EP4673113A1 - Inhalateurs doseurs et solutions comprenant des cannabinoïdes dans hfo-1234ze(e) - Google Patents

Inhalateurs doseurs et solutions comprenant des cannabinoïdes dans hfo-1234ze(e)

Info

Publication number
EP4673113A1
EP4673113A1 EP24715376.0A EP24715376A EP4673113A1 EP 4673113 A1 EP4673113 A1 EP 4673113A1 EP 24715376 A EP24715376 A EP 24715376A EP 4673113 A1 EP4673113 A1 EP 4673113A1
Authority
EP
European Patent Office
Prior art keywords
metered dose
dose inhaler
formulation
actuation
ethanol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24715376.0A
Other languages
German (de)
English (en)
Inventor
Philip COCKS
Sarah WRIGGLESWORTH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Breath Of Life International Ltd
Kindeva Drug Delivery LP
Original Assignee
Breath Of Life International Ltd
Kindeva Drug Delivery LP
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Breath Of Life International Ltd, Kindeva Drug Delivery LP filed Critical Breath Of Life International Ltd
Publication of EP4673113A1 publication Critical patent/EP4673113A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • 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

Definitions

  • Metered dose inhalers are familiar to many patients who suffer from asthma or chronic obstructive pulmonary disease (COPD).
  • Metered dose inhaler devices can include an aluminum canister, sealed with a metering valve, that contains a medicament formulation.
  • a typical current medicament formulation includes one or more medicinal compounds present in a liquefied hydrofluoroalkane (HF A) propellant.
  • HF A liquefied hydrofluoroalkane
  • Cannabinoids are the main active component of cannabis and are known to have various neurological effects.
  • a cannabinoid may be combined with a liquified propellant to prepare a formulation to be delivered using a metered dose inhaler.
  • CFCs chlorofluorocarbons
  • HF As hydrofluoroalkanes
  • HFA- 134a also called HFC-134a, R-134a, or norflurane (CF3CH2F, 1,1,1,2-tetrafluoroethane) and HFA-227, also called HFC-227, FM-200, or apaflurane (CF3CHFCHF3, 1,1, 1,2, 3, 3, 3 -heptafluoropropane) having stated 100-year GWP values of 1300 to 1430 and 3220 to 3350, respectively.
  • norflurane CF3CH2F, 1,1,1,2-tetrafluoroethane
  • HFA-227 also called HFC-227, FM-200
  • apaflurane CF3CHFCHF3, 1,1, 1,2, 3, 3, 3 -heptafluoropropane
  • HFOs hydrofluoroolefins
  • CO2 carbon dioxide
  • HFO-1234ze(E)’s differences from other pMDI propellants, a practical pMDI can be made using HFO-1234ze(E).
  • One advantage of such pMDIs is HFO-1234ze(E)’s stated GWP of less than 1.
  • a pMDI (also referred to herein as an MDI or a metered dose inhaler) that includes: a metering valve; a canister; and an actuator that includes an actuator nozzle; wherein the canister includes a formulation (i.e., a composition), the formulation including a propellant including HFO-1234ze(E), at least 1% of ethanol by weight, and one or more cannabinoids; and wherein the one or more cannabinoids is dissolved in the formulation to form a solution.
  • the one or more cannabinoids includes tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof.
  • a pMDI in one embodiment, includes: a metering valve; a canister; and an actuator that includes an actuator nozzle; wherein the canister includes a formulation, the formulation including a propellant including HFO-1234ze(E), at least 1% of ethanol by weight, and CBD; and wherein the CBD is dissolved in the formulation to form a solution.
  • a pMDI is provided that includes: a metering valve; a canister; and an actuator that includes an actuator nozzle; wherein the canister includes a formulation, the formulation including a propellant including HFO-1234ze(E), at least 1% of ethanol by weight, and THC; and wherein the THC is dissolved in the formulation to form a solution.
  • dissolved in the formulation or “dissolved in the composition” means that the recited components (e g., cannabinoids) are dissolved in the propellant, or dissolved in the propellant and other components such as a cosolvent, to form a solution.
  • the recited components e g., cannabinoids
  • the term “comprises” and variations thereof do not have a limiting meaning where these terms appear in the description and claims. Such terms will be understood to imply the inclusion of a stated step or element, or group of steps or elements, but not the exclusion of any other step or element, or group of steps or elements.
  • the phrase “consisting of’ means including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present.
  • the phrase “consisting essentially of’ means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements.
  • the phrase “consisting essentially of’ indicates that the listed elements are required or mandatory, but that other elements are optional and may, or may not, be present depending upon whether or not they materially affect the activity or action of the listed elements.
  • ambient conditions refers to an environment of room temperature (approximately 20 °C to 25 °C) and 30% to 60% relative humidity.
  • Numerical ranges for example “between x and y” or “from x to y”, include the endpoint values of x and y. Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range as well as the endpoints (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
  • FIG. l is a cross-sectional side view of an inhaler including a canister containing a valve according to the present disclosure.
  • FIG. 2 is a detailed cross-sectional side view of the inhaler of FIG. 1.
  • FIG. 3 is a cross-sectional side view of a metering valve for an inhaler.
  • the formulations described herein include one or more cannabinoids.
  • Cannabinoids are psychoactive compounds and are the main psychoactive component of cannabis.
  • the medicinal properties of cannabinoids have been known for many years including their use for treating or alleviating chronic pain, seizures, arthritis, nausea, neurodegenerative diseases, such as multiple sclerosis, cancer and HIV. They may also be effective as bronchodilators in the treatment of asthma and COPD.
  • bronchodilators in the treatment of asthma and COPD.
  • the less desirable effects including the psychotropic effects and the risk of diseases such as cancer if the cannabinoids are inhaled by smoking.
  • metered dose inhalers such as pressurized metered dose inhalers (pMDIs)
  • pMDIs pressurized metered dose inhalers
  • the cannabinoid is dissolved in a liquefied propellant and optional cosolvent and stored in a pressurized container, such as a pMDI canister.
  • the container is then coupled to a suitable delivery device which typically includes a mouthpiece, a nozzle, and a valve assembly. Actuation of the valve assembly releases a dose of the cannabinoid/propellant mixture from the container that is then dispensed from the nozzle into the mouthpiece where it can be inhaled.
  • Cannabinoid as used herein encompasses naturally occurring as well as synthetic and semi -synthetic cannabinoids.
  • Cannabinoids may naturally exist in plants in the family Cannabaceae and extracts derived therefrom, such as hemp oil.
  • Cannabaceae plants that may naturally produce cannabinoids include Cannabis indica, Cannabis sativa, and Cannabis ruderalis.
  • Cannabinoids may be derived from wild-type Cannabaceae plants or genetically modified variants thereof, such as those generated from genetic crosses, self-crosses, or hybridization.
  • Variants may include varieties characterized by chemical composition that naturally contain different amounts of the individual cannabinoids, such as cannabis chemovars, or Cannabis sativa subspecies indica including the variants var. indica and var. kafiristanica.
  • Suitable cannabinoids include phytocannabinoids, which can be isolated from plants to produce highly purified extract or can be reproduced synthetically, e.g., tetrahydrocannabinols (THC), cannabidiol (CBD), cannabigerols (CBG), cannabi chromenes (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabielsoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabitriol (CBT), and cannabinol (CBN).
  • THC tetrahydrocannabinols
  • CBD cannabidiol
  • CBG cannabigerols
  • CBC cannabi chromenes
  • CBD cannabinol
  • CBN cannabinodiol
  • CBDL cannabicyclol
  • Highly purified cannabinoid extracts are also included and defined as cannabinoids that have been extracted from the cannabis plant and purified (to the extent that other cannabinoids and non-cannabinoid components that are coextracted with the target cannabinoids have been substantially removed).
  • Highly purified cannabinoid extracts can include at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of cannabinoid.
  • Suitable synthetic cannabinoids are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than extracted from plants.
  • Synthetic cannabinoids include cannabinoids structurally related to tetrahydrocannabinol (THC), cannabimimetics, and eicosanoids. More particular examples of synthetic cannabinoids for use in the present disclosure include nabilone, rimonabant, cannabicyclohexanol, JHW-018, JWH-073, and HU-210.
  • Tetrahydrocannabinol (THC, C21H30O2) refers to two isomers, A-8-THC ((6aR, 10aR)-6,6,9- trimethyl-3-pentyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-l-ol) and A-9-THC ((6aR,10aR)- 6,6,9-trimethyl-3-pentyl-6a,7,8, 10a-tetrahydro-6H-benzo[c]chromen-l-ol).
  • the formulations described as including THC herein may include A-9-THC and/or A-8-THC.
  • THC is typically known for its psychoactive effects, but is also used in the treatment of pain, chronic diseases such as multiple sclerosis, and as an appetite stimulant.
  • CBD Cannabidiol
  • 2-[(lR,6R)-6-Isopropenyl-3-methylcyclohex-2-en-l-yl]- 5-pentylbenzene-l,3-diol is another cannabinoid of interest. While there is limited evidence for the clinical efficacy of CBD, there is nonetheless interest in its use in managing neurological disorders. Unlike THC, CBD does not typically have psychoactive effects, and is thus generally less governmentally regulated.
  • WPE Whole plant extract
  • the starting material of CBD and THC drug substances is the extract from the dried, ground and decarboxylated cannabis flowers which is prepared with super critical carbon dioxide to yield WPE used to manufacture the CBD and THC drug substances.
  • the materials and solvents used in the manufacturing processes of the drug substances are commonly used materials suitable for their intended purpose, purchased from reputable and controlled suppliers in compliance with predetermined quality standards.
  • the cannabinoids of the present disclosure may be prepared using any suitable method, such as pharmaceutical grade, commercial-scale extraction methods.
  • ICH International Council for Harmonization
  • R7 guideline for residual solvents which are allowed in low levels as impurities in pharmaceutical products or “Q6A guideline” for Dronabinol.
  • relevant test methods include USP ⁇ 1111>, USP ⁇ 921>, USP ⁇ 467>, USP ⁇ 61>, USP ⁇ 62> and USP ⁇ 281>.
  • the extraction method may be from any “plant material” as well as exudates.
  • Plant material as used herein includes plants, plant parts (e.g., bark, leaves, stems, roots, flowers, fruit, seeds), herbal cannabis, dried cannabis biomass, or cannabis flowers.
  • the plant material may be decarboxylated cannabis plant material, used herein to refer to cannabis plant material which has been subject to a decarboxylation step.
  • Exudates include material falling within the definition of "botanical raw material” in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research.
  • the extraction method may involve single or multiple-step extraction and chromatographic purification and may include the methods that have been disclosed in U.S. Patent No. 7,344,736 (Whittle et al.) and PCT Application Publication No. WO2018/167038 (Vorobjov et al.).
  • Typical methods include extracting cannabinoids from cannabis plant material using an extractor with super critical, critical or near-critical fluids such as carbon dioxide, nitrous oxide, ethylene, ethane, propane or chlorodifluoromethane.
  • supercritical carbon dioxide is used, which behaves like an organic solvent with the solubilization characteristics of a liquid and the permeabilization characteristics of a gas.
  • the formulations described herein include CBD and do not include a substantial amount of THC. In one or more embodiments, the formulations described herein include THC and do not include a substantial amount of CBD. In certain other situations, it may be desirable to provide a formulation including more than one cannabinoid, such as THC and CBD. In one or more embodiments, the formulations described herein include both THC and CBD. It is understood that the ratio of THC to CBD in any particular formulation may be varied to balance the psychotropic and therapeutic effects of the formulation.
  • the ratio between cannabinoids may be controlled.
  • the ratio of THC to CBD may be, for example, at least 1 : 1 by weight, at least 1 :2 by weight, at least 1 :3 by weight, at least 1 :4 by weight, at least 1 :5 by weight, at least 1 :6 by weight, at least 1 :7 by weight, at least 1 :8 by weight, at least 1 : 10 by weight, at least 1 : 12 by weight, at least 1 :14 by weight, at least 1 : 16 by weight, at least 1 :18 by weight, or at least 1 :20 by weight.
  • the ratio of THC to CBD may be, for example, at most 20: 1 by weight, at most 18: 1 by weight, at most 16: 1 by weight, at most 14: 1 by weight, at most 12: 1 by weight, at most 10:1 by weight, at most 8: 1 by weight, at most 7: 1 by weight, at most 6: 1 by weight, at most 5 : 1 by weight, at most 4: 1 by weight, at most 3 : 1 by weight, or at most 1 : 1 by weight.
  • the ratio of THC to CBD may be, for example, from 1 :20 to 20: 1, such as from 1 :8 to 8: 1, such as from 1 :4 to 4: 1, such as 1 :1.
  • the ratio of THC to CBD in a formulation that includes both THC and CBD may be expressed as a molar ratio.
  • the cannabinoid may be provided in any form suitable for formulation as a solution.
  • the cannabinoid may be provided as a solid, such as a powder or a micronized powder, a resin, a semi-solid, or as a liquid, such as a stock solution. Any suitable form of cannabinoid compatible with preparation of a solution may be used for the formulations of the present disclosure.
  • the cannabinoid is dissolved in the formulations described herein to form a solution.
  • cannabidiol is typically a white, crystalline powder, stored in room temperature in sealed aluminum bags to limit exposure to air and light.
  • Pharmaceutical grade delta 9 tetrahydrocannabinol is a transparent, amber viscous liquid, typically stored at a temperature of approximately -20 °C or a temperature of 2 °C to 8 °C.
  • the delta 9 tetrahydrocannabinol is typically stored with argon atmosphere, in sealed amber glass vials, having limited exposure to light.
  • the formulations of the present disclosure are solutions (i.e., solution formulations or solution compositions). That is, the formulations include one or more cannabinoids dissolved in the formulations (i.e., solubilized in the propellant, cosolvent, and optional other components) to form solutions.
  • a “solution” is a homogeneous solution that does not have particulate material visible to the unaided human eye.
  • the stability of a solution across a range of temperatures may be a factor to consider when selecting a formulation for a metered dose inhaler.
  • the components of solution formulations described herein may remain dissolved at a temperature of at least 25 °C, at least 20 °C, at least 15 °C, at least 10 °C, at least 9 °C, at least 8 °C, at least 7 °C, at least 6 °C, at least 5 °C, at least 4 °C, at least 3 °C, at least 2 °C, at least 1 °C, or at least 0 °C.
  • Solution and suspension formulations are fundamentally different metered dose inhaler formulation approaches. Different factors need to be considered when undertaking the development of products using either of these formulation approaches. Accordingly, it is not possible to apply the same knowledge and understanding of suspension formulations to solution formulations.
  • solubility of the active pharmaceutical ingredient (API) in the propellant, and optional cosolvent is a key consideration.
  • Various strategies can be used to improve solubility via use of additional excipients such as polyethylene glycol or water.
  • solutions give smaller aerosol particle size distributions than suspensions and are generally more efficient than suspensions, but the overall dose may be limited due to the amount of API that can be solubilized.
  • the primary propellant of the composition (i.e., formulations) described herein is HFO- 1234ze(E), also known as trans- 1,1,1,3-tetrafluoropropene, trans-l,3,3,3-tetrafluoropropene, or trans-l,3,3.3-tetrafluoroprop-l-ene.
  • HFO- 1234ze(E) also known as trans- 1,1,1,3-tetrafluoropropene, trans-l,3,3,3-tetrafluoropropene, or trans-l,3,3.3-tetrafluoroprop-l-ene.
  • trans and cis isomers of HFO- 1234ze are very different. As a result, these isomers have very different physical and thermodynamic properties.
  • trans (E) isomer The significantly lower boiling point and higher vapor pressure of the trans (E) isomer relative to that of the cis (Z) isomer, at ambient conditions, makes the trans isomer a far more thermodynamically suitable propellant for achieving efficient pMDI atomization.
  • the amount of HFO-1234ze(E) by weight in the formulation is at least 50%, greater than 50%, at least 60%, greater than 60%, at least 70%, greater than 70%, at least 80%, greater than 80%, at least 85%, greater than 85%, at least 90%, or greater than 90%. In one or more embodiments, the amount of HFO-1234ze(E) by weight is between 50% and 99%, between 55% and 95%, between 60% and 90%, or between 70% and 80%. In one or more embodiments, HFO-1234ze(E) is the sole propellant in the formulation. That is, the pharmaceutical product performance parameters, such as emitted dose and emitted particle size distribution, are not significantly different than if HFO-1234ze(E) were the sole propellant in the formulation.
  • the propellant HFO-1234ze(E) is very different from other propellants, including propellants HFA-227, HFA-134a, and the low GWP propellant HFA-152a.
  • These propellants have different physical, chemical, and thermodynamic properties such as boiling point, vapor pressure, water solubility, liquid density, and surface tension. The differences in these properties make replacing one propellant with another without significantly compromising or altering pMDI product performance difficult to achieve.
  • the thermodynamic differences in propellant boiling point and vapor pressure can significantly affect pMDI aerosolization efficiency and give rise to differences in primary and secondary atomization mechanisms. Differences in dipole moment and polarity between the propellants can affect the solubility of APIs and excipients in the formulation.
  • Differences in hygroscopicity between the propellants can affect moisture uptake, which could be problematic for solution formulations, particularly if physical stability due to moisture uptake or chemical degradation in which water is involved is likely.
  • Chemical interactions of the different propellants with APIs and excipients may also be significantly different, which could affect the long-term chemical stability of the product over the intended shelf life.
  • Different propellants interact chemically and physically with valve plastics and elastomeric components, which could give rise to differences in the types and amounts of extractables and leachables, as well as impact mechanical valve function.
  • the thermodynamic properties of the propellants can give rise to different droplet particle sizes due to different evaporation rates and can also result in differences in spray characteristics such as spray force, temperature, and spray duration.
  • the total amount of formulation is desirably selected so that at least a portion of the propellant in the canister is present as a liquid after a predetermined number of medicinal doses have been delivered.
  • the predetermined number of doses may be 5 doses to 300 doses, 30 doses to 200 doses, 60 doses to 200 doses, 60 doses to 120 doses, 60 doses, 120 doses, 200 doses, or any other number of doses.
  • the total amount of formulation in the canister may be from 1.0 grams (g) to 30.0 g, 2.0 g to 20.0 g, or 5.0 g to 15.0 g.
  • the total amount of formulation is typically selected to be greater than the product of the predetermined number of doses and the metering volume of the metering valve.
  • the total amount of formulation is greater than 1.1 times, greater than 1.2 times, greater than 1.3 times, greater than 1.4 times, or greater than 1.5 times the product of the predetermined number of doses and the metering volume of the metering valve. This typically ensures that the amount of each dose remains relatively constant through the life of the inhaler.
  • the formulation may include one or more additional APIs.
  • Cannabinoids are effective in the treatment of many conditions, and the efficacy of treatment may be improved when cannabinoids are co-administered with an additional API.
  • Exemplary APIs can include those for the treatment of respiratory disorders, e.g., a bronchodilator, such as a short- or long-acting beta agonist, an anti-inflammatory (e.g., a corticosteroid), an anti-allergic, an anti-asthmatic, an antihistamine, a TYK inhibitor, an anesthetic, or an anticholinergic agent.
  • Exemplary APIs can include terbutaline, ipratropium, oxitropium, tiotropium, beclomethasone, flunisolide, ciclesonide, cromolyn sodium, nedocromil sodium, ketotifen, azelastine, ergotamine, cyclosporine, aclidinium, umeclidinium, glycopyrronium (i.e., glycopyrrolate), salmeterol, formoterol, procaterol, indacaterol, carmoterol, milveterol, olodaterol, vilanterol, abediterol, omalizumab, zileuton, insulin, pentamidine, calcitonin, leuprolide, alpha-I-antitrypsin, interferon, triamcinolone, nintedanib, lidocaine, a pharmaceutically acceptable salt or ester of any of the listed APIs, or a mixture of any of the listed APIs, their pharmaceutical
  • the API(s) are dissolved in the formulation (i.e., as a solution). In the event that a combination of two or more APIs are used, all of the APIs are in solution.
  • the amount of cannabinoid delivered may be determined by the required dose per actuation and the pMDI metering valve size, that is, the size of the metering chamber, which may be between 5 microliters (pL or mcl) and 200 microliters, between 25 microliters and 200 microliters, between 25 microliters and 150 microliters, between 25 microliters and 100 microliters, between 50 microliters and 100 microliters, between 25 microliters and 65 microliters, between 50 microliters and 65 microliters, or between 50 microliters and 63 microliters.
  • the dose delivered by a metered dose inhaler may be expressed as the amount of cannabinoid that exits the actuator with each actuation (also referred to herein as the "ex-actuator" dose).
  • This amount refers to the amount of cannabinoid that exits the nozzle, which may be substantially similar to the amount of cannabinoid delivered to a subject.
  • the dose delivered by a metered dose inhaler may additionally or alternately be expressed as the amount of cannabinoid that exits the inhaler valve with each actuation.
  • the amount of API that exits the inhaler valve and the amount of API that exits the nozzle may or may not be substantially similar.
  • typical formulations of the present disclosure include the cannabinoid in an amount of at least 0.05 milligram per actuation (mg/actuation), or at least 0.5 mg/actuation. In certain embodiments, formulations of the present disclosure include the cannabinoid in an amount of less than 6.0 mg/actuation.
  • typical formulations of the present disclosure include the cannabinoid in an amount of at least 0.05 mg/actuation, at least 0.075 mg/actuation, at least 0.1 mg/actuation, at least 0.2 mg/actuation, at least 0.3 mg/actuation, at least 0.4 mg/actuation, at least 0.5 mg/actuation, at least 0.75 mg/actuation, at least 1.0 mg/actuation, at least 1.5 mg/actuation, at least 2.0 mg/actuation, at least 3.0 mg/actuation, or at least 4.0 mg/actuation.
  • typical formulations of the present disclosure include the cannabinoid in an amount of less than 6.0 mg/actuation, at most 5.0 mg/actuation, at most 4.0 mg/actuation, at most 3.0 mg/actuation, at most 2.0 mg/actuation, at most 1.5 mg/actuation, or at most 1 .0 mg/actuation.
  • formulations of the present disclosure include the cannabinoid in an amount of 0.05 mg/actuation to 6.0 mg/actuation, such as 0.1 mg/actuation to 5.0 mg/actuation, 0.5 mg/actuation to 1.5 mg/actuation, or 1.0 mg/actuation to 3.0 mg/actuation.
  • the amount of cannabinoid delivered by a metered dose inhaler may depend on the composition of cannabinoid(s) in the formulation.
  • a formulation including only CBD may include an amount of CBD such that from 0.05 mg/actuation to 6.0 mg/actuation, such as from 0.5 mg/actuation to 3.0 mg/actuation, or from 0.5 mg/actuation to 1.5 mg/actuation is delivered.
  • a formulation including only THC may include an amount of THC such that from 0.2 mg/actuation to 6.0 mg/actuation, such as from 0.5 mg/actuation to 3.0 mg/actuation, such as 0.5 mg/actuation to 1.5 mg/actuation is delivered.
  • a formulation including both THC and CBD may include an amount of THC and CBD such that 0.05 mg/actuation to 6.0 mg/actuation of each of THC and CBD is delivered. In some embodiments, a total of 0.05 mg/actuation to 6.0 mg/actuation of combined THC and CBD is delivered.
  • the amount of cannabinoid delivered by a metered dose inhaler is the result of a specific combination of multiple elements, including the concentration of cannabinoid in the formulation, the size of the actuator used, and the volume of the valve. Each of these metrics must be carefully considered when selecting an amount of cannabinoid to be delivered with each metered dose inhaler actuation.
  • the concentration of cannabinoid may be described by the weight percentage of cannabinoid in the complete formulation.
  • the formulation may include at least 0.5 mg/mL, at least 1.0 mg/mL, at least 1.5 mg/mL, at least 2.0 mg/mL, at least 2.5 mg/mL, at least 3.0 mg/mL, at least 3.5 mg/mL, at least 4.0 mg/mL, at least 5.0 mg/mL, at least 6.0 mg/mL, at least 7.0 mg/mL, at least 8.0 mg/mL, at least 9.0 mg/mL, at least 10 mg/mL, at least 12 mg/mL, at least 14 mg/mL, at least 15 mg/mL, at least 16 mg/mL, at least 17 mg/mL, at least
  • 60 mg/mL at least 65 mg/mL, at least 70 mg/mL, at least 75 mg/mL, at least 80 mg/mL, at least
  • At least 90 mg/mL at least 95 mg/mL, at least 100 mg/mL, at least 110 mg/mL, at least 120 mg/mL, at least 130 mg/mL, at least 140 mg/mL, at least 150 mg/mL, at least 160 mg/mL, at least 170 mg/mL, at least 180 mg/mL, at least 190 mg/mL, or at least 200 mg/mL of cannabinoid, such as CBD and/or THC.
  • cannabinoid such as CBD and/or THC.
  • the formulation may include at most 240 mg/mL, at most 230 mg/mL, at most 220 mg/mL, at most 210 mg/mL, at most 200 mg/mL, at most 190 mg/mL, at most 180 mg/mL, at most 160 mg/mL, at most 140 mg/mL, at most 120 mg/mL, at most 100 mg/mL, at most 90 mg/mL, at most 80 mg/mL, at most 70 mg/mL, at most 60 mg/mL, at most 50 mg/mL, at most 40 mg/mL, or at most 30 mg/mL of cannabinoid, such as THC and/or CBD.
  • cannabinoid such as THC and/or CBD.
  • the formulation may include, for example, from 0.5 mg/mL to 240 mg/mL, such as from 5 mg/mL to 80 mg/mL, from 10 mg/mL to 40 mg/mL, or about 16 mg/mL of cannabinoid, such as THC and/or CBD.
  • the formulation includes a cosolvent.
  • a cosolvent is ethanol.
  • ethanol is used as a cosolvent in solution formulations, i.e., where the cannabinoid is dissolved in the formulation.
  • the cosolvent may aid in dissolving the cannabinoid whereas the cannabinoid may not be soluble in the formulation in the absence of a cosolvent.
  • the amount of ethanol sufficient to solubilize a cannabinoid in a propellent differs depending on the propellant and cannabinoid(s) used in a given formulation.
  • the amount of ethanol sufficient to solubilize THC, CBD, or a combination of THC and CBD in HFO-1234ze(E) depends on the cannabinoid(s) in the formulation.
  • the formulations described herein may include ethanol in an amount on a weight percent basis of the total formulation of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% of ethanol by weight.
  • the formulations described herein generally may include ethanol in an amount on a weight percent basis of the total formulation of at most 20%, at most 25%, at most 14%, at most 13%, at most 12%, at most 11%, at most 10%, at most 9%, at most 8%, at most 7%, at most 6%, at most 5%, at most 4%, at most 3%, or at most 2%.
  • the formulations described herein may include, for example, from 1% to 20% of ethanol, such as 1% to 15%, 1% to 8%, or 2% to 6% of ethanol by weight.
  • the formulation may include ethanol in an amount on a weight percentage basis of the total formulation from 1% to 20%, such as from 4% to 15%, or 5% to 8%.
  • the formulation may include ethanol in an amount on a weight percentage basis of the total formulation from 3% to 20%, such as from 4% to 15%, or 5% to 8%.
  • the formulation may include ethanol in an amount on a weight percentage basis of the total formulation from 1% to 15%, such as from 1% to 10%, or 1% to 4%.
  • a cosolvent may decrease deposition of the cannabinoid during actuation of the metered dose inhaler.
  • some propellants may evaporate rapidly as or before the formulation passes through the actuator.
  • ethanol may delay evaporation of the formulation until it has passed through the actuator and out of the metered dose inhaler. In this way, inclusion of ethanol may decrease the amount of deposition of formulation on the components of the metered dose inhaler.
  • the formulations described herein may include an amount of cosolvent sufficient to prevent occlusion of the actuator. In one or more embodiments, the formulations described herein may include an amount of cosolvent sufficient to prevent occlusion of the actuator after at least 5, at least 10, at least 20, at least 30, at least 60, at least 90, at least 120, at least 150, at least 180, or at least 240 actuations as compared to a formulation without a cosolvent.
  • the formulation may include an amount of cosolvent to improve the consistency of delivered dose throughout the lifetime of the metered dose inhaler.
  • the formulation may include an amount of cosolvent sufficient to decrease deposition of the formulation during actuation of the metered dose inhaler. Deposition of the formulation during actuation of the metered dose inhaler may occlude the valve stem or upper valve stem component or otherwise clog the actuator nozzle. If the deposition of the formulation during actuation is decreased, the delivered dose consistency may stay relatively consistent throughout the lifetime of the metered dose inhaler. Deposition of the formulation during actuation may entirely prevent the metered dose inhaler from functioning. For example, deposition of the formulation may prevent further actuation of the metered dose inhaler. Deposition of the formulation may additionally or alternatively lower or otherwise undesirably alter the dose delivered by a metered dose inhaler.
  • the metered dose inhalers described herein deliver an amount of cannabinoid per actuation that is consistent within a predetermined range throughout the lifetime of the metered dose inhaler.
  • the metered dose inhalers described herein may deliver an amount of cannabinoid per actuation within 5%, within 10%, within 15%, within 20%, within 25%, within 30%, within 35%, or within 40% of an intended dose throughout the lifetime of the metered dose inhaler.
  • the “lifetime” and “unit life” of a metered dose inhaler encompasses the time taken to actuate a predetermined number of doses from the inhaler.
  • “Lifetime” and “unit life” of a metered dose inhaler should be understood to be distinct from “shelf life” of a metered dose inhaler. While the “shelflife” of a metered dose inhaler typically refers to the length of time through which the product is considered stable and safe for delivery, the “unit life” or “lifetime” may be measured without a significant storage time, e.g., the unit may be tested through predetermined number of actuations in close series, such as over the course of one or several hours.
  • the consistency of dose delivered by a metered dose inhaler may additionally or alternatively be expressed as the minimum percentage of an initial intended dose delivered through the life of the metered dose inhaler.
  • a metered dose inhaler intended to deliver 1.0 mg/actuation which delivers between 1.0 and 0.8 mg/actuation throughout its lifetime may be said to have delivered at least 80% of an intended dose throughout its lifetime.
  • a metered dose inhaler may deliver at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% of a predetermined dose per actuation throughout its lifetime.
  • additional components e.g., excipients beyond propellant, cosolvent, and cannabinoid can be added to the formulation.
  • these components may have various uses and functions, including, but not limited to, aiding in dissolution of the cannabinoid or other components, and/or aiding in chemical stabilization of cannabinoid or other components.
  • the formulations described herein may also include additional components to confer a desired consumer property, such as scent, taste, color, or viscosity.
  • additional components include, for example, colorants or flavor or masking components.
  • Flavor or masking components may include flavonoids, terpenes or terpenoids.
  • flavonoids include quercetin, luteolin, vitexin, isovitexin, cannflavine A, cannflavine B, cannflavine C, apigenin, kaempferol, and orientin).
  • Non-limiting examples of terpenes include Hemiterpenes, Monoterpenes, Sesquiterpenes, Diterpenes, Sesterterpenes, Triterpenes, Sesquarterpenes, Tetraterpenes, Polyterpenes, and Norisoprenoids as well as naturally present terpenes found in Cannabis plants, including but not limited to, myrcene, limonene, caryophyllene, pinene, terpinene, terpinolene, camphene, terpineol, phellandrene, carene, humulene, pulegone, sabinene, geraniol, linalool, fenchol, borneol, eucalyptol, and nerolidol.
  • the formulations described herein display physical stability such that no particles are visible for at least 6 months, such as at least 12 months or at least 18 months, and often from 6 months to 36 months under typical storage conditions (e.g., refrigeration at a temperature of 2 °C to 8 °C).
  • formulations of the present disclosure preferably display chemical stability such that no degradation products are formed for at least 6 months, such as at least 12 months or at least 18 months, and often from 6 months to 36 months under typical storage conditions (e.g., refrigeration at a temperature of 2 °C to 8 °C).
  • FIG. 1 shows one embodiment of a metered dose inhaler 100, including an aerosol canister 1 fitted with a metered dose metering valve 10 (shown in its resting position).
  • the metering valve 10 is typically affixed, i.e., crimped, onto the canister 1 via a cap or ferrule 1 1 (typically made of aluminum or an aluminum alloy) which is generally provided as part of the valve assembly. Between the canister and the ferrule there may be one or more seals.
  • the can may be uncoated, such as an uncoated aluminum canister.
  • the can may be coated, such as with a silicon-containing coating. The coating may reduce the likelihood of deposition of the cannabinoid on the internal surface of the canister.
  • the canister/valve dispenser is typically provided with an actuator 5 including an appropriate patient port 6, such as a mouthpiece.
  • an appropriate patient port 6 such as a mouthpiece.
  • the patient port is generally provided in an appropriate form (e.g., smaller diameter tube, often sloping upwardly) for delivery through the nose.
  • Actuators are generally made of a plastic material, for example polypropylene or polyethylene.
  • inner walls 2 of the canister 1 and outer walls 101 of the portion(s) of the metering valve 10 located within the canister define a formulation chamber 3 in which aerosol formulation 4 is contained.
  • the valve 10 shown in FIG. 1 and 2 includes a metering chamber 12, defined in part by an inner valve body 13, through which a valve stem 14 passes.
  • the valve stem 14, which is biased outwardly by a compression spring 15, is in sliding sealing engagement with an inner tank seal 16 and an outer diaphragm seal 17.
  • the valve 10 also includes a second valve body 20 in the form of a bottle emptier.
  • the inner valve body 13 also referred to as the “primary” valve body
  • the second valve body 20 defines in part a pre-metering region or chamber besides serving as a bottle emptier.
  • aerosol formulation 4 can pass from the formulation chamber 3 into a pre-metering chamber 22 provided between the secondary valve body 20 and the primary valve body 13 through an annular space 21 between a flange 23 of the secondary valve body 20 and the primary valve body 13.
  • the valve stem 14 is pushed inwardly relative to the canister 1 from its resting position shown in FIGS. 1 and 2, allowing formulation to pass from the metering chamber 12 through a side hole 19 in the valve stem and through a stem outlet 24 to an actuator nozzle 7 then out to the patient.
  • formulation enters into the valve 10, in particular into the pre-metering chamber 22, through the annular space 21 and thence from the pre-metering chamber through a groove 18 in the valve stem past the tank seal 16 into the metering chamber 12.
  • FIG. 3 shows another embodiment of a metered dose aerosol metering valve 102, different from the embodiment shown in FIGS. 1 and 2, in its rest position.
  • the valve 102 has a metering chamber 112 defined in part by a metering tank 113 through which a stem 114 is biased outwardly by spring 115.
  • the stem 114 is made in two parts that are push fit together before being assembled into the valve 102.
  • the stem 114 has an inner seal 116 and an outer seal 117 disposed about it and forming sealing contact with the metering tank 113.
  • a valve body 120 crimped into a ferrule 111 retains the aforementioned components in the valve.
  • formulation enters the metering chamber via orifices 121 and 118.
  • the formulation’s outward path from the metering chamber 112 when a dose is dispensed is via orifice 119.
  • Devices that may be used with medicament formulations of the present disclosure include those described in U.S. Patent No. 6,032,836 (Hiscocks et al ), U.S. Patent No. 9,010,329 (Hansen), and U.K. Patent GB 2544128 B (Friel).
  • the metered dose inhaler can include a dose counter for counting the number of doses.
  • Suitable dose counters are known in the art, and are described in, for example, U.S. Patent Nos. 8,740,014 (Purkins et al.); 8,479,732 (Stuart et al.); and 8,814,035 (Stuart), and U.S. Patent Application Publication No. 2012/0234317 (Stuart) all of which are incorporated by reference in their entirety with respect to their disclosures of dose counters.
  • Suitable coatings may include polytetrafluoroethylene (PTFE), fluorinated ethylene propylene resins (FEP), and fluorocarbon polymer (FCP).
  • PTFE polytetrafluoroethylene
  • FEP fluorinated ethylene propylene resins
  • FCP fluorocarbon polymer
  • the actuator nozzle is sized so as to optimize the fine particle fraction (FPF) and/or respirable dose delivered of the formulation within the canister.
  • the cross-sectional shape of the actuator nozzle is essentially circular or circular and has a predetermined diameter.
  • an effective diameter may be determined by taking an average over the distances spanning the opening (e.g., the average of major and minor axes of an ellipse).
  • the exit orifice (effective diameter) of the actuator nozzle may be 0.08 mm or greater, 0.10 mm or greater, 0.12 mm or greater, 0.15 mm or greater, 0.175 mm or greater, 0.225 mm or greater, 0.3 mm or greater, or 0.4 mm or greater. In one or more embodiments, the exit orifice (effective diameter) of the actuator nozzle may be 0.5 mm or less, 0.4 mm or less, 0.3 mm or less, 0.225 mm or less, 0.175 mm or less, or 0.15 mm or less.
  • the exit orifice (effective diameter) of the actuator nozzle may be 0.10 mm to 0.50 mm. In one or more embodiments, the exit orifice (effective diameter) of the actuator nozzle may be 0.15 mm to 0.50 mm. In one or more embodiments, the exit orifice (effective diameter) of the actuator nozzle may be 0.20 mm to 0.45 mm. In one or more embodiments, the exit orifice (effective diameter) of the actuator nozzle may be 0.25 mm to 0.40 mm. In one or more embodiments, the exit orifice (effective diameter) of the actuator nozzle may be 0.28 mm to 0.35 mm.
  • a given actuator nozzle exit orifice may not be suitable for delivery of any formulation, and that selection of a suitable actuator nozzle exit orifice for a given formulation involves considerable effort. Selection of a suitable actuator nozzle exit orifice may improve the consistency of dose delivered by a metered dose inhaler and/or decrease the likelihood of deposition of the formulation during actuation.
  • An actuator nozzle exit orifice may additionally modify the properties of the aerosol delivered, such as fine particle fraction (FPF) and/or median mass aerodynamic diameter (MMAD) as described in more detail herein.
  • FPF fine particle fraction
  • MMAD median mass aerodynamic diameter
  • the metered dose inhalers disclosed herein may deliver a dose comprising a particular fine particle fraction (FPF).
  • FPF refers to the mass percentage of API particles with an aerodynamic diameter below 5 micrometers (pm) relative to the total emitted dose.
  • FPF may be determined using any field standard method, such as using an impactor apparatus.
  • the FPF delivered by a metered dose inhaler is impacted by multiple considerations including actuator size and shape.
  • a metered dose inhaler may deliver an aerosol including a FPF of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.
  • a metered dose inhaler may deliver an aerosol including a FPF of at most 90%, at most 85%, at most 80%, at most 75%, at most 70%, at most 65%, at most 60%, or at most 55%.
  • MMAD median mass aerodynamic diameter
  • the MMAD is a measure of the size of particles delivered by a metered dose inhaler. Different MMAD measurements and ranges may be desirable in different applications.
  • a metered dose inhaler may deliver particles with a MMAD of at least 0.5 pm, at least 1 pm, at least 1.25 pm, at least 1.5 pm, at least 1.75 pm, at least 2 pm, at least 2.25 pm, at least 2.5 pm, at least 2.75 pm, at least 3 pm, at least 3.5 pm, or at least 4 pm.
  • a metered dose inhaler may deliver particles with a MMAD of at most 10 pm, at most 9 pm, at most 8 pm, at most 7 pm, at most 6.5 pm, at most 6.0 pm, at most 5.5 pm, or at most 5 pm.
  • the metering valve of a metered dose inhaler may have any suitable volume to deliver a dose of the formulation. Selection of a metering valve volume may impact the amount of formulation delivered. Therefore, in embodiments wherein the metered dose inhaler comprises a formulation comprising one or more cannabinoids, the metering valve volume will impact the amount of cannabinoid delivered.
  • the metering valve volume may be at least 30 pL, at least 40 pL, at least 50 pL, at least 60 pL, at least 70 pL, at least 80 pL, at least 90 pL, at least 100 pL, at least 110 pL, at least 120 pL, at least 130 pL, at least 140 pL, at least 150 pL, at least 175 pL, at least 200 pL, at least 225 pL, at least 250 pL, at least 275 pL, at least 300 pL, or at least 400 pL.
  • the metering valve volume may be at most 500 pL, at most 450 pL, at most 400 pL, at most 350 pL, at most 300 pL, at most 275 pL, at most 250 pL, at most 225 pL, at most 200 pL, at most 175 pL, at most 150 pL, at most 125 pL, at most 100 pL, at most 75 pL, or at most 50 pL.
  • the metering valve volume may be from 30 to 100 pL, such as 40 to 80 pL, or 50 to 70 pL.
  • valve volume may not be suitable for delivery of any formulation, and that selection of a valve volume for a given formulation involves considerable effort.
  • the metered dose inhaler is manufactured by pressure filling.
  • pressure filling the liquid or powdered medicament, combined with one or more excipients (e.g., co-solvents), is placed in a suitable aerosol container (i.e., canister) capable of withstanding the vapor pressure of the propellant and fitted with a metering valve prior to filling.
  • the propellant is then forced as a liquid through the valve into the container.
  • the particulate API is combined in a process vessel with propellant and one or more excipients (e.g., cosolvents), and the resulting API solution is transferred through the metering valve fitted to a suitable metered dose inhaler container.
  • the metered dose inhaler is manufactured by cold filling.
  • cold filling the liquid or powdered medicament is combined with one or more excipients (e.g., co-solvents) and propellant that is chilled below its boiling point and, optionally, one or more excipients are added to the metered dose inhaler container.
  • excipients e.g., co-solvents
  • propellant that is chilled below its boiling point
  • a metering valve is fitted to the container post-filling.
  • Embodiment 1 is a metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister comprises a formulation, the formulation comprising a propellant comprising HFO-1234ze(E), at least 1% of ethanol by weight, and one or more cannabinoids; and wherein the one or more cannabinoids is dissolved in the formulation to form a solution.
  • the canister comprises a formulation, the formulation comprising a propellant comprising HFO-1234ze(E), at least 1% of ethanol by weight, and one or more cannabinoids; and wherein the one or more cannabinoids is dissolved in the formulation to form a solution.
  • Embodiment 2 is the metered dose inhaler of embodiment 1, wherein the metered dose inhaler delivers 1.0 milligram (mg) per actuation to 3.0 mg/actuation of the one or more cannabinoids.
  • Embodiment 3 is the metered dose inhaler of embodiment 2, wherein the formulation comprises 4% to 15% of ethanol by weight.
  • Embodiment 4 is the metered dose inhaler of embodiment 3, wherein the formulation comprises 5% to 8% of ethanol by weight.
  • Embodiment 5 is the metered dose inhaler of any one of embodiments 1 to 4, wherein the one or more cannabinoids comprises tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • Embodiment 6 is the metered dose inhaler of embodiment 5, wherein the ratio of THC to CBD is 1 : 1 by weight.
  • Embodiment 7 is a metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister comprises a formulation, the formulation comprising a propellant comprising HFO-1234ze(E), at least 1% of ethanol by weight, and THC; and wherein the THC is dissolved in the formulation to form a solution.
  • Embodiment 8 is the metered dose inhaler of embodiment 7, wherein the formulation comprises 0.5% to 15% of ethanol by weight.
  • Embodiment 9 is the metered dose inhaler of embodiment 8, wherein the formulation comprises 1% to 4% ethanol by weight.
  • Embodiment 10 is the metered dose inhaler of any one of embodiments 5 to 9, wherein the THC is delta-9- tetrahydrocannabinol.
  • Embodiment 11 is the metered dose inhaler of any one of embodiments 7 to 10, wherein the metered dose inhaler delivers 0.5 mg/actuation to 1.5 mg/actuation of THC.
  • Embodiment 12 is a metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister comprises a formulation, the formulation comprising a propellant comprising HFO-1234ze(E), at least 1% of ethanol by weight, and CBD; and wherein the CBD is dissolved in the formulation to form a solution.
  • the canister comprises a formulation, the formulation comprising a propellant comprising HFO-1234ze(E), at least 1% of ethanol by weight, and CBD; and wherein the CBD is dissolved in the formulation to form a solution.
  • Embodiment 13 is the metered dose inhaler of embodiment 12, wherein the formulation comprises 4% to 15% of ethanol by weight.
  • Embodiment 14 is the metered dose inhaler of embodiment 13, wherein the formulation comprises 5% to 8% of ethanol by weight.
  • Embodiment 15 is the metered dose inhaler of any one of embodiments 12 to 14, wherein the metered dose inhaler delivers 0.5 mg/actuation to 1.5 mg/actuation of CBD.
  • Embodiment 16 is the metered dose inhaler of any preceding embodiment, further comprising an excipient.
  • Embodiment 17 is the metered dose inhaler of any preceding embodiment, wherein HFO-1234ze(E) is the sole propellant.
  • Embodiment 18 is the metered dose inhaler of any preceding embodiment, wherein the formulation comprises an amount of ethanol sufficient to decrease deposition of the formulation within the valve or actuator during actuation of the metered dose inhaler as compared to a formulation free of ethanol.
  • Embodiment 19 is the metered dose inhaler of any preceding embodiment, wherein the formulation comprises an amount of ethanol sufficient to decrease deposition of the formulation within the valve or actuator during actuation of the metered dose inhaler as compared to a formulation free of excipient after at least 15 actuations.
  • Embodiment 20 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler delivers a consistent dose of cannabinoid through at least 60 actuations.
  • Embodiment 21 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler demonstrates a through-unit life dose consistency of at least 0.5 mg/actuation.
  • Embodiment 22 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler demonstrates a through-life dose consistency of at least 1.0 mg/actuation.
  • Embodiment 23 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler delivers at least 50% of a predetermined dose per actuation through its lifetime.
  • Embodiment 24 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler delivers particles with a mean mass aerodynamic diameter of 2.0 pm to 4.0 pm.
  • Embodiment 25 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler delivers an aerosol including a fine particle fraction from 10% to 70%.
  • Embodiment 26 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler delivers particles with a median mass aerodynamic diameter of 1.5 pm to 6 pm.
  • Embodiment 27 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler delivers an amount of cannabinoid per actuation within 35% of an intended dose throughout the lifetime of the metered dose inhaler.
  • CBD was soluble at a concentration of at least 15.87 mg/mL in formulations including HFO- 1234ze(E) and 6% ethanol by weight. It was learned that A-9-THC was soluble at a concentration of at least 15.87 mg/mL in formulations including HFO-1234ze(E) and 4%, 5%, or 6% ethanol by weight. It was also learned that the mixture of at least 15.87 mg/mL of A-9-THC and at least 15.87 mg/mL of CBD was soluble in formulations including HFO-1234ze(E) and 6% or 8% ethanol by weight.
  • Formulations of either CBD or A-9-THC were prepared in HFO-1234ze(E) without any additional cosolvents. Saturated solutions were prepared by adding an excess of drug to the propellant to ensure saturated solubility was achieved. Each solution was covered with aluminum foil to prevent UV light from reaching the drug. A first set of solutions was then shaken at room temperature for 4 days. A second set of solutions was stored at 5 °C and manually shaken several times per day. After 4 days, each solution was filtered to remove undissolved CBD and/or A-9- THC, and the concentration of each cannabinoid was measured. Formulations were assessed for solubility at room temperature and at 5°C.
  • Formulations of either CBD or A-9-THC were prepared in HFA-227 or HFA-134A. Saturated solutions were prepared by adding an excess of drug to the propellant to ensure saturated solubility was achieved. Each solution was shaken at room temperature for 4 days, after which each solution was filtered to remove undissolved CBD and/or A-9-THC, and the concentration of each cannabinoid was measured. The equilibrium saturated solubility of each cannabinoid in each propellant was measured at room temperature.
  • CBD and A-9-THC were similarly soluble in HFO-1234ze(E), but CBD was observed to be more soluble in HFO-1234ze(E) than in both HFA-134a and HFA-227.
  • the aerodynamic particle size distribution (APSD) of three formulations including HFO-1234ze(E), ethanol, and CBD, A-9-THC, or a combination of A-9-THC and CBD was measured using a next generation impactor (NGI).
  • NTI next generation impactor
  • a first formulation was prepared in HFO-1234ze(E) including 15.87 mg/mL A-9-THC and 5% ethanol by weight.
  • a second formulation was prepared in HFO-1234ze(E) including 15.87 mg/mL CBD and 6% ethanol by weight.
  • a third formulation was prepared in HFO- 1234ze(E) including 15.78 mg/mL CBD, 15.87 mg/mL A-9-THC, and 8% ethanol by weight.
  • Each formulation was pressure filled into an uncoated aluminum canister and fitted with a 63 pL valve (APT AR). Three replicate units were prepared for each formulation and tested as described below. Each unit was primed using four actuations before measurements were taken. Following priming of the units, APSD measurements were conducted at start of unit life.
  • FPM fine particle mass
  • MMAD median mass aerodynamic diameter
  • ex-actuator delivered dose
  • exvalve dose exiting the pMDI valve
  • delivery to the throat were measured for each unit tested as well.
  • FPF was calculated using the FPM percentage of the ex-actuator delivered dose. The mean results of three replicates are presented in TABLE 2.

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Abstract

L'invention concerne divers modes de réalisation d'un inhalateur doseur. L'inhalateur comprend une valve doseuse, une cartouche et un actionneur ayant une buse d'actionnement. La cartouche comprend une formulation ayant un propulseur comprenant du HFO-1234ze(E), au moins 1 % d'éthanol en poids, et un ou plusieurs cannabinoïdes, le ou les cannabinoïdes étant dissous dans la formulation pour former une solution. Dans un ou plusieurs modes de réalisation, le cannabinoïde comprend du tétrahydrocannabinol (THC) et/ou du cannabidiol (CBD).
EP24715376.0A 2023-03-02 2024-03-01 Inhalateurs doseurs et solutions comprenant des cannabinoïdes dans hfo-1234ze(e) Pending EP4673113A1 (fr)

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PCT/US2024/018067 WO2024182699A1 (fr) 2023-03-02 2024-03-01 Inhalateurs doseurs et solutions comprenant des cannabinoïdes dans hfo-1234ze(e)

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JP (1) JP2026508384A (fr)
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GB0328635D0 (en) 2003-12-10 2004-01-14 3M Innovative Properties Co Dose counter for dispensers
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JP5571561B2 (ja) 2007-11-06 2014-08-13 スリーエム イノベイティブ プロパティズ カンパニー 医薬品吸入装置及びそれらの構成要素
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GB0921555D0 (en) 2009-12-09 2010-01-27 3M Innovative Properties Co Dose indicator
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WO2024182699A1 (fr) 2024-09-06
AU2024230822A1 (en) 2025-10-16

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