV (Cannabivarin), THCV (Tetrahydrocannabivarin), CBDV (Cannabidivarin), CBCV (Cannabichromevarin), CBGV (Cannabigerovarin), and/or CBGM (Cannabigerol Monomethyl Ether).
  • the at least one cannabinoid can be at least one of tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), and tetrahydrocannabinovarinic acid (THCV A).
  • the at least one cannabinoid comprises both THC and CBD.
  • the formulation further comprises at least one terpene.
  • the formulation comprises at least one activated cannabinoid.
  • the at least one terpene comprises at least caryophyllene.
  • the at least one terpene is present in an amount of at least about 3 meg / mL, for example, at least 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 or more mcg/mL.
  • the amount of fat present in the formulation is greater than 10 micrograms/mL and less than 50 mg/mL. In some embodiments, the wax is present in at least 0.03 mg/mL in the final formulation.
  • the natural carbon dioxide cannabis extract has ⁇ 10 ppm of residual solvent.
  • the solvent comprises an amount of ethanol, methanol, butane, acetone, propane, hexane, heptane, pentane, chloroform, octane, benzene, toluene, methyl tert-butyl ether, ethyl tert-butyl ether, methylene chloride chloromethane and/or isopropanol.
  • the ethanol is present in an amount of up to 30% w/w, for example, up to 5, 10, 15, 20, 25, or 30% w/w.
  • the propellant comprises at least a HFA.
  • the HFA is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1, 1,1, 2, 3,3,3- Heptafluoropropane (HFA 227).
  • alternative solvents can be employed.
  • the formulation further comprises a surfactant.
  • the surfactant is present in an amount adequate for improving solubility. In some embodiments, the surfactant is present in an amount of up to 10% w/w. In some embodiments, the surfactant comprises oleic acid. In some embodiments, additional or alternative surfactants can be applied if confirmed for the uses as provided herein.
  • a formulation for a metered dose inhalation can comprise an amount of an activated cannabinoid, wherein the activated cannabinoid comprises at least tetrahydrocannabinolic acid (THCA), and cannabidiol (CBD) , an amount of ethanol sufficient to serve as a solvent, and an amount of a propellant, wherein the propellant is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227).
  • THCA tetrahydrocannabinolic acid
  • CBD cannabidiol
  • the formulation can also include at least one of: a) an amount of a wax, wherein the amount of wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation, and wherein the wax comprises a wax that naturally occurs in a cannabis plant, or b) an amount of a natural terpene.
  • the natural terpene is one that is present in a cannabis plant, and wherein the amount of the natural terpene is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation.
  • the wax is one that is natural to a cannabis plant, but is not removed fully during the processing of the cannabis plant.
  • the formulation further comprises Cannabidiol (CBD) and further comprises nicotine. In some embodiments, the formulation comprises nicotine.
  • any one of the formulations provided herein can be configured for nasal delivery.
  • a satisfactory amount of the desired ingredients is effectively administered through the nose by such a formulation.
  • the formulation includes a fatty acid and/or a triglyceride. In some embodiments, the formulation includes a wax.
  • the ingredients can be isolated from the native hemp plant or added from a separate source.
  • the carrier particles included in the co-suspension compositions described herein work to facilitate stabilization and delivery of the active agent included in the compositions.
  • the carrier particles are typically formed from pharmacologically inert material that is acceptable for inhalation and is substantially insoluble in the propellant selected.
  • the majority of carrier particles are sized within a inhalable range. In particular embodiments, therefore, the MMAD of the carrier particles will not exceed about 10 mem but is not lower than about 500 nm.
  • the MMAD of the carrier particles is between about 5 mem and about 750 nm.
  • the MMAD of the carrier particles is between about 1 mem and about 3 mem.
  • the MMAD of the carrier particles is between 10 mem and 50 mem.
  • the carrier particles will typically exhibit a volume median optical diameter between about 0.2 mem and about 50 mem. In one embodiment, the carrier particles exhibit a volume median optical diameter that does not exceed about 25 mem. In another embodiment, the carrier particles exhibit a volume median optical diameter selected from between about 0.5 mem and about 15 mem, between about 1.5 mem and about 10 mem, and between about 2 mem and about 5 mem.
  • the concentration of carrier particles included in a composition according to the present description can be adjusted, depending on, for example, the amount of active agent particles and suspension medium used.
  • the carrier particles are included in the suspension medium at a concentration selected from about 1 mg/ml to about 15 mg/ml, about 3 mg/ml to about 10 mg/ml, 5 mg/ml to about 8 mg/ml, and about 6 mg/ml.
  • the carrier particles are included in the suspension medium at a concentration of up to about 30 mg/ml.
  • the carrier particles are included in the suspension medium at a concentration of up to about 25 mg/ml.
  • the relative amount of carrier particles to active agent particles is selected to achieve a co-suspension as contemplated herein.
  • a co-suspension composition may be achieved where the amount of carrier particles, as measured by mass, exceeds that of the active agent particles.
  • the ratio of the total mass of the carrier particles to the total mass of active agent particles may be between about 3:1 and about 15:1, or alternatively from about 2:1 and 8:1.
  • the ratio of the total mass of the carrier particles to the total mass of active agent particles may be above about 1, such as up to about 1.5, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200, depending on the nature of the carrier particles and active agent particles used.
  • the ratio of the total mass of the carrier particles to the total mass of the active agent particles may be selected from between about 10 and about 200, between about 60 and about 200, between about 15 and about 60, between about 15 and about 170, between about 15 and about 60, about 16, about 60, and about 170.
  • the amount of carrier particles, as measured by mass, is less than that of the active agent particles.
  • the mass of the carrier particles may be as low as 20% of the total mass of the active agent particles.
  • the total mass of the carrier particles may also approximate or equal the total mass of the active agent particles.
  • Carrier particles suitable for use in the compositions described herein may be formed of one or more pharmaceutically acceptable materials or excipients that are suitable for inhaled delivery and do not substantially degrade or dissolve in the suspension medium.
  • perforated microstructures, as defined herein may be used as the carrier particles.
  • excipients that may be used in the formulation of carrier particles described herein include but are not limited to (a) carbohydrates, e.g., monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as sucrose, lactose, trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropyl- -cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, starches, chitin, chitosan, inulin, and the like; (b) amino acids, such as alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leucine, isoleucine, valine, and the like; (c) metal and organic salts prepared from organic acids and bases, such as sodium citr
  • phospholipids from both natural and synthetic sources may be used in preparing carrier particles suitable for use in the compositions described herein.
  • the phospholipid chosen will have a gel to liquid crystal phase transition of greater than about 40° C.
  • Exemplary phospholipids are relatively long chain (i.e., C16-C22) saturated lipids and may comprise saturated phospholipids, such as saturated phosphatidylcholines having acyl chain lengths of 16 C or 18 C (palmitoyl and stearoyl).
  • Exemplary phospholipids include phosphoglycerides such as dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, and long-chain saturated phosphatidylinositols. Additional excipients are disclosed in International Patent Publication No. WO 96/32149 and U.S. Pat. Nos. 6,358,530, 6,372,258 and 6,518,239.
  • the carrier particles may be formed using one or more lipids, phospholipids or saccharides, as described herein.
  • carrier particles include one or more surfactants.
  • the use of carrier particles formed of or incorporating one or more surfactants may promote absorption of the selected active agent, thereby increasing bioavailability.
  • the carrier particles described herein, such as, for example, carrier particles formed using one or more lipids can be formed to exhibit a desired surface rugosity (roughness), which can further reduce inter-particle interactions and improve aerosolization by reducing the surface area available for particle-particle interaction.
  • a lipid that is naturally occurring in the lung could be used in forming the carrier particles, as such carrier particles that have the potential to reduce opsonization (and thereby reducing phagocytosis by alveolar macrophages), thus providing a longer- lived controlled release particle in the lung.
  • the carrier particles utilized in the compositions described herein may be selected to increase storage stability of the selected active agent, similar to that disclosed in International Patent Publication No WO 2005/000267.
  • the carrier particles my include pharmaceutically acceptable glass stabilization excipients having a Tg of at least 55° C., at least 75° C., or at least 100° C.
  • Glass formers suitable for use in compositions described herein include, but are not limited to, one or more of trileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinyl pyrrolidone, mannitol, sucrose, trehalose, lactose, and, proline. Examples of additional glass-forming excipients are disclosed in U.S. Pat. Nos. RE 37,872, 5,928,469, 6,258,341.
  • the carrier particles may be designed, sized and shaped as desired to provide desirable stability and active agent delivery characteristics.
  • the carrier particles comprise perforated microstructures as described herein. Where perforated microstructures are used as carrier particles in the compositions described herein, they may be formed using one or more excipients as described herein.
  • perforated microstructures may include at least one of the following: lipids, phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof, particularly those approved for pulmonary use.
  • perforated microstructures include poloxamer 188, poloxamer 407 and poloxamer 338.
  • Other specific surfactants include oleic acid or its alkali salts.
  • the perforated microstructures include greater than about 10% w/w surfactant.
  • carrier particles may be prepared by forming an oil-in- water emulsion, using a fluorocarbon oil (e.g., perfluorooctyl bromide, perfluorodecalin) which may be emulsified using a surfactant such as a long chain saturated phospholipid.
  • a fluorocarbon oil e.g., perfluorooctyl bromide, perfluorodecalin
  • the resulting perfluorocarbon in water emulsion may be then processed using a high pressure homogenizer to reduce the oil droplet size.
  • the perfluorocarbon emulsion may be fed into a spray dryer, optionally with an active agent solution, if it is desirable to include active agent within the matrix of the perforated microstructures.
  • Spray drying is a one-step process that converts a liquid feed to a dried particulate form.
  • Spray drying has been used to provide powdered pharmaceutical material for various administrative routes, including inhalation.
  • Operating conditions of the spray dryer (such as inlet and outlet temperature, feed rate, atomization pressure, flow rate of the drying air and nozzle configuration) can be adjusted to produce the desired particle size producing a yield of the resulting dry microstructures.
  • Such methods of producing exemplary perforated microstructures are disclosed in U.S. Pat. No. 6,309,623 to Weers et al. [0090]
  • Perforated microstructures as described herein may also be formed through lyophilization and subsequent milling or micronization.
  • Lyophilization is a freeze-drying process in which water is sublimed from the composition after it is frozen. This process allows drying without elevated temperatures.
  • the carrier particles may be produced using a spray freeze drying process, such as is disclosed in U.S. Pat. No. 5,727,333.
  • carrier particles as described herein may include bulking agents, such as polymeric particles.
  • Polymeric polymers may be formed from biocompatible and/or biodegradable polymers, copolymers or blends.
  • polymers capable of forming aerodynamically light particles may be used, such as functionalized polyester graft copolymers and biodegradable polyanhydrides.
  • bulk eroding polymers based on polyesters including poly(hydroxy acids) can be used.
  • Polygly colic acid (PGA), polyactic acid (PLA) or copolymers thereof may be used to form carrier particles.
  • the polyester may include a charged or functionalizable group, such as an amino acid.
  • carrier particles may be formed of poly(D,L- lactic acid) and/or poly(D,L-lactic-co-glycolic acid) (PLGA), which incorporate a surfactant such as DPPC.
  • polymer candidates for use in carrier particles may include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and polyvinyl esters, polymers of acrylic and methacrylic acids, celluloses and other polysaccharides, and peptides or proteins, or copolymers or blends thereof. Polymers may be selected with or modified to have the appropriate stability and degradation rates in vivo for different controlled drug delivery applications.
  • compositions described herein may include two or more species of carrier particles. Even further, compositions according to the present description can include carrier particles that include cannabinoid incorporated into the carrier particles. Where active agent is incorporated into carrier particles, the carrier particles will be of a inhalable size and can be formulated and produced using, for example, the methods and materials described herein.
  • compositions formulated according to the present teachings can inhibit degradation of active agent included therein.
  • the compositions described herein inhibit one or more of flocculation, aggregation and the solution mediated transformation of active agent material included in the compositions.
  • the pharmaceutical compositions described herein are suited for respiratory delivery via and MDI in a manner that achieves desirable delivered dose uniformity (“DDU”) of cannabinoid agents, including potent and highly potent cannabinoid agents throughout emptying of an MDI canister.
  • DDU delivered dose uniformity
  • compositions described herein can achieve a DDU for the active agent of ⁇ 30%, or better throughout emptying of an MDI canister. In one such embodiment, compositions described herein achieve a DDU for the active agent of ⁇ 25%, or better throughout emptying of an MDI canister. In yet another such embodiment, compositions described herein achieve a DDU for the active agent of ⁇ 20%, or better throughout emptying of an MDI canister.
  • compositions described herein also serve to substantially preserve FPF and FPD performance throughout emptying of an MDI canister, even after being subjected to accelerated degradation conditions.
  • compositions according to the present description maintain as much as 80%, 90%, 95%, or more, of the original FPF and FPD performance throughout emptying of an MDI canister, even after being subjected to accelerated degradation conditions.
  • Compositions described herein provide the added benefit of achieving such performance while being formulated using non-chlorofluorocarbon (non-CFC) propellants.
  • non-CFC non-chlorofluorocarbon
  • compositions described herein achieve desired one or all of a targeted DDU, FPF and FPD performance while being formulated with suspension medium including only one or more non-CFC propellants and without the need to modify the characteristics of the non-CFC propellant, such as by the addition of, for example, one or more cosolvent, antisolvent, solubilizing agent, adjuvant or other propellant modifying material.
  • a co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant; a plurality of active agent particles comprising cannabinoid including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of cannabinoid of between about 20 pg and about 150 pg per actuation of the metered dose inhaler; and a plurality of inhalable carrier particles comprising perforated microstructures as described herein exhibiting a volume median optical diameter of between about 1.5 mem and about 10 mem, wherein perforated microstructures associate with the plurality of active agent particles to form a co suspension.
  • HFA hydrofluoroalkane
  • the cannabinoid active agent particles are formed of crystalline cannabinoid material.
  • the ratio of the total mass of the carrier particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.
  • the cannabinoid active agent particles are formed of crystalline cannabinoid material and the ratio of the total mass of the carrier particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.
  • the cannabinoid active agent particles are formed of crystalline cannabinoid material, at least 90% of the cannabinoid active agent particles by volume exhibit an optical diameter of less than 7 mcm, and the ratio of the total mass of the carrier particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.
  • a co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising cannabinoid including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of cannabinoid of between about 5 pg and about 40 pg per actuation of the metered dose inhaler; and a plurality of inhalable carrier particles comprising perforated microstructures as described herein exhibiting a volume median optical diameter of between about 1.5 mcm and about 10 mcm, wherein perforated microstructures associate with the plurality of active agent particles to form a co-suspension.
  • the cannabinoid active agent particles are formed of crystalline cannabinoid material.
  • the ratio of the total mass of the carrier particles to the total mass of the active agent particles is selected from between about 3 : 1 and about 15:1 and between about 2:1 and 8:1.
  • the cannabinoid active agent particles are formed of crystalline cannabinoid material and the ratio of the total mass of the carrier particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.
  • the cannabinoid active agent particles are formed of crystalline cannabinoid material, at least 90% of the cannabinoid active agent particles by volume exhibit an optical diameter of less than 7 mcm, and the ratio of the total mass of the carrier particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.
  • Some embodiments relate to a pharmaceutical composition deliverable from a metered dose inhaler, including: a suspension medium substantially free of co solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of inhalable cannabinoid particles (CP); and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP.
  • a pharmaceutical composition deliverable from a metered dose inhaler, including: a suspension medium substantially free of co solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of inhalable cannabinoid particles (CP); and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP.
  • CP cannabinoid particles
  • ICP inhalable carrier particles
  • the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP that ranges from above 0.05:1 up to 200:1
  • Some embodiments relate to a method for treating a neurological disorder, cancer or pain in a patient, the method including: providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising: a suspension medium substantially free of cosolvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of inhalable cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP; and administering the co-suspension to the patient by actuating the metered dose inhaler at least once, wherein said administering of the co suspension composition comprises delivering a therapeutically effective amount of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids to the patient.
  • metered dose inhaler comprising a pharmaceutically acceptable co-suspension
  • the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP that ranges from above 0.05:1 up to 200:1; and administering the co suspension to the patient includes actuating the metered dose inhaler at least once, wherein the administering of the co-suspension composition comprises delivering a therapeutically effective amount of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids to the patient.
  • Other embodiments relate to a method for respiratory delivery of a cannabinoids active agent to a patient, the method comprising: providing metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium substantially free of co-solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP; and actuating the metered dose inhaler at least once to provide respiratory delivery of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids to the patient.
  • CP cannabinoid particles
  • ICP inhalable carrier particles
  • the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP that ranges from above 0.05:1 up to 200:1; and the method involves actuating the metered dose inhaler at least once to provide respiratory delivery of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids to the patient.
  • the CP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 1 pg and about 10 mg, between about 0.5 pg and about 100 pg, between about 2 pg and 5 pg, between about 2 pg and about 10 pg, between about 5 pg and about 10 pg, or between 3 pg and about 30 pg per actuation of the metered dose inhaler.
  • the CP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from up to about 30 mg, up to about 10 mg, up to about 100 pg, up to about 2.5 pg, up to about 2 pg, or up to about 1.5 pg per actuation of the metered dose inhaler.
  • the CP are included in the co-suspension in an amount sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 0.01 mg/ml and about 10 mg/ml, between about 0.01 mg/ml and about 2 mg/ml, or between about 0.03 mg/ml and about 0.4 mg/ml.
  • At least 90% of the CP by volume exhibit an optical diameter of 5 mcm or less.
  • At least 50% of the CP by volume exhibit an optical diameter of 3 mcm or less.
  • the ICP comprise perforated microstructures.
  • the perforated microstructures are prepared using a spray drying process.
  • the perforated microstructures comprise 1,2- disteroyl-sn-glycero-3-phosphocholine and calcium chloride.
  • the ICP exhibit a mass median aerodynamic diameter (MMAD) selected from between about 10 mem and about 500 nm, between about 5 mem and about 750 nm, or between about 1 mem and about 3 mem.
  • MMAD mass median aerodynamic diameter
  • the ICP exhibit a volume median optical diameter selected from between about 0.2 mem and about 50 mem, between about 0.5 mem and about 15 mem, between about 1.5 mem and about 10 mem, or between about 2 mem and about 5 mem.
  • the method includes providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising an amount of CP sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) within the co-suspension selected from between about 0.01 mg/ml and about 10 mg/ml, between about 0.01 mg/ml and about 3 mg/ml, or between about 0.03 mg/ml and about 0.4 mg/ml.
  • administering the pharmaceutically acceptable co-suspension includes administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 1 pg and about 50 pg, between about 1 pg and about 30 pg, between about 2 pg and 5 pg, between about 2 pg and about 10 pg, between about 5 pg and about 10 pg, or between 3 pg and about 30 pg per actuation.
  • administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer or solvate of cannabinoids selected from up to about 5 mg, up to about 1 mg, up to about 100 pg, up to about 5 pg, up to about 2 pg, or up to about 1 pg per actuation.
  • administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount resulting in a clinically significant decrease in pain, tumor size or anxiety.
  • actuating the metered dose inhaler to provide respiratory delivery of the cannabinoid(s) active agent includes delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids to the patient at a delivered dose uniformity (DDU) selected from a DDU of ⁇ 30%, or better, a DDU of ⁇ 25%, or better, or a DDU of ⁇ 20%, or better, throughout emptying of the canister.
  • DDU delivered dose uniformity
  • actuating the metered dose inhaler to provide respiratory delivery of the cannabinoid(s) active agent includes delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction.
  • the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction.
  • the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 0.05:1 up to 200:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 0.0:1 up to 60:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 10:1 up to 200:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 15:1 up to 60:1.
  • the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid comprises a cannabinoid salt selected from the group consisting of delta 9 THC, delta 8 THC, delta 8 THCV, delta 9 thcv, delta 10 THC and delta 10 thcv.
  • a co-suspension composition deliverable from a metered dose inhaler for pulmonary administration of a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s), the suspension composition prepared by a process including: providing a pharmaceutically acceptable propellant substantially free of cosolvents and solubilizing agents; providing inhalable cannabinoid particles (CP) comprising the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) in crystalline form; providing inhalable carrier particles (ICP), wherein the ICP are formed using a dry particulate phospholipid material that is substantially insoluble in the propellant and are free of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s); and dispersing the CP and the ICP within the pharmaceutically acceptable propellant to form a co-suspension composition.
  • CP inhalable cannabinoid particles
  • ICP inhalable carrier particles
  • the ICP are included in the suspension medium at a weight ratio of total mass of the ICP to total mass of the CP ranging from above 1:1 up to 200:1 and the ICP co-locate with the CP in the pharmaceutically acceptable propellant.
  • the weight ratio of total mass of the ICP to total mass of the CP ranges from 10:1 up to 200:1.
  • the pharmaceutically acceptable propellant comprises a hydrofluoroalkane propellant.
  • a pharmaceutical composition deliverable from a metered dose inhaler comprising: a suspension medium substantially free of co solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of inhalable cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of a cannabinoid, e.g., selected from the group consisting of Cannabidiol, Tetrahydrocannabinol, Tetrahydrocannabinolic acid, Cannabidiolic acid, Cannabidivarin and Cannabidivaric acid; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprise a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL, for example 1 mg/mL, 5 mg/m
  • a suspension medium may comprise a continuous phase. It is an advantage of the present invention that any biocompatible suspending medium having an appropriate vapor pressure to act as a propellant is used. Particularly preferred suspending media are compatible for use in metered dose inhalers. That is, they can form an aerosol upon actuation of the measurement valve and associated pressure release.
  • the selected suspending medium should be biocompatible (i.e., relatively non- toxic) and non reactive with respect to the suspended perforated microstructure containing the bioactive agent is there.
  • the suspending medium does not act as a substantial solvent for any component incorporated into the perforated microspheres.
  • Selected embodiments of the present invention are suspensions selected from the group consisting of fluorocarbons (including those substituted with other halogens), hydrofluoroalkanes, perfluorocarbons, hydrocarbons, alcohols, ethers, or combinations thereof. Contains turbid media. It will be appreciated that the suspending medium may comprise a mixture of various compounds selected to impart particular properties.
  • the suspending medium may be comprised of a propellant or propellant system that is substantially free of additional materials, including, for example, anti- solvents, solubilizing agents or co-solvents.
  • the properties of the particles in suspension or the nature of the active agents to be administered additional materials, such as, for example, one or more of the solubilizing and anti solvent agents
  • additional materials such as, for example, one or more of the solubilizing and anti solvent agents
  • co-solvents may be added, for example, to adjust the vapor pressure, stability or solubility of the suspended particles.
  • propane, ethanol, isopropyl alcohol, butane, isobutane, pentane, isopentane, or a dialkyl ether, such as dimethyl ether can be incorporated with the propellant in the suspending medium.
  • the suspending medium can contain a volatile fluorocarbon.
  • one or both of polyvinylpyrrolidone (“PVP”) or polyethylene glycol (“PEG”) can be added to the suspending medium.
  • PVP or PEG to the medium Suspension can achieve one or more desired functional characteristics, and in one example, PVP or PEG can be added to the suspension medium as an inhibitor of crystal growth.
  • up to about 1% w / w of the propellant may comprise a co-solvent or volatile builder such as a hydrocarbon or fluorocarbon.
  • the suspending medium may comprise less than about 0.01%, 0.1%, or 0.5% w / w of co-solvent or adjuvant.
  • PVP or PEG are included in the suspending medium, such components may be included up to about 1% w / w, or they may comprise less than about 0.01%, 0.1%, or 0.5% w / w of the suspending medium.
  • plural of inhalable cannabinoid particles indicates a number of inhalable cannabinoid particles greater than one.
  • non-limiting amounts in the plurality of inhalable cannabinoid particles may be 2, 10, 100, 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 or 10 10 .
  • Inhalable particles refers to particles that comprise one or more active agents and an excipient, which is at least partially in a crystalline or amorphous form, wherein the particles are of respirable size with a mean optical diameter less than 8 microns.
  • the particles may have an aerodynamic diameter in the respirable size range from 1 to 5 mem. Fine particles of this size are highly cohesive with poor bulk powder properties (e.g., poor powder flow, fluidization, and dispersibility).
  • micronized drug particles are often blended with coarse lactose monohydrate carrier particles with a geometric diameter between 50 and 200 mem. The blend forms a mixture with the fine particles adhering to the carrier, and the mixture taking on the bulk powder characteristics of the coarse carrier particles.
  • an inhalable particle comprising one or more active agents and an excipient which is at least partially in crystalline form, wherein the particle is of respirable size and is hollow.
  • the particles of the present invention consist essentially of a single or two or more active agents and an excipient.
  • Some embodiments relate to a method for treating a neurological disorder, cancer or pain in a patient, the method including: providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension including: a suspension medium substantially free of cosolvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of inhalable cannabinoid particles (CP) including a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP include a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL, for example 1 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg
  • Some embodiments relate to a method for respiratory delivery of a cannabinoid active agent to a patient, the method including: providing metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium substantially free of co-solvents and solubilizing agents and including a pharmaceutically acceptable propellant; a plurality of cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprise a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL, for example 1 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg
  • Some embodiments relate to a method for respiratory delivery of a cannabinoid active agent to a patient, the method including: administering or receiving a suspension medium substantially free of co-solvents and solubilizing agents and including a pharmaceutically acceptable propellant; a plurality of cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprise, for example, a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL, for example 1 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL and 50 mg/mL, and at
  • the CP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 1 pg and about 10 mg, between about 0.5 pg and about 400 pg, between about 2 pg and 50 pg, between about 2 pg and about 10 pg, between about 5 pg and about 10 pg, or between 3 pg and about 30 pg per actuation of the metered dose inhaler.
  • the CP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from up to about 30 mg, up to about 10 mg, up to about 100 pg, up to about 2.5 pg, up to about 2 pg, or up to about 1.5 pg per actuation of the metered dose inhaler.
  • the CP are included in the co-suspension in an amount sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 0.01 mg/ml and about 10 mg/ml, between about 0.01 mg/ml and about 2 mg/ml, or between about 0.03 mg/ml and about 0.4 mg/ml.
  • At least 70%, 80% or 90% of the CP by volume exhibit an optical diameter of 5 mem or less.
  • At least 50%, 60%, 70%, 80% or 90 of the CP by volume exhibit an optical diameter of 3 mem or less.
  • the ICP comprise perforated microstructures.
  • the perforated microstructures are prepared using a spray drying process.
  • the perforated microstructures include 1,2- disteroyl-sn-glycero-3-phosphocholine and calcium chloride.
  • the ICP exhibit a mass median aerodynamic diameter (MMAD) selected from between about 10 mem and about 500 nm, between about 5 mem and about 750 nm, or between about 1 mem and about 3 mem.
  • MMAD mass median aerodynamic diameter
  • the ICP exhibit a volume median optical diameter selected from between about 0.2 mem and about 50 mem, between about 0.5 mem and about 15 mem, between about 1.5 mem and about 10 mem, or between about 2 mem and about 5 mem.
  • providing a pharmaceutically acceptable co suspension includes providing a co-suspension comprising an amount of CP sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) within the co-suspension selected from between about 0.01 mg/ml and about 10 mg/ml, between about 0.01 mg/ml and about 3 mg/ml, or between about 0.03 mg/ml and about 0.4 mg/ml.
  • administering the pharmaceutically acceptable co suspension includes administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids selected from between about 1 pg and about 50 pg, between about 1 pg and about 30 pg, between about 2 pg and 5 pg, between about 2 pg and about 10 pg, between about 5 pg and about 10 pg, or between 3 pg and about 30 pg per actuation.
  • administering the pharmaceutically acceptable co suspension includes administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer or solvate of cannabinoids selected from up to about 5 mg, up to about 1 mg, up to about 100 pg, up to about 5 pg, up to about 2 pg, or up to about 1 pg per actuation.
  • administering the pharmaceutical composition includes administering the pharmaceutical composition in an amount resulting in a clinically significant decrease in pain, tumor size or anxiety.
  • actuating a metered dose inhaler to provide respiratory delivery of the cannabinoid(s) active agent includes delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids to the patient at a delivered dose uniformity (DDU) selected from a DDU of ⁇ 30%, or better, a DDU of ⁇ 25%, or better, or a DDU of ⁇ 20%, or better, throughout emptying of the canister.
  • DDU delivered dose uniformity
  • actuating the metered dose inhaler to provide respiratory delivery of the cannabinoid(s) active agent includes delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction.
  • the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction.
  • the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 0.05:1 up to 200:1, for example 0.05:1, 0.5:1, 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 75:1, 100:1, 125:1, 150:1, 175:1 and 200:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 0.0:1 up to 60:1, for example 0.1:1, 0.5:1, 2:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1 and 60:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 10:1 up to 200:1, for example 10:1, 20:1, 30:1, 40:1, 50:1, 75:1, 100:1, 125:1, 150:1, 175:1 and 200:1.
  • the ICP are included in the suspension medium at a weight ratio of total mass of ICP to total mass of CP that ranges from 15:1 up to 60:1, for example 15:1, 20:1, 30:1, 40:1, 50:1 and 60:1.
  • the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid includes a cannabinoid salt selected from the group consisting of delta-9-tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), delta-8- tetrahydrocannabinol (D8THC), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), tetrahydrocannabinovarin (THCV), tetrahydrocannabinovarinic acid (THCV A), cannabidivarin (CBDV), cannabidivarin acid (CBDVA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabinodiol (THC), tetra
  • Some embodiments relate to a co-suspension composition deliverable from a metered dose inhaler for pulmonary administration of a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s), the suspension composition prepared by a process including: providing a pharmaceutically acceptable propellant substantially free of cosolvents and solubilizing agents; providing inhalable cannabinoid particles (CP) including the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) in crystalline form; providing inhalable carrier particles (ICP), wherein the ICP are formed using a dry particulate phospholipid material that is substantially insoluble in the propellant and are free of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s); and dispersing the CP and the ICP within the pharmaceutically acceptable propellant to form a co-suspension composition wherein the ICP are included in the suspension medium at a weight ratio of total mass of the
  • any of the methods herein can involve simply administering the solutions provided herein, and thus, need not also include providing an inhaler itself or a canister itself, etc.
  • the weight ratio of total mass of the ICP to total mass of the CP ranges from 10:1, 20:1, 30:1, 40:1, 50:1, 75:1, 100:1, 125:1, 150:1, 175:1 and 200:1.
  • the pharmaceutically acceptable propellant includes a hydrofluoroalkane propellant.
  • compositions including: a cannabinoid, a phospholipid, and a pharmaceutically acceptable propellant, wherein the cannabinoid, the phospholipid and the pharmaceutically acceptable propellant are in solution.
  • any of the methods herein can involve simply administering the composition(s) provided herein, and thus, need not also include providing an inhaler itself or a canister itself, etc.
  • the cannabinoid is selected from the group consisting of Cannabidiol, Tetrahydrocannabinol, Tetrahydrocannabinolic acid, Cannabidiolic acid, Cannabidivarin and Cannabidivaric acid.
  • the phospholipid has a gel to liquid crystal phase transition of greater than about 40°C.
  • the phospholipid is a C16-C22 saturated lipid.
  • the phospholipid is selected from the group consisting of a phosphoglyceride, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerol, a short-chain phosphatidylcholines, a long-chain saturated phosphatidylethanolamine, long-chain saturated phosphatidylserine, long-chain saturated phosphatidylglycerol, and long-chain saturated phosphatidylinositol.
  • the pharmaceutically acceptable propellant include a hydrofluoroalkane propellant.
  • the plurality of inhalable carrier particles (ICP) include a fat.
  • the fat is a phospholipid.
  • the plurality of inhalable carrier particles (ICP) include a sugar.
  • the plurality of inhalable carrier particles (ICP) are part of an emulsion.
  • the plurality of inhalable carrier particles (ICP) include a surfactant.
  • compositions contained within a metered dose inhaler including: a) a suspension medium substantially free of co-solvents and solubilizing agents and including a pharmaceutically acceptable propellant.
  • the composition can further include b) a plurality of inhalable cannabinoid particles (CP) including: a pharmaceutically acceptable salt, ester, isomer, or solvate of a cannabinoid selected from the group consisting of Cannabidiol, Tetrahydrocannabinol, Tetrahydrocannabinolic acid, Cannabidiolic acid, Cannabidivarin and Cannabidivaric acid; wherein an amount of the CP is sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) from between about 0.03 mg/ml and about 0.4 mg/ml, and wherein the CP is in crystalline form.
  • CP cannabinoid particles
  • the composition can further include c) a plurality of inhalable carrier particles (ICP), wherein the ICP comprises a dry particulate phospholipid material that is substantially insoluble in the suspension medium, wherein the dry particular phospholipid comprises a C16-C22 saturated lipid, wherein the phospholipid has a gel to liquid crystal phase transition of greater than about 40°C; and a sugar, wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL, for example 1 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL and 50 mg/mL, and at a weight ratio of total mass of ICP to total mass of CP that ranges from above 0.05:1 up to 200:1, for example, 0.05:1, 0.5:1, 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 75:
  • the ICP are part of an emulsion, the ICP exhibit a mass median aerodynamic diameter (MMAD) from about 1 mem and about 3 mem.
  • the composition can further include: d) a surfactant; and e) a hydrofluoroalkane propellant.
  • an MDI system includes a pressurized, liquid phase formulation-filled canister disposed in an actuator formed with a mouthpiece.
  • the MDI system may include the formulations described herein, which include a suspension medium, cannabinoid and at least one species of carrier particles.
  • the canister used in the MDI be any of any suitable configuration, and in one exemplary embodiment, the canister may have a volume ranging from about 3 mL to about 25 mL, such as, for example a canister having a 19 mL volume.
  • a metering valve including a metering chamber capable of holding a defined volume of the formulation (e.g., 63 pi or any other suitable volume available in commercially available metering valves), which is released into an expansion chamber at the distal end of the valve stem when actuated.
  • the actuator retains the canister and may also include a port with an actuator nozzle for receiving the valve stem of the metering valve. When actuated, the specified volume of formulation travels to the expansion chamber, out the actuator nozzle and into a high-velocity spray that is drawn into the lungs of a patient.
  • a teaching that two elements are combined in a claimed combination is further to be understood as also allowing for a claimed combination in which the two elements are not combined with each other, but may be used alone or combined in other combinations.
  • the excision of any disclosed element of the embodiments is explicitly contemplated as within the scope of the embodiments.
  • the present example outlines a method for respiratory delivery of a cannabinoid active agent to a patient.
  • One first identifies a patient having a neurological disorder.
  • One then administers the compound to the patient via a MDI.
  • One provides a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co suspension comprising: a suspension medium substantially free of co-solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprises a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP that
  • the present example outlines a method for respiratory delivery of a cannabinoid active agent to a patient.
  • One first identifies a patient having cancer.
  • One then administers the compound to the patient via a MDI.
  • One provides a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium substantially free of co-solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprises a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP
  • the present example outlines a method for respiratory delivery of a cannabinoid active agent to a patient.
  • One first identifies a patient having pain.
  • One then administers the compound to the patient via a MDI.
  • One provides a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium substantially free of co-solvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of cannabinoid particles (CP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoids; and a plurality of inhalable carrier particles (ICP) formed separately from the plurality of CP, wherein the ICP comprises a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the ICP are present in the suspension medium at a concentration of up to about 50 mg/mL and at a weight ratio of total mass of ICP to total mass of CP
  • the present example outlines a method of preparing for respiratory delivery a cannabinoid active agent.
  • the process includes providing a pharmaceutically acceptable propellant substantially free of cosolvents and solubilizing agents.
  • the process further includes providing inhalable cannabinoid particles (CP) including the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s) in crystalline form; providing inhalable carrier particles (ICP).
  • CP cannabinoid particles
  • ICP inhalable carrier particles
  • the ICP are formed using a dry particulate phospholipid material that is substantially insoluble in the propellant and are free of the pharmaceutically acceptable salt, ester, isomer, or solvate of cannabinoid(s).
  • the process further includes dispersing the CP and the ICP within the pharmaceutically acceptable propellant to form a co-suspension composition wherein the ICP are included in the suspension medium at a weight ratio of total mass of the ICP to total mass of the CP ranging from above 1:1 up to 200:1 and the ICP co-locate with the CP in the pharmaceutically acceptable propellant.
  • the present example outlines a method for respiratory delivery of a cannabinoid active agent to a patient.
  • One first identifies a patient having a medical condition, such as cancer, pain or a neurological disorder.

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Abstract

L'invention concerne une composition pharmaceutique pouvant être administrée depuis un aérosol-doseur, comprenant un milieu de suspension sensiblement exempt de co-solvants et d'agents solubilisants et comprenant un agent propulseur pharmaceutiquement acceptable ; une pluralité de particules cannabinoïdes (CP) pouvant être inhalées comprenant un sel, un ester, un isomère ou un solvate pharmaceutiquement acceptables d'un cannabinoïde choisi dans le groupe constitué du delta-9-tétrahydrocannabinol (THC), de l'acide tétrahydrocannabinolique (THCA), du delta-8-tétrahydrocannabinol (D8THC), du cannabidiol (CBD), de l'acide cannabidiolique (CBDA), du cannabinol (CBN), de l'acide cannabinolique (CBNA), de la tétrahydrocannabinovarine (THCV), de l'acide tétrahydrocannabinovarinique (THCVA), de la cannabidivarine (CBDV), de l'acide cannabidivarinique (CBDVA), du cannabigérol (CBG), de l'acide cannabigérolique (CBGA), du cannabichromène (CBC), de l'acide cannabichroménique (CBCA), du cannabinodiol (CBND), et de l'acide cannabinodiolique (CBNDA) ; et une pluralité de particules porteuses pouvant être inhalées (ICP) formées séparément de la pluralité de CP, et des méthodes de traitement d'un trouble neurologique, d'un cancer ou d'une douleur chez un patient.
PCT/US2020/054609 2019-10-09 2020-10-07 Compositions permettant l'administration par voie pulmonaire de cannabinoïdes, méthodes et systèmes associés WO2021071967A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117357485A (zh) * 2023-11-01 2024-01-09 山东京卫制药有限公司 一种改良的可吸入的载体颗粒及应用
US11992497B2 (en) 2021-08-04 2024-05-28 Demeetra Agbio, Inc. Cannabinoid derivatives and their use

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027359A1 (fr) * 1998-11-12 2000-05-18 Pilkiewicz Frank G Systeme d'inhalation
US20050079136A1 (en) * 2001-07-10 2005-04-14 Woolfe Austen John Aerosol formulations of delta tetrahydrocannabinol
WO2006133941A2 (fr) * 2005-06-16 2006-12-21 Euro-Celtique S.A. Ingredient pharmaceutique actif a base de cannabinoides pour formes posologiques ameliorees
WO2012158166A1 (fr) * 2011-05-17 2012-11-22 Pearl Therapeutics, Inc. Compositions, procédés et systèmes d'administration par voie respiratoire d'au moins deux agents actifs
WO2012174559A1 (fr) * 2011-06-17 2012-12-20 Berg Pharma Llc Compositions pharmaceutiques inhalables
US20150136130A1 (en) * 2012-02-29 2015-05-21 Pulmatrix, Inc. Inhalable dry powders
US20170209409A1 (en) * 2014-06-26 2017-07-27 Island Breeze Systems Ca, Llc Mdi related products and methods of use
US20180140787A1 (en) * 2015-05-21 2018-05-24 Island Breeze Systems Ca, Llc Propellant based metered dose inhaler and food applicators and applicators

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027359A1 (fr) * 1998-11-12 2000-05-18 Pilkiewicz Frank G Systeme d'inhalation
US20050079136A1 (en) * 2001-07-10 2005-04-14 Woolfe Austen John Aerosol formulations of delta tetrahydrocannabinol
WO2006133941A2 (fr) * 2005-06-16 2006-12-21 Euro-Celtique S.A. Ingredient pharmaceutique actif a base de cannabinoides pour formes posologiques ameliorees
WO2012158166A1 (fr) * 2011-05-17 2012-11-22 Pearl Therapeutics, Inc. Compositions, procédés et systèmes d'administration par voie respiratoire d'au moins deux agents actifs
WO2012174559A1 (fr) * 2011-06-17 2012-12-20 Berg Pharma Llc Compositions pharmaceutiques inhalables
US20150136130A1 (en) * 2012-02-29 2015-05-21 Pulmatrix, Inc. Inhalable dry powders
US20170209409A1 (en) * 2014-06-26 2017-07-27 Island Breeze Systems Ca, Llc Mdi related products and methods of use
US20180140787A1 (en) * 2015-05-21 2018-05-24 Island Breeze Systems Ca, Llc Propellant based metered dose inhaler and food applicators and applicators

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11992497B2 (en) 2021-08-04 2024-05-28 Demeetra Agbio, Inc. Cannabinoid derivatives and their use
CN117357485A (zh) * 2023-11-01 2024-01-09 山东京卫制药有限公司 一种改良的可吸入的载体颗粒及应用

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