Quantitative inhaler and high-dose suspension

Abstract

A metered-dose inhaler comprising a metering valve, a canister, and an actuator equipped with an actuator nozzle, wherein the canister contains a formulation comprising more than 70% by weight of HFO-1234ze(E) and at least one active pharmaceutical ingredient suspended in the formulation, and the metered-dose inhaler delivers at least 0.5 milligrams (mg) of at least one active pharmaceutical ingredient per action. A metered-dose inhaler comprising a metering valve, a canister, and an actuator equipped with an actuator nozzle, wherein the canister contains a formulation comprising more than 70% by weight of HF-152a and at least one active pharmaceutical ingredient suspended in the formulation, and the metered-dose inhaler delivers at least 0.5 milligrams (mg) of at least one active pharmaceutical ingredient per action.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 315,337, filed Mar. 1, 2022, the entire contents of which are incorporated herein by reference.

Background Art

[0002] Delivery of aerosolized drugs to the airway for the treatment of respiratory and other diseases can be performed, for example, using pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), or nebulizers. PMDIs are well known to many patients suffering from asthma or chronic obstructive pulmonary disease (COPD). A pMDI device can include an aluminum canister sealed with a metering valve that contains a pharmaceutical formulation. Generally, typical current pharmaceutical formulations include one or more pharmaceutical compounds present in a liquefied hydrofluoroalkane (HFA) propellant.

[0003] Historically, most propellants in pMDIs were chlorofluorocarbons (CFCs). However, due to environmental concerns in the 1990s, CFCs were replaced by hydrofluoroalkanes (HFAs) as the most commonly used propellants in pMDIs. HFAs do not cause ozone depletion, but they have a high published global warming potential (GWP), which is a measure of the future radiative effects of emissions of a substance compared to emissions of the same amount of carbon dioxide (CO2). The two most commonly used HFA propellants in pMDI 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.

[0004] Various other propellants have been proposed over the years. Among them, hydrofluoroolefins (HFOs) and carbon dioxide (CO2) have been mentioned as potential propellants for pMDI, but no pMDI products have been successfully developed or commercialized using either of these as propellants. HFA-152a, also known as HFC-152a, DFE, or R-152a (C2H4F2, 1,1-difluoroethane), and HFO-1234ze(E), also known as R-1234ze (C3H2F4, (1E)-1,3,3,3-tetrafluoropropene) have been found to be usable as pMDI propellants. One advantage of such pMDI is its low specified GWP. [Overview of the project]

[0005] 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 including an actuator nozzle, wherein the canister comprises a formulation, the formulation (i.e., composition) comprising more than 70% by weight of HFO-1234ze(E) and at least one active pharmaceutical ingredient suspended in the formulation, and the metered-dose inhaler delivers at least 0.5 milligrams (mg) of the at least one active pharmaceutical ingredient per action.

[0006] In one embodiment, a metered-dose inhaler is provided, comprising a metering valve, a canister, and an actuator including an actuator nozzle, wherein the canister contains a formulation, the formulation comprising more than 70% by weight of HFA-152a and at least one active pharmaceutical ingredient suspended in the formulation, and the metered-dose inhaler delivers at least 0.5 milligrams (mg) of the at least one active pharmaceutical ingredient per action.

[0007] In this specification, the term “comprises” and its variations are not limited in meaning when they appear in the specification and claims. Such terms are understood to mean that they include the steps or elements, or groups of steps or elements, described, but not exclude any other steps or elements, or groups of steps or elements. The phrase “consisting of” means “including” and is limited to what follows the phrase. Thus, the phrase “consisting of” indicates that the enumerated elements are necessary or essential, and other elements are optional. The phrase “consisting essentially of” means that it includes any elements enumerated after it, and is limited to other elements that do not interfere with or contribute to the activity or action of the enumerated elements as expressed in this disclosure. Thus, the phrase “consisting essentially of” indicates that the enumerated elements are necessary or essential, but other elements are optional and may or may not be present, depending on whether they substantially affect the activity or action of the enumerated elements. Any element or combination of elements described in this specification using non-restrictive language (e.g., comprise and its derivatives) is considered to be further described using restrictive language (e.g., consist and its derivatives) and partially restrictive language (e.g., consist essentially and its derivatives).

[0008] The terms “preferred” and “preferably” refer to embodiments of the Disclosure that may provide a particular benefit under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the enumeration of one or more preferred embodiments does not imply that other embodiments are unhelpful, nor is it intended to exclude other embodiments from the scope of the Disclosure.

[0009] Throughout this disclosure, singular forms such as "a," "an," and "the" are often used for convenience. The singular form, unless explicitly specified by the singular alone or clearly indicated by the context, includes the plural form.

[0010] As used herein, the term “or” is generally used in its ordinary sense, including “and / or,” unless the context clearly indicates otherwise.

[0011] The term "and / or" means one or all of the enumerated elements, or any combination of two or more of the enumerated elements.

[0012] As used herein, the term "ambient conditions" refers to an environment with room temperature (approximately 20°C to 25°C) and relative humidity of 30% to 60%.

[0013] Furthermore, in this specification, all numbers are assumed to be modified by the term “about,” and, in certain embodiments, preferably by the term “exactly.” Where used herein in relation to a quantity being measured, the term “about” refers to the variation of the quantity being measured that would be expected by a person skilled in the art who performs the measurement and exercises a degree of care commensurate with the purpose of the measurement and the precision of the measuring instrument used. In this specification, “up to” a number (e.g., up to 50) includes that number (e.g., 50). In this specification, “at least” a number (e.g., at least 50) includes that number (e.g., 50). In this specification, “less than” a number (e.g., 50 or less) includes that number (e.g., 50).

[0014] A numerical range, such as "between x and y" or "from x to y," includes the endpoint values ​​of x and y. Furthermore, in this specification, an enumeration of numerical ranges by endpoints includes all numbers contained within that range, as well as both endpoints (for example, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0015] Some terms used in this application have special meanings as defined herein. All other terms are known to those skilled in the art and should be given the meanings that those skilled in the art would have given them at the time of the invention.

[0016] Elements referred to herein as “common,” “commonly used,” “conventional,” “typical,” and “typically” should be understood as common within the context of the compositions, inhalers, and other articles, as well as the methods, of this disclosure. These terms are not used to imply that these features are present in the prior art and are not particularly common in the prior art. Unless otherwise specified, only the background art section of this application refers to the prior art.

[0017] Throughout this specification, references to “one embodiment,” “embodiment,” “a particular embodiment,” “one or more embodiments,” or “several embodiments” mean that any particular feature, configuration, composition, or characteristic described in relation to an embodiment is included in at least one embodiment of this disclosure. Therefore, the appearance of such phrases in various places throughout this specification does not necessarily refer to the same embodiment of this disclosure. Furthermore, particular features, configurations, compositions, and characteristics can be combined in any suitable manner in one or more embodiments.

[0018] This disclosure will be described with reference to specific drawings with respect to embodiments, but the present invention is not limited thereto. The drawings described are schematic and non-limiting. In the drawings, the sizes of some elements may be exaggerated for illustrative purposes and may not be drawn to scale.

[0019] The above summary of this disclosure is not intended to describe each embodiment or all implementations disclosed herein. The following description provides more specific examples of exemplary embodiments. Guidance is provided in several places in this disclosure through lists of examples, which can be used in various combinations. In each example, the enumerated list is presented only as a representative group and should not be construed as an exclusive or exhaustive list. Accordingly, the scope of this disclosure should not be limited to the specific exemplary structures described herein, but rather to structures described at least by the language of the claims, and their equivalents. Any of the elements positively listed herein as substitutes may be expressly included in the claims or excluded from the claims in any desired combination. Various theories and possible mechanisms are discussed herein, but such discussions should not serve to limit the subject matter of the claims.

[0020] The complete disclosure of all patents, patent applications, and publications, as well as electronically available materials, referenced herein are incorporated by reference in their entirety. In the event of any inconsistency between this disclosure and any disclosure of any document incorporated herein by reference, this disclosure shall prevail. The detailed description and examples herein are provided for the purpose of clarifying understanding; no unnecessary limitations should be construed therefrom. The present invention is not limited to the exact details shown and described, and modifications that are obvious to those skilled in the art are included within the scope of the invention as defined by the claims.

[0021] All headings are for the reader's convenience and should not be used to limit the meaning of the text that follows them unless otherwise specified. [Brief explanation of the drawing]

[0022] This disclosure relates to embodiments and is described with reference to specific drawings, but the invention is not limited thereto. The described drawings are merely schematic and non-limiting. In the drawings, the sizes of some elements may be exaggerated for illustrative purposes and may not be drawn to scale.

[0023] [Figure 1] It is a side cross-sectional view of an inhaler including a canister containing a valve according to this disclosure.

[0024] [Figure 2] It is a detailed side cross-sectional view of the inhaler of FIG. 1.

[0025] [Figure 3] It is a side cross-sectional view of a metering valve for an inhaler. <00了0088>

Mode for Carrying Out the Invention

[0026] The formulation of this disclosure is a suspension (i.e., a suspension formulation or suspension composition). That is, the formulation contains one or more active pharmaceutical ingredients (APIs) that are dispersed in the formulation (e.g., suspended in a propellant) to form a suspension. In this specification, in a "suspension", the API is in the form of fine particulate solids (typically micronized, but may be size-reduced by a number of other particle size reduction techniques such as ball or jet milling, spray drying, freeze drying, spray freeze drying, high pressure homogenization, supercritical fluid technology, controlled crystallization, ultrasonic crystallization, wet milling, etc.), and is optionally dispersed in a propellant together with other soluble or non-solubilizing excipients to assist the suspension behavior of the particles. In this specification, a suspension is a dispersion of particles of fine particulate matter (e.g., API) visible to the naked eye of a human, but a small amount of solubilized fine particulate matter may be present within the composition. For suspension formulations, solubilization of the API is generally not desirable. In embodiments, it may be desirable to minimize solubilization of the API.

[0027] Solution and suspension formulations are fundamentally different pMDI formulation approaches. When developing a product using either of these formulation approaches, different factors need to be considered. Therefore, it is not possible to apply the same knowledge and understanding of solution formulations to suspension formulations. For example, suspensions need to achieve a certain degree of physical stability to avoid significant separation of the physical mixture due to sedimentation or creaming of the suspended particles. This can lead to poor dose consistency over time. Thus, in the case of suspensions, suspending aids are often used to control aggregation. Also, in suspensions, the resulting aerosol particle size is mainly influenced by the geometric particle size of the micronized API, which can vary when the API particles are partially soluble in the propellant / formulation, and this can lead to physical instability over time through particle growth. In suspensions, the aerosol particle size is affected by the size and geometric shape of the micronized API used in the suspension, which can vary when the API dissolves in the formulation. The dissolved API particles can grow over time and lead to changes in the physical instability of the formulation and product performance. Inhalers containing suspension formulations often have problems related to the deposition of suspended API particles on the inner surfaces of the canister and valve, which can again cause changes in product performance over time. These problems are specific to suspensions and no teachings specific to solutions necessarily overcome them.

[0028] Various embodiments of the formulations described herein can be used with any suitable inhaler. For example, Figure 1 shows one embodiment of a metered-dose inhaler 100, which includes an aerosol canister 1 to which a metered-dose metering valve 10 (shown in its resting position) is attached. The metering valve 10 is typically secured, i.e., crimped, to the canister via a cap or ferrule 11 (typically made of aluminum or an aluminum alloy), which is commonly provided as part of the valve assembly. One or more seals may be present between the canister and the ferrule. In the embodiments shown in Figures 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.

[0029] As shown in Figure 1, a canister / valve dispenser typically includes an actuator 5 with a suitable patient port 6, such as a mouthpiece. For nasal administration, the patient port is generally provided in a suitable form for delivery through the nose (e.g., a tube of a smaller diameter, often angled upward). The actuator is generally made of a plastic material, such as polypropylene or polyethylene. As can be seen from Figure 1, the inner wall 2 of the canister 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.

[0030] The valve 10 shown in Figures 1 and 2 includes a metering chamber 12 partially defined by an internal valve body 13, through which a valve stem 14 passes. The valve stem 14, biased outward by a compression spring 15, is in sliding seal engagement with an internal tank seal 16 and an external diaphragm seal 17. The valve 10 also includes a second valve body 20 in the form of a bottle emptyer. The internal valve body 13 (also called the “primary” valve body) partially defines the metering chamber 12. The second valve body 20 (also called the “secondary” valve body) functions as a bottle emptyer and also partially defines a pre-metering area or chamber.

[0031] Referring to Figure 2, the aerosol formulation 4 can enter the pre-metering chamber 22 located between the secondary valve body 20 and the primary valve body 13, through the annular space 21 between the flange 23 of the secondary valve body 20 and the primary valve body 13, from the formulation chamber 3. To activate (fire) the valve 10, the valve stem 14 is pushed inward relative to the canister 1 from its resting position shown in Figures 1 and 2, allowing the formulation to pass from the metering chamber 12 through the side hole 19 of the valve stem, through the stem outlet 24 to the actuator nozzle 7, and then to the patient. When the valve stem 14 is released, the formulation enters the valve 10, particularly the pre-metering chamber 22, through the annular space 21, and from there enters the metering chamber 12 through the groove 18 in the valve stem and through the tank seal 16.

[0032] Figure 3 shows another embodiment of the quantitative aerosol metering valve 102, different from the embodiments shown in Figures 1 and 2, in its resting position. The valve 102 has a metering chamber 112 partially defined by a metering tank 113, and a stem 114 is biased outward through the metering chamber 112 by a spring 115. The stem 114 is made of two parts that are press-fitted together before being assembled into the valve 102. The stem 114 has an inner seal 116 and an outer seal 117 arranged around it, forming a sealed contact with the metering tank 113. The valve body 120, crimped within a ferrule 111, holds the aforementioned components within the valve. When in use, the formulation enters the metering chamber through orifices 121 and 118. The outward path of the formulation from the metering chamber 112 when the dose is dispensed is through an orifice 119.

[0033] Propellant HFO-1234ze(E) In certain embodiments, the primary propellant of the composition (i.e., formulation) according to the present disclosure is HFO-1234ze(E), also known as trans-1,1,1,3-tetrafluoropropene, trans-1,3,3,3-tetrafluoropropene, or trans-1,3,3,3-tetrafluoropropane-1-ene. The trans and cis isomers of HFO-1234ze have very different chemical structures. As a result, these isomers have very different physical and thermodynamic properties. At room temperature, the trans(E) isomer has a significantly lower boiling point and higher vapor pressure compared to the cis(Z) isomer, making the trans isomer a thermodynamically much more suitable propellant for achieving efficient pMDI atomization.

[0034] In some embodiments, the amount of HFO-1234ze(E) by weight in the formulation is 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, greater than 90% by weight, at least 95% by weight, or greater than 95% by weight. In some embodiments, the amount of HFO-1234ze(E) by weight in the formulation is 80% to 99% by weight, 80% to 98% by weight, 80% to 95% by weight, or 85% to 90% by weight.

[0035] In some embodiments, the propellant is at least 90% or at least 95% HFO-1234ze(E) and a small amount of another propellant. In some of these embodiments, other propellants such as hydrofluoroalkanes (e.g., HFA-134a, HFA-227, or HFA-152a) may be included as adjuncts. Further adjuncts that may be included as adjuncts include other hydrofluoroolefins, including HFO-1234yf (C3H2F4, 2,3,3,3-tetrafluoroprop-1-ene) and HFO-1234ze(Z) (i.e., cis-HFO-1234ze). The amount of such secondary propellants may include 0.1% to 10% by weight, 0.5% to 5% by weight, 1% to 5% by weight, or 5% to 10% by weight of the propellant. Accordingly, in some embodiments, the differences between HFA-152a and HFO-1234ze(E) discussed herein can be advantageously utilized by using a small amount of HFA-152a. For example, in some embodiments, a small amount of HFA-152a can be used to prevent the accumulation of API particles on the surface of the metering inhaler that the formulation comes into contact with as it passes from the canister in which the formulation is stored to the nozzle exit.

[0036] In some embodiments, the amount of HFO-1234ze(E) by weight of the total propellant in the formulation is at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.8%. In some embodiments, HFO-1234ze(E) is the sole propellant in the composition. That is, pharmaceutical performance parameters such as release dose and release particle size distribution do not differ significantly from when HFO-1234ze(E) is the sole propellant in the composition.

[0037] The propellant HFO-1234ze(E) is very different from alternative low-GWP propellants such as HFA-152a, as well as other propellants such as HFA-227 and HFA-134a. These propellants differ in physical, chemical, and thermodynamic properties such as boiling point, vapor pressure, water solubility, liquid density, and surface tension. Due to these differences in properties, it is difficult to replace one propellant with another without significantly impairing or altering the performance of the pMDI product. For example, thermodynamic differences in the boiling point and vapor pressure of propellants can significantly affect the aerosolization efficiency of pMDI and may lead to differences in the primary and secondary atomization mechanisms. Density differences between liquid propellants and suspended API particles can affect suspension behavior, such as sedimentation velocity. Differences in hygroscopicity between propellants can affect water uptake, which can be problematic for suspension formulations, especially when water uptake is expected to affect the physical stability of the product (e.g., suspended API particles) or chemical decomposition involving water. The chemical interactions between different propellants and APIs and excipients can also differ significantly, which can affect the long-term chemical stability of the product over its intended shelf life. Different propellants interact chemically and physically differently with valve plastics and elastomer components, which can lead to differences in the type and amount of extractables and leached materials, as well as affecting mechanical valve function or unit leakage. The thermodynamic properties of propellants can result in different residual droplet / particle sizes due to differences in initial atomization and subsequent droplet evaporation rates, and can also lead to differences in spray characteristics such as spray force, temperature, rate, and spray duration. Historically, the transition from CFCs to HFA propellants required considerable effort in developing new formulations and high-performance hardware to achieve adequate pMDI product performance. In other words, it was not possible to simply replace one propellant with another. For example, in pMDI, changing propellants from HFA-152a to HFO-1234ze(E), or from HFA-227 to HFO-1234ze(E), or from HFA-134a to HFO-1234ze(E) is equally difficult due to many of the factors highlighted above.

[0038] Generally, aerosols having a mass median aerodynamic diameter (MMAD) of at least 1 μm but less than 5 μm are suitable for effective deep lung deposition for therapeutic effects. Herein, the fine particle fraction (FPF) is defined as the percentage of off-actuator delivered API having an MMAD of less than 5 μm when tested in vitro. Herein, the “off-actuator” delivery dose is used to describe the amount of API delivered through the actuator of the pMDI. Therefore, aerosols with high FPF are typically suitable for deep lung deposition.

[0039] Surprisingly, pMDIs containing APIs in a suspension in HFO-1234ze(E), when tested in vitro, were found to deliver doses containing higher FPF than equivalent pMDI suspensions in HFA-152a using equivalent components. In some embodiments, a metered-dose inhaler containing a suspension of at least one API in HFO-1234ze(E) delivers a dose containing at least 15%, at least 17.5%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% of the particulate fraction of at least one API.

[0040] Propellant HFA-152a In certain embodiments, the primary propellant of the composition (i.e., formulation) according to the present disclosure is HFC-152a, R-152a, 1,1-difluoroethane, or HFA-152a, also known as DFE.

[0041] In some embodiments, the amount of HFA-152a by weight in the formulation is 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, greater than 90% by weight, at least 95% by weight, or greater than 95% by weight. In some embodiments, the amount of HFA-152a by weight in the formulation is 80% to 99% by weight, 80% to 98% by weight, 80% to 95% by weight, or 85% to 90% by weight.

[0042] In some embodiments, the propellant is at least 90% or at least 95% HFA-152a and a small amount of another propellant. In some of these embodiments, other propellants such as hydrofluoroalkanes (e.g., HFA-134a or HFA-227) may be included as adjuncts. Further adjuncts that may be included as adjuncts include other hydrofluoroolefins, including HFO-1234yf, HFO-1234ze(E), and HFO-1234ze(Z) (i.e., cis-HFO-1234ze). The amount of such secondary propellants may be 0.1% to 10% by weight, 0.5% to 5% by weight, 1% to 5% by weight, or 5% to 10% by weight of the composition (i.e., formulation). In some embodiments, the amount of HFA-152a by weight of the total propellant in the formulation is at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.8%. In some embodiments, HFA-152a is the sole propellant in the composition. That is, pharmaceutical performance parameters such as release dose and release particle size distribution do not differ significantly from those when HFA-152a is the sole propellant in the composition.

[0043] The propellant HFA-152a is very different from the alternative low-GWP propellant HFA-1234ze(E), as well as other propellants such as HFA-227 and HFA-134a. These propellants have different physical, chemical, and thermodynamic properties, including boiling point, vapor pressure, water solubility, liquid density, and surface tension. Due to these differences in properties, it is difficult to replace one propellant with another, such as HFA-152a, without significantly impairing or altering the performance of the pMDI product. For example, thermodynamic differences in the boiling point and vapor pressure of propellants can significantly affect the aerosolization efficiency of pMDI and may lead to differences in the primary and secondary atomization mechanisms. Density differences between liquid propellants and suspended API particles can affect suspension behavior, such as sedimentation velocity. Differences in hygroscopicity between propellants can affect moisture uptake, which can be problematic for suspension formulations, especially when moisture uptake is expected to affect the physical stability of the product (e.g., suspended API particles) or chemical degradation involving water. Chemical interactions between different propellants and APIs and excipients can also differ significantly, potentially impacting the long-term chemical stability of the product over its intended shelf life. Different propellants interact chemically and physically differently with valve plastics and elastomer components, leading to differences in the type and amount of extractables and leached materials, and potentially affecting mechanical valve function or unit leakage. Thermodynamic properties of propellants can result in different residual droplet / particle sizes due to differences in initial atomization and subsequent droplet evaporation rates, and can also lead to differences in spray characteristics such as spray force, temperature, velocity, and spray duration. Historically, the transition from CFCs to HFA propellants required significant effort in developing new formulations and high-performance hardware to achieve adequate pMDI product performance. In other words, it was impossible to simply replace one propellant with another. For example, in pMDI, changing from propellants such as HFO-1234ze(E), HFA-227, or HFA-134a to HFA-152a is equally difficult due to many of the factors highlighted above.

[0044] In some embodiments, a metered-dose inhaler containing a suspension of at least one API in HFA-152a delivers an external actuator dose containing an FPF of at least 10%, at least 15%, at least 17.5%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or at least 65% of the at least one API.

[0045] Active pharmaceutical ingredients The API may be a drug (e.g., a small molecule drug), a vaccine, a DNA fragment, a hormone, another therapeutic agent, or any combination of two or more APIs. In certain embodiments, the formulation may contain at least two APIs in the suspension (two or three in certain embodiments, and two in certain embodiments).

[0046] For the preparation of suspension formulations, APIs are preferably provided as pulverized crystalline solids. However, it should be apparent to those skilled in the art that other forms of APIs may be suitable for the preparation of suspension formulations consistent with this disclosure. Examples include APIs prepared by pulverization (e.g., ball or jet grinding), spray drying, freeze-drying, spray freeze-drying, high-pressure homogenization, supercritical fluid technology, controlled crystallization, ultrasonic crystallization, wet polishing, and the like.

[0047] APIs are pharmaceutically acceptable forms. APIs may be in the form of free bases, salts (e.g., inorganic salts such as sodium salts, organic salts such as sulfates and esylates), or esters (e.g., propionates or furoates), all of which are pharmaceutically acceptable. APIs may also be in the form of solvates, hydrates, or anhydrous substances, all of which are pharmaceutically acceptable.

[0048] As used herein, the term “pharmaceutically acceptable” means that an ingredient does not initiate a pharmacological response or adverse reaction when introduced into the relevant biological system. As a non-limiting example, substances found on the U.S. Food and Drug Administration’s “Generally Recognized as Safe” (GRAS) list, or substances used in accordance with the guidelines of its inactive ingredient database, are considered pharmaceutically acceptable. Similarly, substances in corresponding databases or lists maintained by corresponding regulatory bodies, such as the European Medicines Agency, are considered pharmaceutically acceptable. Generally, it is desirable that the formulations of this disclosure use only ingredients that do not cause unacceptable levels of physical or chemical instability in the resulting composition.

[0049] Examples of APIs include those for the treatment of respiratory diseases, such as bronchodilators, e.g., short-acting or long-acting β-agonists, anti-inflammatory agents (e.g., corticosteroids), anti-allergic agents, anti-asthmatic agents, antihistamines, short-acting muscarinic antagonists (SAMAs), long-acting muscarinic antagonists (LAMAs), phosphodiesterase-4 (PDE4) inhibitors, tyrosine kinase (TYK) inhibitors, Janus kinase (JAK) inhibitors, antibiotics (e.g., aminoglycosides), anti-infective agents, or anticholinergic agents.

[0050] In certain embodiments, at least one API is a mast cell stabilizer, a receptor tyrosine kinase inhibitor, a β2 adrenergic receptor agonist, a steroid, or a combination thereof (e.g., a combination of one, two, three, or more different APIs).

[0051] Examples of APIs include salbutamol (i.e., albuterol), revalbuterol, terbutaline, ipratropium, oxytropium, tiotropium, beclomethasone, flunisolide, budesonide, mometasone, ciclesonide, cromolyn sodium, nedocromyl sodium, ketotifen, azelastine, ergotamine, cyclosporine, acridinium, umeclidinium, glycopyrronium (i.e., glycopyrrolate), salmeterol, fluticasone, formoterol, procaterol, Examples include indacaterol, carmoterol, milbeterol, olodaterol, vilanterol, avesiderol, omalizumab, zillotone, insulin, pentamidine, calcitonin, leuprolide, α-I-antitrypsin, interferon, triamcinolone, nintedanib, cromoglycate, any pharmaceutically acceptable salt or ester of any of the listed APIs, or mixtures of any of the listed APIs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable esters.

[0052] In certain embodiments, at least one API comprises nintedanib or a pharmaceutically acceptable free base or salt thereof.

[0053] In certain embodiments, at least one API comprises mometasone or a pharmaceutically acceptable free base or ester thereof. One example is mometasone furoate.

[0054] In certain embodiments, at least one API comprises a cromoglycate or a pharmaceutically acceptable salt thereof. One example is sodium cromoglycate (i.e., cromolyn sodium).

[0055] In certain embodiments, at least one API comprises salbutamol (i.e., albuterol) or a pharmaceutically acceptable free base or salt thereof. An example is salbutamol sulfate (i.e., albuterol sulfate).

[0056] In all embodiments, the API is dispersed or suspended in the formulation (i.e., as a suspension). If a combination of two or more APIs is used, all of the APIs are suspended. If the API exists in particulate form, i.e., suspended, it generally has a median mass aerodynamic diameter in the range of 1 micrometer (μm) to 10 μm, preferably 1 μm to 5 μm.

[0057] formulation The amount of API can be determined by the required volume per operation and the size (i.e., volume) of the pMDI metering valve, i.e., the size of the metering chamber. In certain embodiments, the metering valve volume may be up to 100 microliters (μL or mcl) or up to 75 microliters. In certain embodiments, the metering valve volume may be at least 25 microliters.

[0058] The total amount of composition is preferably selected such that at least a portion of the propellant in the canister remains liquid after a predetermined number of drug doses have been delivered. The predetermined number of doses may be about 30 to about 200, about 60 to about 200, about 60 to about 120, about 60, about 120, about 200, or any other number of doses. The total amount of composition may be about 1.0 to about 30.0 g, about 2.0 to about 20.0 g, or about 5.0 to about 10.0 g. The total amount of composition is typically selected to be greater than the product of the predetermined number of doses and the metering volume of the metering valve. In some embodiments, the total amount of composition is greater than about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, or about 1.5 times the product of the predetermined number of doses and the metering volume of the metering valve. This ensures that each dose remains relatively constant throughout the life of the inhaler.

[0059] In certain embodiments, the formulation includes at least one API with a concentration of at least 5 mg / mL, at least 10 mg / mL, at least 20 mg / mL, or at least 30 mg / mL. In certain embodiments, the formulation includes at least one API with a concentration of up to 40 mg / mL. In embodiments where the formulation includes at least two APIs, the formulation may include APIs with concentrations of at least 0.1 mg / mL, at least 0.5 mg / mL, at least 1.0 mg / mL, at least 2.0 mg / mL, at least 5.0 mg / mL, at least 10 mg / mL, or at least 20 mg / mL. In embodiments where the formulation includes at least two APIs, the formulation may include APIs with concentrations of up to 35 mg / mL, up to 37.5 mg / mL, up to 39 mg / mL, or up to 39.9 mg / mL. For example, the formulation may include a first API in the range of 0.1 mg / mL to 39.9 mg / mL and a second API in the range of 0.1 mg / mL to 39.9 mg / mL, such as a first API of 10 mg / mL and a second API of 30 mg / mL.

[0060] In certain embodiments, the formulation contains at least one API in an amount of at least 0.5% by weight, at least 1% by weight, at least 2% by weight, or at least 3% by weight. In certain embodiments, the formulation contains at least one API in an amount of up to 5% by weight. In embodiments where the formulation contains more than one API, the formulation may contain at least 0.5%, at least 1%, or at least 4% by weight of each API. In embodiments where the formulation contains more than one API, the formulation may contain up to 4.5% by weight of each API. For example, the formulation may contain a first API in an amount of 0.5% to 4.5% by weight and a second API in an amount of 0.5% to 4.5% by weight, e.g., 2% by weight of the first API and 3% by weight of the second API.

[0061] In certain embodiments, a typical formulation of the Disclosure includes an API or a combination of APIs in an amount of at least 0.5 milligrams (mg / action) (500 micrograms (μg, mcg) per action) or at least 1.0 mg / action (1000 μg / action). In certain embodiments, a typical formulation of the Disclosure includes an API in an amount of up to 2.0 mg / action (2000 μg / action).

[0062] High-dose pMDI suspensions are known to suffer from dose sampling inconsistencies due to the low uniformity of the suspension. This can result from particle interactions with other particles or internal surfaces (e.g., deposition), and / or undesirable aggregation, agglomeration, or phase separation of high concentrations of solid suspended particles in liquid formulations, which can be further exacerbated without the addition of excipients. These phenomena can lead to the non-ideal dispersion of suspended APIs in high-dose pMDI suspension formulations, potentially causing inconsistent valve sampling and reduced dose consistency throughout the unit lifetime of the formulation. Furthermore, interactions between API particles and valve components and elastomers can affect valve functionality and / or lead to clogging of valve or actuator orifices, again resulting in inconsistent or incomplete dose delivery.

[0063] Another consideration affecting the suspension performance of high-dose pMDIs is that high concentrations of suspended particles in the formulation lead to reduced aerosolization efficiency. In high-API concentration suspensions, the number of particles contained in the resulting aerosol droplets will be greater than in typical low-dose suspension pMDIs. The more suspended particles there are in the atomized droplets of the formulation, the slower the evaporation of those droplets becomes, and therefore the larger the residual droplet size often becomes. Aerosols with larger residual droplet sizes have lower FPFs and are more likely to accumulate in the oral cavity and pharynx, reducing the achievable therapeutic dose in the lungs.

[0064] In some embodiments, additional components such as excipients and cosolvents other than propellants and APIs may be added to the formulation. These components may have a variety of uses and functions, including, but not limited to, facilitating suspension formation, stabilizing the suspension, and assisting the mechanical functionality of the unit.

[0065] Preferably, the suspension formulations of the present disclosure are substantially free of excipients (e.g., acids, surfactants), substantially free of co-solvents (e.g., alcohols, water), or substantially free of both excipients and co-solvents. In this context, "substantially free" means that excipients and co-solvents are not intentionally added to the formulation and may be present at trace levels. Furthermore, product performance parameters such as release dose and release particle size distribution are not significantly different from comparable formulations that do not contain excipients or co-solvents. In some embodiments, the amount of excipient or co-solvent is 2% or less, 1% or less, 0.5% or less, or 0.2% or less, based on the weight of the total composition.

[0066] For suspension formulations of APIs at concentrations less than 10 mg / mL in HFO-1234ze(E), it has been previously demonstrated that the inclusion of ethanol increases the stability of the API in the suspension and reduces API deposition. API deposition and reduced stability often lead to API buildup and / or blockage of valves and / or actuator nozzles after multiple operations. This buildup results in dose inconsistency. Therefore, suspension formulations containing APIs at concentrations of 10 mg / mL or higher without excipients or co-solvents (e.g., ethanol) are expected to exhibit reduced stability and increased API deposition, ultimately leading to inconsistent dose delivery.

[0067] Surprisingly, the data presented herein demonstrate that ethanol does not significantly alter the stability or deposition of one or more APIs in suspension formulations containing one or more APIs in HFO-1234ze(E) or HFA-152a at concentrations of 10 mg / mL or higher. Therefore, pMDIs containing suspension formulations that do not contain excipients or co-solvents (e.g., ethanol) in either HFO-1234ze(E) or HFA-152a result in consistent lifetime dose delivery. Consequently, the suspensions of this disclosure do not require ethanol.

[0068] The suspension formulations of this disclosure do not require a cosolvent such as ethanol, but it may be desirable to include a small amount of ethanol for some applications. In some embodiments, the pMDI comprises a suspension formulation containing a small amount of ethanol by weight. For example, the formulation may contain up to 5% by weight, up to 4% by weight, up to 3% by weight, up to 2% by weight, or up to 1% by weight of a cosolvent, such as ethanol. For example, the formulation may contain 0.5% to 5% by weight of ethanol, 1% to 4% by weight of ethanol, or 2% to 3% by weight of ethanol.

[0069] In certain embodiments, a small amount of water may be present in the suspension formulation. However, preferably, the added water is not used in preparing the suspension formulation of the present disclosure.

[0070] metered dose inhaler Returning to Figure 1, during use, the patient activates the inhaler 100 by pushing the canister 1 downwards. This moves the canister 1 into the body of the actuator 5, pressing the valve stem 14 against the actuator stem socket 8, resulting in the opening of the canister metering valve 10 and the release of a predetermined amount of composition that passes through the actuator nozzle 7 and exits the mouthpiece 6 into the patient's mouth. Other operating modes, such as respiratory operation, can be used similarly and should be understood to operate as described, except that the force pushing down the canister is provided by the device in response to a trigger event such as the patient's inhalation, for example, by a spring or a motor-driven screw.

[0071] Devices that may be used in conjunction with the pharmaceutical formulations of the present invention include those described in U.S. Patent No. 6,032,836 (Hiscocks et al.), U.S. Patent No. 9,010,329 (Hansen), and British Patent No. 2544128(B) (Friel).

[0072] A metered-dose inhaler may include a dosing counter for counting the number of doses. Suitable dosing counters are known in the art and are described, for example, in U.S. Patent No. 8,740,014 (Purkins et al.); No. 8,479,732 (Stuart et al.); and No. 8,814,035 (Stuart); and U.S. Patent Application Publication 2012 / 0234317 (Stuart), all of which, with respect to disclosures relating to dosing counters, are incorporated herein by reference in their entirety.

[0073] At least one of the various internal components of an inhaler, such as a metered-dose inhaler, as described herein, for example, one or more of a canister, valve, gasket, seal, or O-ring, may be coated with one or more coatings. Some of these coatings provide a low surface energy. Such coatings are not always necessary for the good operation of all inhalers, and are therefore not always required. Accordingly, some metered-dose inhalers do not have coated internal components.

[0074] Several usable coatings are described in U.S. Patent No. 8,414,956 (Jiinks et al.), No. 8,815,325 (David et al.), and U.S. Patent Publication No. 2012 / 0097159 (Iyer et al.), all of which are incorporated by reference in their entirety with respect to the disclosure of coatings for inhalers and inhaler components. Other coatings, such as fluorinated ethylene propylene resin, i.e., FEP, are also suitable. FEP is particularly suitable for use as a coating for canisters.

[0075] Several usable coating systems are described in European Patent Publication Nos. 3661577 (Jiinks et al.), 3146000 (Jiinks et al.), and 3561004 (Jiinks et al.). These coating systems are particularly useful for coating valve components, including one or more of the valve stem, bottle emptyer, spring, and tank. These coating systems can be used with any type of inhaler and any formulation described herein.

[0076] In some embodiments, the actuator nozzle is sized to optimize the particulate fraction and / or breathable dose delivered of the formulation in the canister when aerosolized. As described above, a high FPF is typically desirable for pMDIs. The FPF is determined by the formulation in the pMDI, as well as by the physical components of the pMDI, such as the actuator nozzle. In some embodiments, the actuator nozzle may have a nominal outlet orifice diameter of at least 0.18 mm, e.g., at least 0.2 mm, at least 0.24 mm, 0.25 mm, at least 0.3 mm, or at least 0.35 mm. In some embodiments, the nominal outlet orifice diameter of the actuator nozzle may be 0.5 mm or less (i.e., at most 0.5 mm), e.g., 0.45 mm or less, 0.4 mm, 0.35 mm or less, 0.3 mm or less, or 0.25 mm or less. The actuator nozzle may have an outlet orifice diameter of 0.3 mm to 0.5 mm, for example, 0.35 mm to 0.45 mm, or 0.38 mm to 0.43 mm.

[0077] As used herein, the “nominal diameter” of the actuator nozzle outlet orifice refers to a given diameter with slight variations due to manufacturing tolerances. For example, typical nozzle manufacturing allows for approximately ±0.02 mm. Therefore, a nominal diameter of 0.4 mm (or 0.40 mm) could be between 0.38 mm and 0.42 mm. In some embodiments, the cross-sectional shape of the actuator nozzle is essentially circular or round and has a given diameter. In some 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 extending to the opening (e.g., the average of the major and minor axes of the ellipse).

[0078] Those skilled in the art will understand that a given actuator nozzle outlet orifice may not be suitable for delivering a particular formulation, and that selecting an actuator nozzle outlet orifice suitable for a given formulation requires considerable effort.

[0079] In some embodiments, MDIs are manufactured by pressurized filling. In pressurized filling, a powdered drug, combined with optionally one or more excipients (e.g., cosolvents), is placed before filling into a suitable aerosol container (i.e., a canister) that can withstand the vapor pressure of the propellant and is equipped with a metering valve. The propellant is then forced into the container as a liquid through the valve. In an alternative process to pressurized filling, particulate APIs are combined in a process container with a propellant and optionally one or more excipients (e.g., cosolvents), and the resulting API suspension is transferred through a metering valve attached to a suitable MDI container.

[0080] In some embodiments, MDI is manufactured by cold filling. In cold filling, a powdered drug, a propellant cooled below its boiling point, and optionally one or more excipients (e.g., a cosolvent) are added to the MDI container. Furthermore, a metering valve is attached to the container after filling.

[0081] For both pressurized and cryogenic filling processes, further steps, such as mixing of formulations, sonication, and homogenization, may be optionally used.

[0082] Embodiment Embodiment of HFO-1234ze(E) Embodiment A1 is a metered-dose inhaler comprising a metering valve, a canister, and an actuator equipped with an actuator nozzle, wherein the canister contains a formulation, the formulation comprising more than 70% by weight of HFO-1234ze(E) and at least one active pharmaceutical ingredient suspended in the formulation, and the metered-dose inhaler delivers at least 0.5 milligrams (mg) of at least one active pharmaceutical ingredient per action.

[0083] Embodiment A2 is a metered-dose inhaler of Embodiment A1, wherein the formulation contains at least 95% by weight of HFO-1234ze(E). Embodiment A3 is a metered-dose inhaler of Embodiment A2, wherein HFO-1234ze(E) is the sole propellant.

[0084] Embodiment A4 is a metered-dose inhaler according to any of the preceding Embodiments A, wherein the metered-dose inhaler delivers a dose containing at least 20% of the particulate fraction of at least one active pharmaceutical ingredient. Embodiment A5 is a metered-dose inhaler according to Embodiment A4, wherein the metered-dose inhaler delivers a dose containing at least 30% of the particulate fraction of at least one active pharmaceutical ingredient. Embodiment A6 is a metered-dose inhaler according to Embodiment A5, wherein the metered-dose inhaler delivers a dose containing at least 40% of the particulate fraction of at least one active pharmaceutical ingredient. Embodiment A7 is a metered-dose inhaler according to Embodiment A6, wherein the metered-dose inhaler delivers a dose containing at least 60% of the particulate fraction of at least one active pharmaceutical ingredient.

[0085] Embodiment A8 is a metered-dose inhaler according to any of the preceding Embodiments A, wherein the metered-dose inhaler delivers at least 1.0 mg of at least one active pharmaceutical ingredient per action. Embodiment A9 is a metered-dose inhaler according to any of the preceding Embodiments A, wherein the metered-dose inhaler delivers up to 2.0 mg of at least one active pharmaceutical ingredient per action.

[0086] Embodiment A10 is a metered-dose inhaler of any of the preceding Embodiments A, wherein at least one active pharmaceutical ingredient comprises a mast cell stabilizer, a receptor tyrosine kinase inhibitor, a β2-adrenergic receptor agonist, a steroid, or a combination thereof. Embodiment A11 is a metered-dose inhaler of Embodiment A10, wherein at least one active pharmaceutical ingredient comprises nintedanib or a pharmaceutically acceptable free base or salt thereof. Embodiment A12 is a metered-dose inhaler of Embodiment A10, wherein at least one active pharmaceutical ingredient comprises mometasone or a pharmaceutically acceptable ester or free base thereof. Embodiment A13 is a metered-dose inhaler of Embodiment A10, wherein at least one active pharmaceutical ingredient comprises cromoglycate or a pharmaceutically acceptable salt thereof. Embodiment A14 is a metered-dose inhaler of Embodiment A10, wherein at least one active pharmaceutical ingredient comprises salbutamol or a pharmaceutically acceptable salt or free base thereof.

[0087] Embodiment A15 is a metered-dose inhaler according to any of the preceding Embodiments A, wherein at least one active pharmaceutical ingredient is a micronized crystalline solid.

[0088] Embodiment A16 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation is substantially free of excipients. Embodiment A17 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation is substantially free of cosolvents. Embodiment A18 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation is substantially free of water. Embodiment A19 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation is substantially free of ethanol.

[0089] Embodiment A20 is a metered-dose inhaler according to any of Embodiments A1 to A16, wherein the formulation contains up to 5% by weight of ethanol. Embodiment A21 is a metered-dose inhaler according to Embodiment A20, wherein the formulation contains up to 2% by weight of ethanol.

[0090] Embodiment A22 is a metered-dose inhaler of any of the preceding A embodiments, wherein the actuator nozzle includes an outlet orifice diameter of up to 0.5 mm. Embodiment A23 is a metered-dose inhaler of Embodiment A22, wherein the actuator nozzle includes an outlet orifice diameter of up to 0.25 mm. Embodiment A24 is a metered-dose inhaler of any of the preceding A embodiments, wherein the actuator nozzle includes an outlet orifice diameter of at least 0.18 mm.

[0091] Embodiment A25 is a metering inhaler of any of the preceding Embodiments A, wherein the metering valve has a maximum volume of 100 microliters. Embodiment A26 is a metering inhaler of Embodiment A25, wherein the metering valve has a maximum volume of 75 microliters. Embodiment A27 is a metering inhaler of any of the preceding Embodiments A, wherein the metering valve has a volume of at least 25 microliters.

[0092] Embodiment A28 is a metering inhaler according to either of the preceding Embodiment A, wherein the metering valve is coated or uncoated.

[0093] Embodiment A29 is a metered-dose inhaler of any of the preceding Embodiments A, wherein the metered-dose inhaler includes a coated or uncoated canister.

[0094] Embodiment A30 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation contains at least one active pharmaceutical ingredient at a concentration of at least 5 mg / mL. Embodiment A31 is a metered-dose inhaler of Embodiment A30, wherein the formulation contains at least one active pharmaceutical ingredient at a concentration of at least 10 mg / mL. Embodiment A32 is a metered-dose inhaler of Embodiment A31, wherein the formulation contains at least one active pharmaceutical ingredient at a concentration of at least 20 mg / mL. Embodiment A33 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation contains at least one active pharmaceutical ingredient at a concentration of up to 40 mg / mL.

[0095] Embodiment A34 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation contains at least 0.5% by weight of at least one active pharmaceutical ingredient. Embodiment A35 is a metered-dose inhaler of Embodiment A34, wherein the formulation contains at least 1% by weight of at least one active pharmaceutical ingredient. Embodiment A36 is a metered-dose inhaler of Embodiment A35, wherein the formulation contains at least 2% by weight of at least one active pharmaceutical ingredient. Embodiment A37 is a metered-dose inhaler of Embodiment A36, wherein the formulation contains at least 3% by weight of at least one active pharmaceutical ingredient. Embodiment A38 is a metered-dose inhaler of any of the preceding A embodiments, wherein the formulation contains up to 5% by weight of at least one active pharmaceutical ingredient.

[0096] Embodiment of HFA-152a Embodiment B1 is a metered-dose inhaler comprising a metering valve, a canister, and an actuator equipped with an actuator nozzle, wherein the canister contains a formulation, the formulation comprising more than 70% by weight of HFA-152a and at least one active pharmaceutical ingredient suspended in the formulation, and the metered-dose inhaler delivers at least 0.5 milligrams (mg) of at least one active pharmaceutical ingredient per action.

[0097] Embodiment B2 is a metered-dose inhaler of Embodiment B1, wherein the formulation contains at least 95% by weight of HFA-152a. Embodiment B3 is a metered-dose inhaler of Embodiment B2, wherein HFA-152a is the sole propellant.

[0098] Embodiment B4 is a metered-dose inhaler according to any of the preceding Embodiment B, wherein the metered-dose inhaler delivers at least 1.0 mg of at least one active pharmaceutical ingredient per action. Embodiment B5 is a metered-dose inhaler according to any of the preceding Embodiment B, wherein the metered-dose inhaler delivers up to 2.0 mg of at least one active pharmaceutical ingredient per action.

[0099] Embodiment B6 is a metered-dose inhaler of any of the preceding Embodiment B, wherein at least one active pharmaceutical ingredient comprises a mast cell stabilizer, a receptor tyrosine kinase inhibitor, a β2-adrenergic receptor agonist, a steroid, or a combination thereof. Embodiment B7 is a metered-dose inhaler of Embodiment B6, wherein at least one active pharmaceutical ingredient comprises nintedanib or a pharmaceutically acceptable salt or free base thereof. Embodiment B8 is a metered-dose inhaler of Embodiment B6, wherein at least one active pharmaceutical ingredient comprises mometasone or a pharmaceutically acceptable ester or free base thereof. Embodiment B9 is a metered-dose inhaler of Embodiment B6, wherein at least one active pharmaceutical ingredient comprises cromoglycate or a pharmaceutically acceptable salt thereof. Embodiment B10 is a metered-dose inhaler of Embodiment B6, wherein at least one active pharmaceutical ingredient comprises salbutamol or a pharmaceutically acceptable salt or free base thereof.

[0100] Embodiment B11 is a metered-dose inhaler according to any of the preceding Embodiment B, wherein at least one active pharmaceutical ingredient is a micronized crystalline solid.

[0101] Embodiment B12 is a metered-dose inhaler of any of the preceding Embodiments B, wherein the formulation is substantially free of excipients. Embodiment B13 is a metered-dose inhaler of any of the preceding Embodiments B, wherein the formulation is substantially free of cosolvents. Embodiment B14 is a metered-dose inhaler of any of the preceding Embodiments B, wherein the formulation is substantially free of ethanol. Embodiment B15 is a metered-dose inhaler of any of the preceding Embodiments B, wherein the formulation is substantially free of water.

[0102] Embodiment B16 is a metered-dose inhaler according to any of Embodiments B1 to B12, wherein the formulation contains up to 5% by weight of ethanol. Embodiment B17 is a metered-dose inhaler according to Embodiment B16, wherein the formulation contains up to 2% by weight of ethanol.

[0103] Embodiment B18 is a metered-dose inhaler of any of the preceding B embodiments, wherein the actuator nozzle includes an outlet orifice diameter of up to 0.50 mm. Embodiment B19 is a metered-dose inhaler of Embodiment B18, wherein the actuator nozzle includes an outlet orifice diameter of up to 0.25 mm. Embodiment B20 is a metered-dose inhaler of any of the preceding B embodiments, wherein the actuator nozzle includes an outlet orifice diameter of at least 0.18 mm.

[0104] Embodiment B21 is a metered-dose inhaler of any of the preceding Embodiment B, wherein the metered-dose inhaler delivers a dose containing at least 15% of the particulate fraction of at least one active pharmaceutical ingredient. Embodiment B22 is a metered-dose inhaler of Embodiment B21, wherein the metered-dose inhaler delivers a dose containing at least 30% of the particulate fraction of at least one active pharmaceutical ingredient. Embodiment B23 is a metered-dose inhaler of Embodiment B22, wherein the metered-dose inhaler delivers a dose containing at least 50% of the particulate fraction of at least one active pharmaceutical ingredient.

[0105] Embodiment B24 is a metering inhaler of any of the preceding Embodiment B, wherein the metering valve has a maximum volume of 100 microliters. Embodiment B25 is a metering inhaler of Embodiment B24, wherein the metering valve has a maximum volume of 75 microliters. Embodiment B26 is a metering inhaler of any of the preceding Embodiment B, wherein the metering valve has a volume of at least 25 microliters.

[0106] Embodiment B27 is a metering inhaler according to either of the preceding Embodiment B, wherein the metering valve is either coated or uncoated.

[0107] Embodiment B28 is a metered-dose inhaler of any of the preceding B embodiments, wherein the metered-dose inhaler includes a coated or uncoated canister. Embodiment B29 is a metered-dose inhaler of any of the preceding B embodiments, wherein the formulation contains at least one active pharmaceutical ingredient at least 5 mg / mL. Embodiment B30 is a metered-dose inhaler of Embodiment B29, wherein the formulation contains at least one active pharmaceutical ingredient at least 10 mg / mL. Embodiment B31 is a metered-dose inhaler of Embodiment B30, wherein the formulation contains at least one active pharmaceutical ingredient at least 20 mg / mL. Embodiment B32 is a metered-dose inhaler of Embodiment B31, wherein the formulation contains at least one active pharmaceutical ingredient at least 30 mg / mL. Embodiment B33 is a metered-dose inhaler of any of the preceding B embodiments, wherein the formulation contains at least one active pharmaceutical ingredient at a maximum of 40 mg / mL.

[0108] Embodiment B34 is a metered-dose inhaler of any of the preceding Embodiments B, wherein the formulation contains at least 0.5% by weight of at least one active pharmaceutical ingredient. Embodiment B35 is a metered-dose inhaler of Embodiment B34, wherein the formulation contains at least 1% by weight of at least one active pharmaceutical ingredient. Embodiment B36 is a metered-dose inhaler of Embodiment B35, wherein the formulation contains at least 2% by weight of at least one active pharmaceutical ingredient. Embodiment B37 is a metered-dose inhaler of Embodiment B36, wherein the formulation contains at least 3% by weight of at least one active pharmaceutical ingredient. Embodiment B38 is a metered-dose inhaler of any of the preceding Embodiments B, wherein the formulation contains up to 5% by weight of at least one active pharmaceutical ingredient. [Examples]

[0109] In the following examples, dose consistency is based on the United States Pharmacopeia. <601> According to the specifications, the flow rate was 28.3 L / min and the single-acting dose content at the beginning, middle, and end of the pMDI unit life was determined by in vitro measurements using apparatus A. The aerodynamic particle size distribution of the pMDI suspension aerosol was determined according to the United States Pharmacopeia (USP) standards. <601> Accordingly, measurements were taken at the start of the unit lifetime using a next-generation impactor (device 6) without a pre-separator and a flow rate of 30 L / min.

[0110] Example 1: Overall life-span dose consistency of mometasone furoate suspensions in HFA-152a or HFO-1234ze(E) with and without ethanol.

[0111] Suspensions of finely powdered mometasone furoate in HFA-152a or HFO-1234ze(E) were prepared. The first set of suspensions did not contain ethanol. The second set of suspensions contained 2% by weight of ethanol. Each suspension contained an amount of mometasone furoate providing a nominal delivery dose (outside the valve) of 0.5 mg / acting (10.0 mg / mL) or 1.0 mg / acting (20.0 mg / mL). Two further suspensions without ethanol were prepared, which contained an amount of mometasone furoate providing a nominal delivery dose (outside the valve) of 2.0 mg / acting (40.0 mg / mL).

[0112] In total, 10 suspension pMDI formulations were prepared in triplicate with sufficient fill weight to provide 60 acts. Each suspension was filled into a Kindeva FEP-coated canister and crimped with a Kindeva 50 μL valve. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm.

[0113] The through-life (TL) dose consistency of each pMDI unit was determined by measuring the average out-of-actuator dose (N=3) of mometasone furoate in micrograms at the start of life (SoL), middle of life (MoL), and end of life (EoL) of the unit. These data are presented in Table 1.

[0114] [Table 1] From this example, it was found that pMDI suspensions of mometasone furoate in HFA-152a or HFO-1234ze(E) with and without 2% by weight ethanol were produced relatively consistently throughout the unit lifetime of the extra-actuator delivery dose. Surprisingly, the addition of ethanol was found not to substantially improve the consistency of the extra-actuator delivery dose throughout the unit lifetime.

[0115] Example 2: Overall life-span dose consistency of sodium cromoglycate suspensions in HFA-152a or HFO-1234ze(E) with and without ethanol.

[0116] Suspensions of finely ground sodium cromoglycate in HFA-152a or HFO-1234ze(E) were prepared. The first set of suspensions did not contain ethanol. The second set of suspensions contained 2% by weight of ethanol. Each suspension contained an amount of sodium cromoglycate providing a nominal delivery dose (outside the valve) of 0.5 mg / acting (10.0 mg / mL) or 1.0 mg / acting (20.0 mg / mL). Two further suspensions without ethanol were prepared, which contained an amount of sodium cromoglycate providing a nominal delivery dose (outside the valve) of 2.0 mg / acting (40.0 mg / mL).

[0117] In total, 10 suspension pMDI formulations were prepared in triplicate with sufficient fill weight to provide 60 acts. Each suspension was filled into a Kindeva FEP-coated canister and crimped with a Kindeva 50 μL valve. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm.

[0118] The lifetime (TL) dose consistency of each pMDI unit was determined by measuring the average extra-actuator delivery dose (N=3) of sodium cromoglycate in micrograms at the start (SoL), middle (MoL), and end (EoL) of the unit's lifetime. These data are presented in Table 2.

[0119] [Table 2] From this example, it was found that pMDI suspensions of sodium cromoglycate in HFA-152a or HFO-1234ze(E) with and without 2% by weight ethanol were produced relatively consistently throughout the unit lifetime of the extra-actuator delivery dose. Surprisingly, the addition of ethanol was found not to substantially improve the extra-actuator delivery dose consistency throughout the unit lifetime.

[0120] Example 3: Overall lifetime dose consistency of salbutamol sulfate suspension in HFA-152a or HFO-1234ze(E).

[0121] Suspensions of finely powdered salbutamol sulfate were prepared in HFA-152a or HFO-1234ze(E). Each suspension contained an amount of salbutamol sulfate providing a nominal delivery dose (outside the valve) of 0.5 mg / acting (10.0 mg / mL), 1.0 mg / acting (20.0 mg / mL), or 2.0 mg / acting (40.0 mg / mL), and did not contain ethanol.

[0122] In total, six suspension pMDI formulations were prepared in triplicate with sufficient fill weight to provide 60 acts. Each suspension was filled into a Kindeva FEP-coated canister and crimped with a Kindeva 50 μL valve. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm.

[0123] The lifetime (TL) dose consistency of each pMDI unit was determined by measuring the average extra-actuator delivery dose (N=3) of salbutamol sulfate in micrograms at the start (SoL), middle (MoL), and end (EoL) of the unit's lifetime. These data are presented in Table 3.

[0124] [Table 3] This example demonstrates that pMDI suspensions of salbutamol sulfate in HFA-152a or HFO-1234ze(E) are generated relatively consistently throughout the unit lifetime of the extra-actuator delivery dose.

[0125] Example 4: Overall lifetime dose consistency of nintedanib (free base) suspension in ethanol-containing and ethanol-free HFA-152a or HFO-1234ze(E).

[0126] Suspensions of micronized nintedanib (free base) in HFA-152a or HFO-1234ze(E) were prepared. The first set of suspensions did not contain ethanol. The second set of suspensions contained 2% by weight of ethanol. Each suspension contained an amount of nintedanib (free base) that provided a nominal delivery dose (outside the valve) of 0.5 mg / acting (7.94 mg / mL) or 1.0 mg / acting (15.87 mg / mL). Two further ethanol-free suspensions were prepared, which contained an amount of nintedanib (free base) that provided a nominal delivery dose (outside the valve) of 2.0 mg / acting (20.0 mg / mL).

[0127] In total, 10 suspension pMDI formulations were prepared in triplicate with sufficient fill weight to provide 60 acts. pMDI formulations containing 0.5 mg / act (7.94 mg / mL) and 1.0 mg / act (15.87 mg / mL) of nintedanib (free base) were filled into Kindeva FEP-coated canisters and crimped with Kindeva 63 μL valves. A pMDI formulation containing 2.0 mg / act (20.0 mg / mL) of nintedanib (free base) was also filled into Kindeva FEP-coated canisters and crimped with Kindeva 100 μL valves. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm.

[0128] The lifetime (TL) dose consistency of each pMDI unit was determined by measuring the average off-actuator dose (N=3) of nintedanib (free base) in micrograms at the start (SoL), middle (MoL), and end (EoL) of the unit's lifetime. These data are presented in Table 4.

[0129] [Table 4] From this example, it was found that pMDI suspensions of nintedanib (free base) in HFA-152a or HFO-1234ze(E) with and without 2% by weight ethanol were generated relatively consistently throughout the unit lifetime of the extra-actuator delivery dose. Surprisingly, the addition of ethanol was found not to substantially improve the extra-actuator delivery dose consistency throughout the unit lifetime.

[0130] Example 5: Aerodynamic particle size measurement of mometasone furoate suspensions in HFA-152a or HFO-1234ze(E) with and without ethanol.

[0131] Suspensions of finely powdered mometasone furoate in HFA-152a or HFO-1234ze(E) were prepared. The first set of suspensions did not contain ethanol. The second set of suspensions contained 2% by weight of ethanol. Each suspension contained an amount of mometasone furoate providing a nominal delivery dose (outside the valve) of 0.5 mg / acting (10.0 mg / mL) or 1.0 mg / acting (20.0 mg / mL). Two further suspensions without ethanol were prepared, which contained an amount of mometasone furoate providing a nominal delivery dose (outside the valve) of 2.0 mg / acting (40.0 mg / mL).

[0132] In total, 10 suspension pMDI formulations were prepared in triplicate with a fill weight sufficient to provide 60 acts. Each suspension was filled into a Kindeva FEP-coated canister and crimped with a Kindeva 50 μL valve. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm or 0.25 mm.

[0133] The median mass aerodynamic diameter (MMAD) and particulate fraction (FPF) of each pMDI unit were measured for each pMDI suspension using next-generation cascade impaction (N=3). The results are shown in Table 5.

[0134] [Table 5] pMDI suspensions of mometasone furoate in HFA-152a or HFO-1234ze(E), with and without ethanol, were observed to generate aerosols with MMAD values ​​within the appropriate respiratory range necessary for therapeutic efficacy when tested in vitro.

[0135] pMDI suspensions of mometasone furoate in ethanol-free HFA-152a or HFO-1234ze(E) were generally found to produce a higher FPF (Focused Plant Factor) than the corresponding pMDI suspensions of mometasone furoate containing 2% by weight ethanol, for all nominal doses.

[0136] Surprisingly, the pMDI suspension of mometasone furoate in HFO-1234ze(E) consistently produced a larger FPF and generally smaller MMAD than the corresponding pMDI suspensions of mometasone furoate in HFA-152a with and without ethanol. From this example, it was found that the aerosolization efficiency of the pMDI suspension of mometasone furoate in HFO-1234ze(E) is consistently better than that in HFA-152a.

[0137] Tests using a Kindeva actuator with an EOD of 0.25 mm showed that pMDI suspensions of 0.5 mg / actuated and 1.0 mg / actuated mometasone furoate in HFO-1234ze(E), and a pMDI suspension of 1.0 mg / actuated mometasone furoate in HFA-152a, consistently generated larger FPFs than when using an actuator with an EOD of 0.4 mm. Therefore, it was found that reducing the size of the actuator's EOD significantly improves aerosolization efficiency.

[0138] Example 6: Aerodynamic particle size measurement of suspensions of sodium cromoglycate in HFA-152a or HFO-1234ze(E) with and without ethanol.

[0139] Suspensions of finely ground sodium cromoglycate in HFA-152a or HFO-1234ze(E) were prepared. The first set of suspensions did not contain ethanol. The second set of suspensions contained 2% by weight of ethanol. Each suspension contained an amount of sodium cromoglycate providing a nominal delivery dose (outside the valve) of 0.5 mg / acting (10.0 mg / mL) or 1.0 mg / acting (20.0 mg / mL). Two further suspensions without ethanol were prepared, which contained an amount of sodium cromoglycate providing a nominal delivery dose (outside the valve) of 2.0 mg / acting (40.0 mg / mL).

[0140] In total, 10 suspension pMDI formulations were prepared in triplicate with a fill weight sufficient to provide 60 acts. Each suspension was filled into a Kindeva FEP-coated canister and crimped with a Kindeva 50 μL valve. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm. The median mass aerodynamic diameter (MMAD) and particulate fraction (FPF) of each pMDI unit were measured for each pMDI suspension using next-generation cascade impaction (N=3). The results are shown in Table 6.

[0141] [Table 6] pMDI suspensions of sodium cromoglycate in HFA-152a or HFO-1234ze(E), with and without ethanol, were observed to generate aerosols with MMAD values ​​within the appropriate respiratory range necessary for therapeutic efficacy when tested in vitro.

[0142] pMDI suspensions of sodium cromoglycate in ethanol-free HFA-152a or HFO-1234ze(E) were found to consistently produce higher FPF and lower MMAD for all nominal doses than the corresponding pMDI suspensions of sodium cromoglycate containing 2% by weight ethanol.

[0143] Surprisingly, the pMDI suspension of sodium cromoglycate in HFO-1234ze(E) consistently produced a larger FPF and generally smaller MMAD than the corresponding pMDI suspensions of sodium cromoglycate in HFA-152a with and without ethanol. From this example, it was found that the aerosolization efficiency of the pMDI suspension of sodium cromoglycate in HFO-1234ze(E) is consistently better than that in HFA-152a.

[0144] Example 7: Aerodynamic particle size of a suspension of salbutamol sulfate in HFA-152a or HFO-1234ze(E).

[0145] Suspensions of finely powdered salbutamol sulfate were prepared in HFA-152a or HFO-1234ze(E). Each suspension contained an amount of salbutamol sulfate providing a nominal delivery dose (outside the valve) of 0.5 mg / acting (10.0 mg / mL), 1.0 mg / acting (20.0 mg / mL), or 2.0 mg / acting (40.0 mg / mL), and did not contain ethanol.

[0146] In total, six suspension pMDI formulations were prepared in triplicate with sufficient fill weight to provide 60 acts. Each suspension was filled into a Kindeva FEP-coated canister and crimped with a Kindeva 50 μL valve. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm.

[0147] The median mass aerodynamic diameter (MMAD) and particulate fraction (FPF) of each pMDI unit were measured for each pMDI suspension using next-generation cascade impaction (N=3). The results are shown in Table 7.

[0148] [Table 7] When tested in vitro, pMDI suspensions of salbutamol sulfate in HFA-152a or HFO-1234ze(E) were observed to generate aerosols with MMAD values ​​within the appropriate respiratory range necessary for therapeutic efficacy.

[0149] Surprisingly, the pMDI suspension of salbutamol sulfate in HFO-1234ze(E) consistently produced a larger FPF and a smaller MMAD than the corresponding pMDI suspension of salbutamol sulfate in HFA-152a. From this example, it was found that the aerosolization efficiency of the pMDI suspension of salbutamol sulfate in HFO-1234ze(E) is consistently better than that in HFA-152a.

[0150] Example 8: Aerodynamic particle size measurement of suspensions of nintedanib (free base) in HFA-152a or HFO-1234ze(E) with and without ethanol.

[0151] Suspensions of micronized nintedanib (free base) in HFA-152a or HFO-1234ze(E) were prepared. The first set of suspensions did not contain ethanol. The second set of suspensions contained 2% by weight of ethanol. Each suspension contained an amount of nintedanib (free base) that provided a nominal delivery dose (outside the valve) of 0.5 mg / acting (7.94 mg / mL) or 1.0 mg / acting (15.87 mg / mL). Two further ethanol-free suspensions were prepared, which contained an amount of nintedanib (free base) that provided a nominal delivery dose (outside the valve) of 2.0 mg / acting (20.0 mg / mL).

[0152] In total, 10 suspension pMDI formulations were prepared in triplicate with sufficient fill weight to provide 60 acts. pMDI formulations containing 0.5 mg / act (7.94 mg / mL) and 1.0 mg / act (15.87 mg / mL) of nintedanib (free base) were filled into Kindeva FEP-coated canisters and crimped with Kindeva 63 μL valves. A pMDI formulation containing 2.0 mg / act (20.0 mg / mL) of nintedanib (free base) was also filled into Kindeva FEP-coated canisters and crimped with Kindeva 100 μL valves. Each pMDI unit was sonicated for at least 10 minutes to disperse the suspension drug and tested with a Kindeva actuator having an exit orifice diameter (EOD) of 0.4 mm. The median mass aerodynamic diameter (MMAD) and particulate fraction (FPF) of each pMDI unit were measured for each pMDI suspension using next-generation cascade impaction (N=3). The results are shown in Table 8.

[0153] [Table 8] pMDI suspensions of nintedanib (free base) in HFA-152a or HFO-1234ze(E), with and without ethanol, were observed to generate aerosols with MMAD values ​​within the appropriate respiratory range required for therapeutic efficacy when tested in vitro.

[0154] pMDI suspensions of nintedanib (free base) in ethanol-free HFA-152a or HFO-1234ze(E) consistently produced higher FPF and lower MMAD for all nominal doses than the corresponding pMDI suspensions of nintedanib (free base) containing 2% by weight ethanol.

[0155] Surprisingly, the pMDI suspension of nintedanib (free base) in HFO-1234ze(E) consistently produced a larger FPF and generally smaller MMAD than the corresponding pMDI suspensions of nintedanib (free base) in HFA-152a with and without ethanol. From this example, it was found that the aerosolization efficiency of the pMDI suspension of nintedanib (free base) in HFO-1234ze(E) is consistently better than that in HFA-152a.

[0156] Example 9: Additional whole-life dose consistency of a suspension of nintedanib (free base) in ethanol-free HFO-1234ze(E).

[0157] A suspension of nintedanib was prepared in HFO-1234ze(E). The concentration of nintedanib (15.9 mg / mL) was selected to provide a nominal working dose of 1 mg / work from a 63 microliter valve. The valve's bottle emptyer, tank, spring, and ferrule components were coated with a fluoropolymer coating according to the general process described in Example 2 of U.S. Patent Application Publication No. 2017 / 0152396(A1) (Jiinks et al., incorporated herein by reference). This formulation was mixed in a high-shear mixer and cryogenically filled into 16 mL FEP-coated canisters.

[0158] The uniformity of medication content throughout life did not show a trend between the start, middle, and end of life at an average dose of 950 μg / acting. The average particulate matter mass (<5 μm) was 434 μg / acting.

[0159] The embodiments described above and shown in the drawings are presented for illustrative purposes only and are not intended to limit the concepts and principles of this disclosure. Those skilled in the art will understand that various modifications of the elements and their configurations and arrangements are possible without departing from the spirit and scope of this disclosure. All references and publications cited herein are incorporated in their entirety by express reference. Various features and aspects of this disclosure are described in the following claims.

Claims

1. A metered-dose inhaler, Measuring valve and Canister and, An actuator equipped with an actuator nozzle, The canister contains the formulation, and the formulation contains more than 70% by weight of HFO-1234ze(E), The formulation comprises at least one active pharmaceutical ingredient suspended in the formulation, A metered-dose inhaler that delivers at least 0.5 milligrams (mg) of the at least one active pharmaceutical ingredient per operation.

2. The metered-dose inhaler according to claim 1, wherein the formulation comprises at least 95% by weight of HFO-1234ze(E).

3. The metered-dose inhaler according to claim 1 or 2, wherein the metered-dose inhaler delivers an external dose containing at least 20% of particulate fractions less than 5 μm in diameter of the at least one active pharmaceutical ingredient.

4. The metered-dose inhaler according to any one of claims 1 to 3, wherein the metered-dose inhaler delivers at least 1.0 mg of the at least one active pharmaceutical ingredient per operation.

5. The metered-dose inhaler according to any one of claims 1 to 4, wherein the at least one active pharmaceutical ingredient comprises a mast cell stabilizer, a receptor tyrosine kinase inhibitor, a β2 adrenergic receptor agonist, a steroid, or a combination thereof.

6. The quantitative inhaler according to any one of claims 1 to 5, wherein the at least one active pharmaceutical ingredient is a finely powdered crystalline solid.

7. A metered-dose inhaler according to any one of claims 1 to 6, wherein the formulation is substantially free of ethanol.

8. The metered-dose inhaler according to any one of claims 1 to 7, wherein the formulation contains up to 5% by weight of ethanol.

9. The metered inhaler according to any one of claims 1 to 8, wherein the actuator nozzle includes an outlet orifice diameter of up to 0.5 mm.

10. The quantitative inhaler according to any one of claims 1 to 9, wherein the formulation comprises at least 1% by weight of the at least one active pharmaceutical ingredient.

11. A metered-dose inhaler, Measuring valve and Canister and, An actuator equipped with an actuator nozzle, The canister contains the formulation, and the formulation contains more than 70% by weight of HFA-152a, The formulation comprises at least one active pharmaceutical ingredient suspended in the formulation, A metered-dose inhaler that delivers at least 0.5 milligrams (mg) of the at least one active pharmaceutical ingredient per operation.

12. The metered-dose inhaler according to claim 11, wherein the formulation contains at least 95% by weight of HFA-152a.

13. The metered-dose inhaler according to claim 11 or 12, wherein the metered-dose inhaler delivers a dose containing at least 15% of particulate fractions less than 5 μm in diameter of the at least one active pharmaceutical ingredient.

14. The metered-dose inhaler according to any one of claims 11 to 13, wherein the metered-dose inhaler delivers at least 1.0 mg of the at least one active pharmaceutical ingredient per operation.

15. The metered-dose inhaler according to any one of claims 11 to 14, wherein the at least one active pharmaceutical ingredient comprises a mast cell stabilizer, a receptor tyrosine kinase inhibitor, a β2 adrenergic receptor agonist, a steroid, or a combination thereof.

16. The quantitative inhaler according to any one of claims 11 to 15, wherein the at least one active pharmaceutical ingredient is a finely powdered crystalline solid.

17. The metered-dose inhaler according to any one of claims 11 to 16, wherein the formulation is substantially free of ethanol.

18. The metered-dose inhaler according to any one of claims 11 to 16, wherein the formulation contains up to 5% by weight of ethanol.

19. The metered inhaler according to any one of claims 11 to 18, wherein the actuator nozzle includes an outlet orifice diameter of up to 0.5 mm.

20. The quantitative inhaler according to any one of claims 11 to 19, wherein the formulation comprises at least 1% by weight of the at least one active pharmaceutical ingredient.

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