Solutions containing cannabinoids in metered dose inhalers and HFO-1234ze(E)

Abstract

Various embodiments of a metered dose inhaler are disclosed. The inhaler includes a metering valve, a canister, and an actuator having an actuator nozzle. The canister contains a formulation having a propellant including HFO-1234ze(E), at least 1% by weight ethanol, and one or more cannabinoids, the one or more cannabinoids dissolved in the formulation to form a solution. In one or more embodiments, the cannabinoids include tetrahydrocannabinol (THC) and / or cannabidiol (CBD).

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 449,439, filed March 02, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Delivery of aerosolized medication to the respiratory tract for the treatment of respiratory and other diseases can be achieved using, for example, a pressurized metered dose inhaler (pMDI), a dry powder inhaler (DPI), or a nebulizer. Metered dose inhalers are familiar to many patients suffering from asthma or chronic obstructive pulmonary disease (COPD). Metered dose inhaler devices can include an aluminum canister sealed with a metering valve containing a pharmaceutical formulation. In general, typical current pharmaceutical formulations include one or more pharmaceutical compounds present in a liquefied hydrofluoroalkane (HFA) propellant.

[0003] One such type of drug is cannabinoids. Cannabinoids are the primary active components of cannabis and are known to have a variety of neurological effects. Cannabinoids can be combined with liquefied propellants to prepare formulations that can be delivered using metered-dose inhalers.

[0004] Historically, the propellant in most metered-dose inhalers was a chlorofluorocarbon (CFC). However, environmental concerns in the 1990s led to the replacement of CFCs with hydrofluoroalkanes (HFAs) as the most commonly used propellants in metered-dose inhalers. HFAs do not cause ozone depletion, but they do have a reported high global warming potential (GWP), which is a measure of the future radiative effect of emitting a substance compared to emitting an equivalent amount of carbon dioxide (CO2). The two HFA propellants most commonly used in pMDIs are HFA-134a, also known as HFC-134a, R-134a, or norflurane (CF3CH2F, 1,1,1,2-tetrafluoroethane), and HFA-227, also known as HFC-227, FM-200, or apaflurane (CF3CHFCHF3, 1,1,1,2,3,3,3-heptafluoropropane), which exhibit 100-year GWP values ​​of 1300-1430 and 3220-3350, respectively.

[0005] Various other propellants have been proposed over the years, among which hydrofluoroolefins (HFOs) and carbon dioxide (CO2) have been mentioned as potential propellants for metered dose inhalers, but there remains a need for metered dose inhaler products that use either as a propellant. Summary of the Invention

[0006] Although HFO-1234ze(E) is different from other pMDI propellants, it has been found that it can be used to make practical pMDIs. One advantage of such pMDIs is that HFO-1234ze(E) has a stated GWP of less than 1.

[0007] In one embodiment, a pMDI (also referred to herein as an MDI or metered dose inhaler) is provided comprising a metering valve, a canister, and an actuator comprising an actuator nozzle, wherein the canister contains a formulation (i.e., a composition), the formulation comprising HFO-1234ze(E), at least 1% by weight of ethanol, and a propellant comprising one or more cannabinoids, the one or more cannabinoids being dissolved in the formulation to form a solution. In certain embodiments, the one or more cannabinoids comprise tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof.

[0008] In one embodiment there is provided a pMDI comprising a metering valve, a canister and an actuator comprising an actuator nozzle, wherein the canister contains a formulation, the formulation comprising HFO-1234ze(E), at least 1% by weight ethanol and a propellant comprising CBD, wherein the CBD is dissolved in the formulation to form a solution.In one embodiment there is provided a pMDI comprising a metering valve, a canister and an actuator comprising an actuator nozzle, wherein the canister contains a formulation, the formulation comprising HFO-1234ze(E), at least 1% by weight ethanol and a propellant comprising THC, wherein the THC is dissolved in the formulation to form a solution.

[0009] As used herein, "dissolved in a formulation" or "dissolved in a composition" means that the described ingredient (e.g., cannabinoid) is dissolved in a propellant or in other ingredients, such as a propellant and a co-solvent, to form a solution.

[0010] As used herein, the term "comprises" and variations thereof do not have a limiting meaning when these terms appear in the description and claims. Such terms are understood to mean the inclusion of the recited 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 "comprises" and is limited to what follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the recited elements are necessary or mandatory, and that other elements may not be present. The phrase "consisting essentially of" means including any elements listed after the phrase, and is limited to other elements that do not interfere with or contribute to the activity or function specified in this disclosure for the recited elements. Thus, the phrase "consisting essentially of" indicates that the recited elements are necessary or mandatory, but that other elements are optional and may or may not be present depending on whether they materially affect the activity or function of the recited elements. Any element or combination of elements described herein with open-ended language (e.g., comprise and its derivatives) is considered to be further described with closed-ended language (e.g., consist of and its derivatives) and partially closed-ended language (e.g., consist essentially and its derivatives).

[0011] The words "preferred" and "preferably" refer to embodiments of the present disclosure that may offer certain benefits, under particular circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, or is intended to exclude other embodiments from the scope of the present disclosure.

[0012] Throughout this disclosure, singular forms such as "a," "an," and "the" are often used for convenience. The singular is intended to include the plural unless the singular form is expressly stated alone or otherwise clearly indicated by context.

[0013] As used herein, the term "or" is generally used in its ordinary sense, including "and / or," unless the content clearly dictates otherwise.

[0014] The term "and / or" means one or all of the listed elements or a combination of any two or more of the listed elements.

[0015] As used herein, the phrase "ambient conditions" refers to an environment at room temperature (approximately 20°C to 25°C) and a relative humidity of 30% to 60%.

[0016] Also, herein, all numbers are intended to be modified by the term "about," and in certain embodiments, preferably, by the term "exactly." When used herein in connection with a measured quantity, the term "about" refers to the variation in the measured quantity that would be expected by one of ordinary skill in the art making the measurement and exercising a degree of care commensurate with the purpose of the measurement and the precision of the measuring device used. As used herein, "up to" a number (e.g., up to 50) includes that number (e.g., 50). As used herein, "at least" a number (e.g., at least 50) includes that number (e.g., 50). As used herein, "not more than" a number (e.g., not more than 50) includes that number (e.g., 50). As used herein, "greater than or equal to" a number (e.g., 50 or greater) includes that number (e.g., 50).

[0017] Numerical ranges, such as "between x and y" or "from x to y," include the endpoints of x and y. Also herein, the recitation of numerical ranges by endpoints includes 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.).

[0018] Some terms used in this application have special meanings as defined herein. All other terms are to be given the meanings known to those of ordinary skill in the art and would have been given to them by one of ordinary skill in the art at the time of the present invention.

[0019] Elements herein referred to as "common," "commonly used," "conventional," "typical," "typically," etc., should be understood to be typical within the context of the compositions, articles, such as inhalers and metered dose inhalers (pMDIs), including pressurized metered dose inhalers, and methods of the present disclosure. This term is not used to imply that these features exist in the prior art or are uncommon in the prior art. Unless otherwise specified, only the Background section of this application refers to prior art.

[0020] Throughout this specification, references to "one embodiment," "an embodiment," "a particular embodiment," "one or more embodiments," "an aspect," "aspect," or "some embodiments" mean that the particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of such phrases in various places throughout this specification do not necessarily refer to the same embodiment of the present disclosure. Furthermore, the particular features, configurations, compositions, and characteristics may be combined in any suitable manner in one or more embodiments.

[0021] While the present disclosure will be described with respect to embodiments and with reference to certain drawings, the invention is not limited thereto. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn to scale for illustrative purposes.

[0022] The above summary of the present disclosure is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The following description more particularly exemplifies illustrative embodiments. In several places in this disclosure, guidance is provided through lists of examples, which can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive or exhaustive list. Thus, the scope of the disclosure should not be limited to the specific exemplary structures described herein, but rather extends to at least the structures described by the language of the claims and equivalents of those structures. Any of the elements affirmatively recited herein as alternatives may be expressly included in or excluded from the claims in any combination desired. While various theories and possible mechanisms have been discussed herein, such discussion should not serve to limit the claimable subject matter.

[0023] The complete disclosures of all patents, patent applications, and publications cited herein, as well as electronically available materials, are incorporated by reference in their entirety. In the event of any inconsistency between this disclosure and the disclosure(s) of any document incorporated herein by reference, the present disclosure shall control. The detailed description and examples herein are given for clarity of understanding only. No unnecessary limitations should be construed therefrom. The invention is not limited to the exact details shown and described, for variations obvious to one skilled in the art are within the scope of the invention as defined by the claims.

[0024] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified. [Brief explanation of the drawings]

[0025] While the present disclosure will be described with respect to embodiments and with reference to certain drawings, the invention is not limited thereto. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn to scale for illustrative purposes.

[0026] [Figure 1] 1 is a side cross-sectional view of an inhaler including a canister including a valve according to the present disclosure;

[0027] [Figure 2] FIG. 2 is a detailed cross-sectional side view of the inhaler of FIG. 1.

[0028] [Figure 3] FIG. 1 is a side cross-sectional view of a metering valve for an inhaler. DETAILED DESCRIPTION OF THE INVENTION

[0029] The formulations described herein contain one or more cannabinoids.Cannabinoids are psychoactive compounds and are the main psychoactive components of cannabis.The medicinal properties of cannabinoids have been known for many years, including their use in treating or alleviating chronic pain, seizures, arthritis, nausea, neurodegenerative diseases such as multiple sclerosis, cancer, and HIV.They can also be effective as bronchodilators in the treatment of asthma and COPD.However, along with their potential benefits, there are also less desirable effects, including psychotropic effects when cannabinoids are inhaled by smoking and the risk of diseases such as cancer.

[0030] It is known to deliver cannabinoids using inhaler devices, including metered dose inhalers, such as pressurized metered dose inhalers (pMDIs), in which the cannabinoid is delivered using a propellant. The cannabinoid is dissolved in a liquefied propellant and optional co-solvent and stored in a pressurized container, such as a pMDI canister. The container is then connected to a suitable delivery device, typically including a mouthpiece, a nozzle, and a valve assembly. Actuation of the valve assembly releases a dose of the cannabinoid / propellant mixture from the container, which is then dispensed through the nozzle into the mouthpiece, where it can be inhaled.

[0031] As used herein, the term "cannabinoid" encompasses naturally occurring cannabinoids as well as synthetic and semi-synthetic cannabinoids. Cannabinoids may naturally occur in plants of the Cannabaceae family and extracts derived therefrom, such as hemp oil. Cannabaceae plants that can 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 produced by genetic crossing, self-crossing, or hybridization. Varieties may include varieties characterized by chemical compositions containing naturally differing amounts of individual cannabinoids, such as chemovarieties of cannabis, or Cannabis sativa subspecies indica, including var. indica and var. kafiristanica.

[0032] Suitable cannabinoids include phytocannabinoids, which can be isolated from plants to produce highly purified extracts or can be synthetically reproduced, such as tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabielsoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabitriol (CBT), and cannabinol (CBN). Highly purified cannabinoid extracts are also included and are defined as cannabinoids extracted from cannabis plants and purified (to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the target cannabinoid have been substantially removed). Highly purified cannabinoid extracts may contain 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% cannabinoids. Suitable synthetic cannabinoids are compounds that have cannabinoid or cannabinoid-like structures and are produced using chemical means rather than being extracted from plants. Synthetic cannabinoids include cannabinoids, cannabinoid mimetics, and eicosanoids structurally related to tetrahydrocannabinol (THC). More specific examples of synthetic cannabinoids for use in the present invention include nabilone, rimonabant, cannabicyclohexanol, JHW-018, JWH-073, and HU-210.

[0033] Two particular cannabinoids of interest are tetrahydrocannabinol and cannabidiol. Tetrahydrocannabinol (THC, C21 H 30 O2) refers to two isomers, delta-8-THC ((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol) and delta-9-THC ((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol). Formulations described herein as containing THC may contain delta-9-THC and / or delta-8-THC. THC is typically known for its psychoactive effects, but is also used to treat chronic conditions such as pain and multiple sclerosis, and as an appetite stimulant.

[0034] Cannabidiol (CBD, C 21 H 30 O2), 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol, is another cannabinoid of interest. While there is limited evidence for the clinical effectiveness of CBD, there is nonetheless interest in its use in the management of neurological disorders. Unlike THC, CBD typically does not have psychoactive effects and is therefore generally subject to less government regulation.

[0035] The starting material for the CBD and THC drug substances, whole plant extract (WPE), is an extract from dried, crushed, and decarboxylated cannabis flower that is prepared using supercritical carbon dioxide to produce the WPE used to manufacture the CBD and THC drug substances. The materials and solvents used in the drug substance manufacturing process are commonly used materials suitable for their intended purposes and are purchased from reputable, controlled suppliers in accordance with established quality standards.

[0036] The cannabinoids of the present disclosure can be prepared using any suitable method, such as pharmaceutical-grade, commercial-scale extraction methods. As used herein, "pharmaceutical grade" refers to compliance with guidelines defined by the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use, including, for example, the ICH "Q3C(R7) Guideline" for residual solvents permitted at low levels as impurities in pharmaceuticals, or the "Q6A Guideline" for dronabinol. At the U.S. Food and Drug Administration (FDA), relevant test methods are defined in accordance with the USP <1111> , U.S.P. <921> , U.S.P. <467> , U.S.P. <61> , U.S.P. <62> , and USP <281> Includes.

[0037] The extraction method may be from any "plant material" as well as exudate. As used herein, "plant material" includes plants, plant parts (e.g., bark, leaves, stems, roots, flowers, fruits, seeds), herbal cannabis, dried cannabis biomass, or cannabis flowers. Plant material may also be decarboxylated cannabis plant material, which is used herein to refer to cannabis plant material that has been subjected to a decarboxylation step. Exudate includes materials included in the definition of "botanical material" in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research.

[0038] Extraction methods may involve single or multi-step extraction and chromatographic purification, and may include those methods disclosed in U.S. Patent No. 7,344,736 (Whittle et al.) and International Application No. PCT / WO2018 / 167038 (Vorobjov et al.). Exemplary methods involve extracting cannabinoids from cannabis plant material using an extractor with supercritical, critical, or near-critical fluids such as carbon dioxide, nitrous oxide, ethylene, ethane, propane, or chlorodifluoromethane. In some embodiments, supercritical carbon dioxide is used, which behaves like an organic solvent with the solubilizing properties of a liquid and the permeability properties of a gas.

[0039] As described herein, different cannabinoids are known to have different pharmaceutical effects. Therefore, in certain situations, it may be desirable to provide a formulation containing only one cannabinoid, such as THC or CBD. In one or more embodiments, the formulations described herein contain CBD and do not contain a substantial amount of THC. In one or more embodiments, the formulations described herein contain THC and do not contain a substantial amount of CBD.

[0040] In certain other situations, it may be desirable to provide a formulation that contains only more than one cannabinoid, such as THC and CBD. In one or more embodiments, the formulations described herein contain both THC and CBD. It is understood that the ratio of THC to CBD in any particular formulation can be varied to balance the psychotropic and therapeutic effects of the formulation. In embodiments where a formulation contains more than one cannabinoid, such as THC and CBD, the ratio between the cannabinoids can be controlled. The THC to CBD ratio 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, 1:20-20:1, e.g., 1:8-8:1, e.g., 1:4-4:1, e.g., 1:1. In one or more other embodiments, the ratio of THC to CBD in a formulation containing both THC and CBD may be expressed as a molar ratio.

[0041] The cannabinoid may be provided in any form suitable for formulation as a solution. In certain embodiments, the cannabinoid may be provided as a solid, such as a powder or micronized powder, a resin, a semi-solid, or as a liquid, such as a liquid concentrate. Any suitable form of cannabinoid that is compatible with the preparation of a solution may be used in the formulations of the present disclosure. The cannabinoid is dissolved in the formulations described herein to form a solution.

[0042] Pharmaceutical grade cannabidiol is typically a white crystalline powder stored at room temperature in sealed aluminum bags to limit exposure to air and light. Pharmaceutical grade delta-9 tetrahydrocannabinol is a clear, amber viscous liquid typically stored at temperatures of approximately -20°C or 2°C to 8°C. Delta-9 tetrahydrocannabinol is typically stored under an argon atmosphere in sealed amber glass vials with limited exposure to light.

[0043] The formulations of the present disclosure are solutions (i.e., solution formulations or solution compositions). That is, the formulations contain one or more cannabinoids dissolved in the formulation (i.e., solubilized in a propellant, co-solvent, and optional other ingredients) to form a solution. As used herein, a "solution" is a homogeneous solution that does not have particulate matter visible to the naked eye.

[0044] Solution stability over a range of temperatures may be a factor to consider when selecting a formulation for a metered-dose inhaler. In one or more embodiments, the components of the solution formulations described herein may remain dissolved at temperatures 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.

[0045] Solution and suspension formulations are fundamentally different metered-dose inhaler formulation approaches. Different factors must be considered when developing a product using either of these formulation approaches. Therefore, the same knowledge and understanding of suspension formulations cannot be applied to solution formulations. In solutions, the solubility of the active pharmaceutical ingredient (API) in the propellant and optional cosolvent is an important consideration. Various strategies can be used to improve solubility through the use of additional excipients, such as polyethylene glycol or water. Solutions typically produce 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 use of cosolvents in metered-dose inhalers containing solution formulations can affect the droplet evaporation rate and also result in changes in the resulting solid-state particles formed in the lungs, which can affect the pharmacological uptake of the API compared to deposited APIs from suspensions. Additionally, some APIs are at higher risk of chemical degradation in solution formulations, often requiring specific formulation strategies, such as the use of stabilizing acids and the selection of specific container closure systems to maximize chemical stability. These problems are specific to solutions, and any teaching specific to suspensions will not necessarily overcome them.

[0046] The primary propellant in the compositions (i.e., formulations) described herein is HFO-1234ze(E), also known as trans-1,3,3,3-tetrafluoropropene, trans-1,3,3,3-tetrafluoropropene, or trans-1,1,1,3-tetrafluoroprop-1-ene. The chemical structures of the trans and cis isomers of HFO-1234ze are very different. As a result, these isomers have very different physical and thermodynamic properties. The significantly lower boiling point and higher vapor pressure of the trans (E) isomer compared to the boiling point and vapor pressure of the cis (Z) isomer at ambient conditions makes the trans isomer a much more thermodynamically favored propellant for achieving efficient pMDI atomization.

[0047] In one or more embodiments, the amount of HFO-1234ze(E) by weight in the formulation is at least 50% by weight, greater than 50% by weight, at least 60% by weight, greater than 60% by weight, at least 70% by weight, greater than 70% by weight, at least 80% by weight, greater than 80% by weight, at least 85% by weight, greater than 85% by weight, at least 90% by weight, or greater than 90% by weight. In one or more embodiments, the amount of HFO-1234ze(E) by weight is 50% to 99% by weight, 55% to 95% by weight, 60% to 90% by weight, or 70% to 80% by weight. In one or more embodiments, HFO-1234ze(E) is the only propellant in the formulation. That is, pharmaceutical performance parameters such as emitted dose and emitted particle size distribution are not significantly different from when HFO-1234ze(E) is the only propellant in the formulation.

[0048] 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, aqueous solubility, liquid density, and surface tension. These differences in properties make it difficult to replace one propellant with another without significantly impairing or altering the performance of pMDI products. For example, thermodynamic differences in propellant boiling point and vapor pressure can significantly affect the aerosolization efficiency of pMDIs and lead to differences in primary and secondary atomization mechanisms. Differences in dipole moment and polarity between propellants can affect the solubility of APIs and excipients in the formulation. Differences in hygroscopicity between propellants can affect water uptake, which can be problematic for solution formulations, especially when water uptake is expected to affect physical stability or water-related chemical degradation. The chemical interactions of different propellants with APIs and excipients can also vary significantly, which can affect the long-term chemical stability of a product over its intended shelf life. Different propellants chemically and physically interact with valve plastic and elastomeric components, which can result in differences in the type and amount of extractables and leachables and affect mechanical valve function. The thermodynamic properties of propellants can result in different droplet sizes due to different evaporation rates and can also lead to differences in spray characteristics such as spray force, temperature, and spray duration. Historically, the transition from CFCs to HFA propellants required significant efforts to develop new formulations and sophisticated hardware to achieve adequate pMDI product performance. This means that simple, direct substitution of one propellant for another was not possible. For example, changing from propellants such as HFA-152a, HFA-227, or HFC-134a to HFO-1234ze(E) in pMDIs is similarly challenging due to many of the factors highlighted above.

[0049] 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 pharmaceutical doses have been delivered. The predetermined number of doses may be 5 to 300, 30 to 200, 60 to 200, 60 to 120, 60, 120, 200, or any other number of doses. The total amount of formulation in the canister may be 1.0 gram (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 metered volume of the metering valve. In one or more embodiments, the total amount of formulation is greater than 1.1, 1.2, 1.3, 1.4, or 1.5 times the product of the predetermined number of doses and the metered volume of the metering valve. This typically ensures that the amount of each dose remains relatively constant throughout the life of the inhaler.

[0050] In one or more embodiments, the formulation may include one or more additional APIs. Cannabinoids are effective in treating many conditions, and co-administration of the cannabinoid with an additional API may improve the effectiveness of the treatment. Exemplary APIs may include those for the treatment of respiratory disorders, such as bronchodilators, e.g., short- or long-acting beta-agonists, anti-inflammatory agents (e.g., corticosteroids), antiallergic agents, antiasthmatic agents, antihistamines, TYK inhibitors, anesthetics, or anticholinergic agents. 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, mirveterol, olodaterol, vilanterol, abesiterol, 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, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof.

[0051] In all embodiments where the formulation includes one or more additional APIs, the APIs are dissolved in the formulation (i.e., in solution). When a combination of two or more APIs is used, all of the APIs are present in solution.

[0052] The amount of cannabinoid delivered may be determined by the required dose per actuation and the pMDI metering valve size, i.e., the size of the metering chamber, which may be 5 microliters (μL or mcl) to 200 microliters, 25 microliters to 200 microliters, 25 microliters to 150 microliters, 25 microliters to 100 microliters, 50 microliters to 100 microliters, 25 microliters to 65 microliters, 50 microliters to 65 microliters, or 50 microliters to 63 microliters.

[0053] As described herein, 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 "off-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 the subject. The dose delivered by a metered dose inhaler may additionally or alternatively be expressed as the amount of cannabinoid that exits the inhaler valve with each actuation. As described in the examples of the present disclosure, 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.

[0054] In certain embodiments, typical formulations of the present disclosure include cannabinoids in an amount of at least 0.05 milligrams per actuation (mg / actuation), or at least 0.5 mg / actuation, hi certain embodiments, formulations of the present disclosure include cannabinoids in an amount of less than 6.0 mg / actuation.

[0055] In one or more embodiments, typical formulations of the disclosure include 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. In embodiments, typical formulations of the disclosure include 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. In some preferred embodiments, the formulations of the present disclosure comprise cannabinoid in an amount of 0.05 mg / actuation to 6.0 mg / actuation, e.g., 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.

[0056] The amount of cannabinoids delivered by a metered-dose inhaler may depend on the composition of cannabinoids in the formulation. For example, a formulation containing only CBD may contain CBD in an amount that delivers 0.05 mg / actuation to 6.0 mg / actuation, e.g., 0.5 mg / actuation to 3.0 mg / actuation, or 0.5 mg / actuation to 1.5 mg / actuation. A formulation containing only THC may contain THC in an amount that delivers 0.2 mg / actuation to 6.0 mg / actuation, e.g., 0.5 mg / actuation to 3.0 mg / actuation, e.g., 0.5 mg / actuation to 1.5 mg / actuation. A formulation containing both THC and CBD may contain THC and CBD in amounts that deliver 0.05 mg / actuation to 6.0 mg / actuation of each of THC and CBD. In some embodiments, a total of 0.05 mg / actuation to 6.0 mg / actuation of combined THC and CBD is delivered.

[0057] It should be noted that the amount of cannabinoid delivered by a metered dose inhaler is the result of a particular combination of factors, including the concentration of the 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 the amount of cannabinoid to be delivered with each metered dose inhaler actuation.

[0058] In one or more embodiments, the concentration of cannabinoids may be described by the weight percent of cannabinoid in the complete formulation. The formulation may be 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 18 mg / mL, at least 19 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL , at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 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 85 mg / mL, 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 cannabinoids, e.g., CBD and / or THC.

[0059] The formulation may contain up to 240 mg / mL, up to 230 mg / mL, up to 220 mg / mL, up to 210 mg / mL, up to 200 mg / mL, up to 190 mg / mL, up to 180 mg / mL, up to 160 mg / mL, up to 140 mg / mL, up to 120 mg / mL, up to 100 mg / mL, up to 90 mg / mL, up to 80 mg / mL, up to 70 mg / mL, up to 60 mg / mL, up to 50 mg / mL, up to 40 mg / mL, or up to 30 mg / mL of cannabinoids, e.g., THC and / or CBD. The formulation may contain, for example, 0.5 mg / mL to 240 mg / mL, e.g., 5 mg / mL to 80 mg / mL, 10 mg / mL to 40 mg / mL, or about 16 mg / mL of cannabinoids, e.g., THC and / or CBD.

[0060] Typically, formulations contain co-solvents.One particularly useful co-solvent is ethanol.In one or more embodiments, ethanol is used as a co-solvent in solution formulations, that is, cannabinoids are dissolved in formulations.In one aspect, co-solvents can help cannabinoids dissolve, but cannabinoids may not be soluble in formulations in the absence of co-solvents.

[0061] Interestingly, it is reported herein that the amount of ethanol sufficient to solubilize cannabinoids in a propellant varies depending on the propellant and cannabinoids used in a given formulation. In particular, the amount of ethanol sufficient to solubilize THC, CBD, or a combination of THC and CBD in HFO-1234ze(E) depends on the cannabinoids in the formulation.

[0062] In one or more embodiments, the formulations described herein may include ethanol in an amount, based on a weight percentage 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% by weight. The formulations described herein may generally include ethanol in an amount, based on a weight percentage of the total formulation, of up to 20%, up to 25%, up to 14%, up to 13%, up to 12%, up to 11%, up to 10%, up to 9%, up to 8%, up to 7%, up to 6%, up to 5%, up to 4%, up to 3%, or up to 2%. The formulations described herein may contain, for example, 1% to 20% by weight ethanol, such as 1% to 15%, 1% to 8%, or 2% to 6% by weight ethanol.

[0063] In one or more embodiments in which the formulation includes CBD and THC, the formulation may include ethanol in an amount between 1% and 20%, e.g., between 4% and 15%, or between 5% and 8%, by weight of the total formulation.

[0064] In one or more embodiments where the formulation includes CBD and does not include a substantial amount of THC, the formulation may include ethanol in an amount between 3% and 20%, e.g., between 4% and 15%, or between 5% and 8%, by weight percent of the total formulation.

[0065] In one or more embodiments where the formulation contains THC but does not contain a substantial amount of CBD, the formulation may contain ethanol in an amount between 1% and 15%, e.g., between 1% and 10%, or between 1% and 4%, by weight percent of the total formulation.

[0066] In another aspect, the co-solvent can reduce the deposition of cannabinoids during actuation of the metered dose inhaler. For example, some propellants may rapidly evaporate when or before the formulation passes through the actuator. When ethanol is included in the formulation, it can delay the evaporation of the formulation until it passes through the actuator and exits the metered dose inhaler. Thus, the inclusion of ethanol can reduce the amount of deposition of the formulation on components of the metered dose inhaler.

[0067] In one or more embodiments, the formulations described herein may include a co-solvent in an amount sufficient to prevent clogging of the actuator, hi one or more embodiments, the formulations described herein may include a co-solvent in an amount sufficient to prevent clogging 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 compared to a formulation without the co-solvent.

[0068] In one or more embodiments, the formulation may include an amount of cosolvent to improve the consistency of the dose delivered throughout the life of the metered-dose inhaler. For example, the formulation may include a sufficient amount of cosolvent to reduce formulation deposition during actuation of the metered-dose inhaler. Formulation deposition during actuation of the metered-dose inhaler can clog the valve stem or upper valve stem components or otherwise clog the actuator nozzle. If formulation deposition during actuation is reduced, the delivered dose consistency can remain relatively consistent throughout the life of the metered-dose inhaler. Formulation deposition during actuation can completely prevent the metered-dose inhaler from functioning. For example, formulation deposition can prevent further actuation of the metered-dose inhaler. Formulation deposition can additionally or alternatively reduce or otherwise undesirably alter the dose delivered by the metered-dose inhaler.

[0069] In one or more embodiments, the metered dose inhalers described herein deliver an amount of cannabinoid per actuation that is consistent within a predetermined range over the life of the metered dose inhaler. The metered dose inhalers described herein may deliver an amount of cannabinoid per actuation that is within 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% of the intended dose over the life of the metered dose inhaler. As used herein, the "life" and "unit life" of a metered dose inhaler encompass the time it takes to actuate a predetermined number of doses from the inhaler. It should be understood that the "life" and "unit life" of a metered dose inhaler are different from the "shelf life" of a metered dose inhaler. The "shelf life" of a metered dose inhaler typically refers to the length of time that the product is considered stable and safe for delivery, although "unit life" or "lifespan" may be measured without significant storage time; for example, a unit may be tested through a series of a predetermined number of closely spaced actuations, such as over the course of one or several hours.

[0070] The consistency of the dose delivered by a metered dose inhaler may additionally or alternatively be expressed as the minimum percentage of the initial intended dose delivered over the life of the metered dose inhaler. For example, a metered dose inhaler intended to deliver 1.0 mg / actuation may deliver 1.0-0.8 mg / actuation over its life and be said to have delivered at least 80% of the intended dose over its life. In one or more embodiments, the 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 the intended dose per actuation over its life.

[0071] In one or more embodiments, propellants, co-solvents, and additional ingredients other than the cannabinoid (e.g., excipients) can be added to the formulation. These ingredients can have a variety of uses and functions, including, but not limited to, aiding in the dissolution of the cannabinoid or other ingredients and / or aiding in the chemical stabilization of the cannabinoid or other ingredients.

[0072] In one or more embodiments, the formulations described herein may also include additional ingredients to impart desired consumer characteristics, such as scent, taste, color, or viscosity. Exemplary additional ingredients include, for example, colorants or flavoring or masking ingredients.

[0073] The flavoring or masking component may comprise a flavonoid, a terpene, or a terpenoid. Non-limiting examples of flavonoids include quercetin, luteolin, vitexin, isovitexin, cannaflavin A, cannaflavin B, cannaflavin C, apigenin, kaempferol, and orientin. Non-limiting examples of terpenoids include A3-carene, B-selinene, 3-pinene, f-phellandrene, β-farnesene, β-caryophyllene, β-pinene, β-eudesmol, o-terpinolene, α-pinene, o-phellandrene, o-humulene, α-bergamotene, α-terpineol, α-terpinene, α-pinene, α-humulene, o-guaiene (t), α-cedrene, α-bisabolol, valencene (t), trans-ocimene, trans-ocimene, trans-caryophyllene, terpinolene, t=2-pinanol (t), serine, Na-3,7-(11)-diene, serina-3,7(11)-diene (t), sabinene hydrate, nerol, myrcene, menthol, linalool, limonene, isoborneol, guaiol, guaia-1(10),11-diene (t), germacrene B (t), geraniol, farnesene (t), eudesmu-7(11)''-en-4-ol (t), elemene (t), cis-ocimene, caryophyllene oxide, camphor, camphene, borneol, and (+)-fenchol. Non-limiting examples of terpenes include hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, sesquiterpenes, tetraterpenes, polyterpenes, and norisoprenoids, as well as naturally occurring terpenes found in the cannabis plant, 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.

[0074] In one or more embodiments, the formulations described herein exhibit physical stability under typical storage conditions (e.g., refrigeration at temperatures between 2° C. and 8° C.) such that no visible particles are present for at least 6 months, e.g., at least 12 months or at least 18 months, and often between 6 months and 36 months. In certain embodiments, the formulations herein preferably exhibit chemical stability under typical storage conditions (e.g., refrigeration at temperatures between 2° C. and 8° C.) such that no degradation products are formed for at least 6 months, e.g., at least 12 months or at least 18 months, and often between 6 months and 36 months.

[0075] Various embodiments of the formulations described herein can be utilized with any suitable inhaler. For example, FIG. 1 shows one embodiment of a metered dose inhaler 100, including an aerosol canister 1 to which is attached a metered dose metering valve 10 (shown in its rest position). The metering valve 10 is typically secured, or crimped, onto the canister 1 via a cap or ferrule 11 (typically made of aluminum or an aluminum alloy) that is commonly provided as part of the valve assembly. There may be one or more seals between the canister and the ferrule. In the embodiment shown in FIGS. 1 and 2, there are two seals between the canister 1 and the ferrule 11, including, for example, an O-ring seal and a gasket seal. In one or more embodiments, the canister may be uncoated, such as an uncoated aluminum canister. In one or more other embodiments, the canister may be coated, such as with a silicon-containing coating. The coating may reduce the likelihood of cannabinoid deposition on the interior surface of the canister.

[0076] As shown in Figure 1, a canister / valve dispenser typically comprises an actuator 5 that includes a suitable patient port 6, such as a mouthpiece. For administration to the nasal cavity, the patient port is generally provided in a suitable form for delivery through the nose (e.g., a smaller diameter tube, often tapered upward). The actuator is generally made from a plastic material, such as polypropylene or polyethylene. As can be seen in Figure 1, the inner wall 2 of the canister 1 and the outer wall 101 of the portion of the metering valve 10 located within the canister define a formulation chamber 3 in which the aerosol formulation 4 is contained.

[0077] The valve 10 shown in Figures 1 and 2 includes a metering chamber 12 defined in part by an inner valve body 13 through which passes a valve stem 14. The valve stem 14, 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) partially defines the metering chamber 12. The second valve body 20 (also referred to as the "secondary" valve body), in addition to functioning as a bottle emptier, partially defines a pre-metering area or chamber.

[0078] 2, aerosol formulation 4 can pass from formulation chamber 3 through an annular space 21 between flange 23 of secondary valve body 20 and primary valve body 13 into a pre-metering chamber 22 located between secondary valve body 20 and primary valve body 13. To actuate (fire) valve 10, valve stem 14 is forced inwardly relative to canister 1 from its rest position shown in FIGS. 1 and 2, allowing formulation to pass from metering chamber 12 through side hole 19 in the valve stem, through stem outlet 24 to actuator nozzle 7 and then to the patient. When valve stem 14 is released, formulation passes through annular space 21 into valve 10, particularly pre-metering chamber 22, and from there from the pre-metering chamber through groove 18 in the valve stem, past tank seal 16 and into metering chamber 12.

[0079] Figure 3 shows another embodiment of a metered dose aerosol metering valve 102 in its rest position, different from the embodiment shown in Figures 1 and 2. Valve 102 has a metering chamber 112 defined in part by a metering reservoir 113, through which a stem 114 is biased outward by a spring 115. Stem 114 is made of two parts that are press-fit together before assembly into valve 102. Stem 114 has inner and outer seals 116 and 117 disposed therearound that form a sealing contact with metering reservoir 113. Valve body 120, crimped into ferrule 111, retains the above-mentioned components within the valve. In use, formulation enters the metering chamber through orifices 121 and 118. The outward path of formulation from metering chamber 112 when a dose is dispensed is through orifice 119.

[0080] Devices that may be used with the pharmaceutical formulations of the present invention include those described in U.S. Pat. No. 6,032,836 (Hiscocks et al.), U.S. Pat. No. 9,010,329 (Hansen), and British Patent No. 2544128(B) (Friel).

[0081] 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, for example, in U.S. Pat. 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 entireties for their disclosures regarding dose counters.

[0082] Some coatings that can be used are described in U.S. Patent No. 8,414,956 (Jiinks et al.), U.S. Patent No. 8,815,325 (David et al.), and U.S. Patent Application Publication No. 2012 / 0097159 (Iyer et al.), all of which are incorporated by reference in their entirety for their disclosure of coatings for inhalers and inhaler components. Suitable coatings can include polytetrafluoroethylene (PTFE), fluorinated ethylene propylene resin (FEP), and fluorocarbon polymer (FCP).

[0083] In one or more embodiments, the actuator nozzle is sized to optimize the delivered fine particle fraction (FPF) and / or respirable dose of the formulation in the canister. In one or more embodiments, the cross-sectional shape of the actuator nozzle is essentially circular or circular and has a predetermined diameter. In one or more embodiments where the cross-sectional shape of the actuator nozzle is non-circular, for example elliptical, the effective diameter may be determined by taking the average over the distance spanning the opening (e.g. the average of the major and minor axes of the ellipse).

[0084] In one or more embodiments, the actuator nozzle exit orifice (effective diameter) 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 actuator nozzle exit orifice (effective diameter) 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.

[0085] In one or more embodiments, the actuator nozzle exit orifice (effective diameter) may be between 0.10 mm and 0.50 mm. In one or more embodiments, the actuator nozzle exit orifice (effective diameter) may be between 0.15 mm and 0.50 mm. In one or more embodiments, the actuator nozzle exit orifice (effective diameter) may be between 0.20 mm and 0.45 mm. In one or more embodiments, the actuator nozzle exit orifice (effective diameter) may be between 0.25 mm and 0.40 mm. In one or more embodiments, the actuator nozzle exit orifice (effective diameter) may be between 0.28 mm and 0.35 mm.

[0086] Those skilled in the art will appreciate that a given actuator nozzle exit orifice may not be suitable for the delivery of every formulation, and that selecting a suitable actuator nozzle exit orifice for a given formulation may require significant effort. Selecting a suitable actuator nozzle exit orifice can improve the consistency of the dose delivered by the metered dose inhaler and / or reduce the likelihood of formulation deposition during actuation. The actuator nozzle exit orifice may further modify the properties of the delivered aerosol, such as the fine particle fraction (FPF) and / or median mass aerodynamic diameter (MMAD), as described in more detail herein.

[0087] In one or more embodiments, the metered dose inhalers disclosed herein can deliver a dose containing a specified fine particle fraction (FPF). As used herein, FPF refers to the mass percentage of API particles having an aerodynamic diameter of less than 5 micrometers (μm) relative to the total emitted dose. The FPF can be determined using any field-standard method, such as using an impactor device. As described herein, the FPF delivered by a metered dose inhaler is affected by several considerations, including the size and shape of the actuator. In one or more embodiments, the metered dose inhaler can deliver an aerosol containing an 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%. In one or more embodiments, the metered dose inhaler can deliver an aerosol containing an 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%.

[0088] One metric used to describe a formulation delivered by a metered dose inhaler is the median mass aerodynamic diameter (MMAD). MMAD is a measure of the size of particles delivered by a metered dose inhaler. Different MMAD measurements and ranges may be desirable for different applications. In one or more embodiments, a metered dose inhaler can deliver particles with an MMAD of at least 0.5 μm, at least 1 μm, at least 1.25 μm, at least 1.5 μm, at least 1.75 μm, at least 2 μm, at least 2.25 μm, at least 2.5 μm, at least 2.75 μm, at least 3 μm, at least 3.5 μm, or at least 4 μm. In one or more embodiments, a metered dose inhaler can deliver particles with an MMAD of at most 10 μm, at most 9 μm, at most 8 μm, at most 7 μm, at most 6.5 μm, at most 6.0 μm, at most 5.5 μm, or at most 5 μm.

[0089] The metering valve of a metered dose inhaler may have any suitable volume for delivering a dose of the formulation. The selection of the volume of the metering valve may affect the amount of formulation delivered. Thus, in embodiments where the metered dose inhaler contains a formulation comprising one or more cannabinoids, the volume of the metering valve will affect the amount of cannabinoid delivered. In one or more embodiments, the volume of the metering valve may be at least 30 μL, at least 40 μL, at least 50 μL, at least 60 μL, at least 70 μL, at least 80 μL, at least 90 μL, at least 100 μL, at least 110 μL, at least 120 μL, at least 130 μL, at least 140 μL, at least 150 μL, at least 175 μL, at least 200 μL, at least 225 μL, at least 250 μL, at least 275 μL, at least 300 μL, or at least 400 μL. The volume of the metering valve may be at most 500 μL, at most 450 μL, at most 400 μL, at most 350 μL, at most 300 μL, at most 275 μL, at most 250 μL, at most 225 μL, at most 200 μL, at most 175 μL, at most 150 μL, at most 125 μL, at most 100 μL, at most 75 μL, or at most 50 μL. The volume of the metering valve may be 30 to 100 μL, for example, 40 to 80 μL, or 50 to 70 μL.

[0090] Those skilled in the art will appreciate that a given valve volume may not be suitable for delivery of every formulation, and that selecting a valve volume for a given formulation can involve considerable effort.

[0091] In one or more embodiments, metered dose inhalers are manufactured by pressure filling. In pressure filling, a liquid or powdered drug combined with one or more excipients (e.g., cosolvents) is placed in a suitable aerosol container (i.e., canister) that can withstand the vapor pressure of the propellant and is equipped with a metering valve before filling. The propellant is then forced as a liquid through the valve into the container. In an alternative process to pressure filling, a particulate API is combined with a propellant and one or more excipients (e.g., cosolvents) in a process container, and the resulting API solution is transferred through a metering valve attached to a suitable metered dose inhaler container.

[0092] In one or more embodiments, the metered dose inhaler is manufactured by cold-filling, in which a liquid or powdered medicament is combined with one or more excipients (e.g., cosolvents) and a propellant cooled below its boiling point, and optionally one or more excipients are added to a metered dose inhaler container, and a metering valve is attached to the container after filling.

[0093] For both pressure-fill and cold-fill processes, additional steps such as mixing, sonication, and homogenization of the formulation may optionally be used.

[0094] Embodiment Embodiment 1 is a metered dose inhaler comprising a metering valve, a canister, and an actuator comprising an actuator nozzle, the canister containing a formulation, the formulation comprising HFO-1234ze(E), at least 1% by weight of ethanol, and a propellant comprising one or more cannabinoids, the one or more cannabinoids being dissolved in the formulation to form a solution.

[0095] Embodiment 2 is the metered dose inhaler of Embodiment 1, wherein the metered dose inhaler delivers between 1.0 milligrams (mg) and 3.0 mg / actuation of the one or more cannabinoids.Embodiment 3 is the metered dose inhaler of Embodiment 2, wherein the formulation comprises between 4% and 15% ethanol by weight.Embodiment 4 is the metered dose inhaler of Embodiment 3, wherein the formulation comprises between 5% and 8% ethanol by weight.Embodiment 5 is the metered dose inhaler of any one of Embodiments 1-4, wherein the one or more cannabinoids comprise tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0096] Embodiment 6 is a metered dose inhaler of embodiment 5, wherein the ratio of THC to CBD is 1:1 by weight.

[0097] Embodiment 7 provides a pMDI metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle, wherein the canister contains a formulation, the formulation comprising a propellant comprising HFO-1234ze(E), at least 1% by weight of ethanol, and THC, wherein the THC is dissolved in the formulation to form a solution.

[0098] Embodiment 8 is the metered dose inhaler of embodiment 7, wherein the formulation comprises 0.5% to 15% 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.

[0099] Embodiment 12 provides a pMDI metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister contains a formulation; the formulation comprises a propellant comprising HFO-1234ze(E), at least 1% by weight of ethanol, and CBD; and the CBD is dissolved in the formulation to form a solution.

[0100] Embodiment 13 is the metered dose inhaler of embodiment 12, wherein the formulation comprises 4% to 15% ethanol by weight.Embodiment 14 is the metered dose inhaler of embodiment 13, wherein the formulation comprises 5% to 8% ethanol by weight.Embodiment 15 is the metered dose inhaler of any one of embodiments 12 to 14, wherein the metered dose inhaler delivers between 0.5 mg / actuation and 1.5 mg / actuation of CBD.

[0101] Embodiment 16 is the metered dose inhaler of any one of embodiments 1 to 15, further comprising an excipient. Embodiment 17 is the metered dose inhaler of any one of embodiments 1 to 16, in which HFO-1234ze(E) is the only propellant. Embodiment 18 is the metered dose inhaler of any one of embodiments 1 to 17, in which the formulation comprises ethanol in an amount sufficient to reduce sedimentation of the formulation in the valve or actuator during actuation of the metered dose inhaler compared to a formulation not comprising ethanol. Embodiment 19 is the metered dose inhaler of any one of embodiments 1 to 18, in which the formulation comprises ethanol in an amount sufficient to reduce sedimentation of the formulation in the valve or actuator during actuation of the metered dose inhaler compared to a formulation not comprising excipients, after at least 15 actuations. Embodiment 20 is the metered dose inhaler of any one of embodiments 1 to 19, in which the metered dose inhaler delivers a consistent dose of cannabinoid through at least 60 actuations. Embodiment 21 is the metered dose inhaler of any one of embodiments 1 to 20, in which the metered dose inhaler exhibits a dose consistency of at least 0.5 mg / actuation over the life of the unit. Embodiment 22 is the metered dose inhaler of any one of embodiments 1 to 21, wherein the metered dose inhaler exhibits a dose consistency of at least 1.0 mg / actuation over its lifetime. Embodiment 23 is the metered dose inhaler of any one of embodiments 1 to 22, wherein the metered dose inhaler delivers at least 50% of the predetermined dose per actuation over its lifetime. Embodiment 24 is the metered dose inhaler of any one of embodiments 1 to 23, wherein the metered dose inhaler delivers particles having a mean mass aerodynamic diameter of 2.0 μm to 4.0 μm. Embodiment 25 is the metered dose inhaler of any one of embodiments 1 to 24, wherein the metered dose inhaler delivers an aerosol comprising a fine particle fraction of 10% to 70%. Embodiment 26 is the metered dose inhaler of any one of embodiments 1 to 25, wherein the metered dose inhaler delivers particles having a median mass aerodynamic diameter of 1.5 μm to 6 μm. Embodiment 27 is the metered dose inhaler of any one of embodiments 1 to 26, wherein the metered dose inhaler delivers an amount of cannabinoid per actuation within 35% of the intended dose over the life of the metered dose inhaler. [Example]

[0102] Example 1 In this example, the visual solubility of formulations containing delta-9-THC, CBD, or a mixture of delta-9-THC and CBD in HFO-1234ze(E) with different amounts of ethanol was evaluated.

[0103] A saturated solution containing HFO-1234ze(E), ethanol, and 15.87 mg / mL CBD was prepared according to Table 1. A formulation containing HFO-1234ze(E) and 15.87 mg / mL delta-9-THC was prepared according to Table 1. A formulation containing HFO-1234ze(E), ethanol, 15.78 mg / mL CBD, and 15.78 mg / mL delta-9-THC was prepared according to Table 1. Each formulation was prepared at ambient conditions. Aliquots of each formulation were stored at ambient conditions or refrigerated at 5°C for 14 days. After 14 days, the visual solubility of each formulation was measured. A cloudy solution or evidence of particles, precipitate, or residue indicated that the CBD and / or delta-9-THC were not visually soluble. The results of this analysis are summarized in Table 1. It was also observed that all formulations containing THC were slightly yellow.

[0104] [Table 1]

[0105] The solubility or insolubility of each formulation was observed to be the same whether the formulation was stored at 5°C or ambient conditions. This example demonstrates that CBD is soluble at a concentration of at least 15.87 mg / mL in formulations containing HFO-1234ze(E) and 6% ethanol by weight. Delta-9-THC is soluble at a concentration of at least 15.87 mg / mL in formulations containing HFO-1234ze(E) and 4%, 5%, or 6% ethanol by weight. Additionally, a mixture of at least 15.87 mg / mL delta-9-THC and at least 15.87 mg / mL CBD was soluble in formulations containing HFO-1234ze(E) and 6% or 8% ethanol by weight.

[0106] Example 2 In this example, the equilibrium saturation solubilities of delta-9-THC and CBD in HFO-1234ze(E) were individually measured.

[0107] Formulations of either CBD or delta-9-THC were prepared in HFO-1234ze(E) without any additional cosolvent. 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. The first set of solutions was then shaken at room temperature for four days. The second set of solutions was stored at 5°C and manually shaken several times daily. After four days, each solution was filtered to remove undissolved CBD and / or delta-9-THC, and the concentration of each cannabinoid was measured. The formulations were evaluated for solubility at room temperature and 5°C.

[0108] This example shows that the equilibrium saturation solubility of CBD in HFO-1234ze(E) is 5.5 mg / mL at room temperature and 5.0 mg / mL at 5° C. The equilibrium saturation solubility of delta-9-THC in HFO-1234ze(E) is also shown to be 5.5 mg / mL at room temperature and 5.1 mg / mL at 5° C.

[0109] Comparative Example 3 In this example, the equilibrium saturation solubility of CBD or delta-9-THC in HFA-227 and HFA-134a was measured individually.

[0110] Formulations of either CBD or delta-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. After shaking each solution at room temperature for 4 days, each solution was filtered to remove undissolved CBD and / or delta-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.

[0111] The equilibrium saturation solubility of CBD in HFA-134a was observed to be 2.5 mg / mL, and the equilibrium saturation solubility of CBD in HFA-227 was observed to be 1.8 mg / mL. The equilibrium saturation solubility of Δ-9-THC in HFA-134a was also observed to be 2.3 mg / mL, and the equilibrium saturation solubility of THC in HFA-227 was observed to be 1.5 mg / mL.

[0112] From this example, and by comparing the results of this example with those of Example 2, it was found that the solubility of CBD or THC in one propellant does not indicate the solubility of the same molecule in a different propellant. For example, CBD and delta-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.

[0113] Example 4 In this example, the aerodynamic particle size distribution (APSD) of three formulations containing HFO-1234ze(E), ethanol, and CBD, delta-9-THC, or a combination of delta-9-THC and CBD was measured using a next generation impactor (NGI).

[0114] The first formulation was prepared in HFO-1234ze(E) containing 15.87 mg / mL delta-9-THC and 5% by weight ethanol. The second formulation was prepared in HFO-1234ze(E) containing 15.87 mg / mL CBD and 6% by weight ethanol. The third formulation was prepared in HFO-1234ze(E) containing 15.78 mg / mL CBD, 15.87 mg / mL delta-9-THC, and 8% by weight ethanol. Each formulation was pressure-filled into an uncoated aluminum canister fitted with a 63 μL valve (APTAR). Three replicate units of each formulation were prepared and tested as described below.

[0115] Each unit was primed using four actuations before measurements were taken. Following unit priming, APSD measurements were taken at the beginning of the unit's life. Each formulation was delivered to the NGI using a USP throat, and APSD metrics for delta-9-THC and / or CBD were measured. Fine particle mass (FPM) smaller than 5 μm per actuation, median mass aerodynamic diameter (MMAD), delivered dose (outside the actuator), dose exiting the pMDI valve (outside the valve), and delivery to the throat were also measured for each unit tested. FPF was calculated using the FPM percentage of the dose delivered outside the actuator. The average results of three replicates are shown in Table 2.

[0116] [Table 2]

[0117] All three formulations were observed to produce satisfactory aerosols and respirable particles with relatively good overall efficiency as measured by FPF%. All three formulations achieved the expected delivered dose. Furthermore, the delivered dose was consistent whether the formulation contained delta-9-THC or CBD alone, or whether the formulation contained both delta-9-THC and CBD.

[0118] The out-of-actuator delivered dose was observed to be lower than the out-of-valve delivered dose for all three formulations, this difference was attributed to loss of cannabinoids as the formulations exited the actuator.

[0119] Formulations containing delta-9-THC but no CBD were observed to produce the highest FPF% and smallest MMAD. Formulations containing both CBD and delta-9-THC were observed to produce a lower FPF% and had the largest MMAD.

[0120] From this example, it is concluded that modifying metered dose inhaler formulations containing delta-9-THC and / or CBD to contain different amounts of delta-9-THC, CBD, and ethanol significantly affects the solubility of the cannabinoids as well as the aerodynamic properties and particle size of the delivered dose.

[0121] The embodiments described above and illustrated in the drawings are presented by way of example only and are not intended as limitations on the concepts and principles of the present disclosure. Accordingly, it will be understood by those skilled in the art that various changes in the elements and their configuration and arrangement may be made without departing from the spirit and scope of the present disclosure. All references and publications cited herein are expressly incorporated by reference in their entirety into this disclosure. Various features and aspects of the present disclosure are set forth in the following claims.

Claims

1. 1. A metered dose inhaler comprising: A metering valve; A canister and an actuator having an actuator nozzle; the canister contains a formulation, the formulation comprising HFO-1234ze(E), at least 1% by weight of ethanol, and a propellant comprising one or more cannabinoids; A metered dose inhaler wherein the one or more cannabinoids are dissolved in the formulation to form a solution.

2. 10. The metered dose inhaler of claim 1, wherein the metered dose inhaler delivers between 1.0 milligrams (mg) and 3.0 mg / actuation of the one or more cannabinoids.

3. 3. A metered dose inhaler according to claim 2, wherein the formulation comprises 4% to 15% ethanol by weight.

4. 4. A metered dose inhaler according to claim 3, wherein the formulation comprises 5% to 8% ethanol by weight.

5. 5. A metered dose inhaler according to any one of claims 1 to 4, wherein the one or more cannabinoids comprise tetrahydrocannabinol (THC) and cannabidiol (CBD).

6. 6. The metered dose inhaler of claim 5, wherein the weight ratio of THC to CBD is 1:

1.

7. 1. A metered dose inhaler comprising: A metering valve; A canister and an actuator having an actuator nozzle; the canister contains a formulation, the formulation comprising HFO-1234ze(E), at least 1% by weight of ethanol, and a propellant comprising THC; A metered dose inhaler, wherein the THC is dissolved in the formulation to form a solution.

8. 8. A metered dose inhaler according to claim 7, wherein the formulation comprises from 1% to 15% ethanol by weight.

9. 9. A metered dose inhaler according to claim 8, wherein the formulation comprises 1% to 4% ethanol by weight.

10. A metered dose inhaler according to any one of claims 5 to 9, wherein the THC is delta-9-tetrahydrocannabinol.

11. 11. A metered dose inhaler according to any one of claims 7 to 10, wherein the metered dose inhaler delivers between 0.5mg / actuation and 1.5mg / actuation of THC.

12. 1. A metered dose inhaler comprising: A metering valve; A canister and an actuator having an actuator nozzle; the canister contains a formulation, the formulation comprising HFO-1234ze(E), at least 1% by weight of ethanol, and a propellant comprising CBD; A metered dose inhaler, wherein the CBD is dissolved in the formulation to form a solution.

13. 13. A metered dose inhaler according to claim 12, wherein the formulation comprises between 4% and 15% ethanol by weight.

14. 14. A metered dose inhaler according to claim 13, wherein the formulation comprises 5% to 8% ethanol by weight.

15. 15. A metered dose inhaler according to any one of claims 12 to 14, wherein the metered dose inhaler delivers between 0.5mg / actuation and 1.5mg / actuation of CBD.

16. A metered dose inhaler according to any preceding claim, further comprising an excipient.

17. A metered dose inhaler according to any preceding claim, wherein HFO-1234ze(E) is the only propellant.

18. 18. A metered dose inhaler according to any one of claims 1 to 17, wherein the formulation comprises ethanol in an amount sufficient to reduce deposition of the formulation in the valve or actuator during actuation of the metered dose inhaler compared to a formulation not containing ethanol.

19. 19. A metered dose inhaler according to any one of claims 1 to 18, wherein the formulation comprises ethanol in an amount sufficient to reduce deposition of the formulation in the valve or actuator during actuation of the metered dose inhaler compared to a formulation containing no excipients after at least 15 actuations.

20. 20. A metered dose inhaler according to any preceding claim, wherein the metered dose inhaler delivers a consistent dose of cannabinoid over at least 60 actuations.

21. 21. A metered dose inhaler according to any preceding claim, wherein the metered dose inhaler exhibits a dose consistency of at least 0.5 mg per actuation over the life of the unit.

22. 22. A metered dose inhaler according to any preceding claim, wherein the metered dose inhaler exhibits a dose consistency of at least 1.0 mg / actuation over its lifetime.

23. A metered dose inhaler according to any preceding claim, wherein the metered dose inhaler delivers at least 50% of the predetermined dose per actuation over its lifetime.

24. 24. A metered dose inhaler according to any preceding claim, wherein the metered dose inhaler delivers particles having a mean mass aerodynamic diameter of between 2.0 μm and 4.0 μm.

25. 25. A metered dose inhaler according to any preceding claim, wherein the metered dose inhaler delivers an aerosol containing a fine particle fraction of from 10% to 70%.

26. 26. A metered dose inhaler according to any preceding claim, wherein the metered dose inhaler delivers particles having a median mass aerodynamic diameter of between 1.5 μm and 6 μm.

27. 27. A metered dose inhaler according to any one of claims 1 to 26, wherein the metered dose inhaler delivers an amount of cannabinoid per actuation within 35% of the intended dose over the life of the metered dose inhaler.

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