Metered dose inhalers and suspension compositions including polyethylene glycol

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 includes a composition having greater than 70% by weight of HFO-1234ze(E), PEG, and at least one active pharmaceutical ingredient suspended in the composition to form a suspension. The compositions are substantially free of ethanol.

Description

[0001] 0625.084017W001

[0002] METERED DOSE INHALERS AND SUSPENSION COMPOSITIONS

[0003] INCLUDING POLYETHYLENE GLYCOL

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 735,159, filed on December 17, 2024, the disclosure of which is incorporated by reference herein in its entirety.

[0006] Background

[0007] Delivery of aerosolized medicament to the respiratory tract for the treatment of respiratory and other diseases can be done using, by way of example, pressurized metered dose inhalers (pMDI), dry powder inhalers (DPI), or nebulizers. pMDIs are familiar to many patients who suffer from asthma or chronic obstructive pulmonary disease (COPD). pMDI devices can include an aluminum canister, sealed with a metering valve, that contains medicament composition. Generally, a typical current medicament composition includes one or more medicinal compounds present in a liquefied hydrofluoroalkane (HF A) propellant.

[0008] Historically, the propellants in most pMDIs have been chlorofluorocarbons (CFCs). However, environmental concerns during the 1990s led to the replacement of CFCs with hydrofluoroalkanes (HF As) as the most commonly used propellant in pMDIs. Although HF As do not cause ozone depletion, they do have a stated high global warming potential (GWP), which is a measurement of the future radiative effect of an emission of a substance relative to that of the same amount of carbon dioxide (CO2). The two HFA propellants most commonly used in pMDIs are HFA- 134a (CF3CH2F) and HFA-227 (CF3CHFCHF3) having stated 100-year GWP values of 1300 to 1430 and 3220 to 3350, respectively. The propellants HFO-1234ze(E) and HFA-152a have been proposed as low- GWP alternatives to HFA propellants.

[0009] However, the stability of various active pharmaceutical ingredients (APIs) in low- GWP propellants, particularly HFO-1234ze(E) is often different from the stability of the same APIs in HFA propellants. Thus, a need exists for compositions including low GWP- propellants, excipients, and APIs. Summary

[0010] It has now been found that despite HFO-1234ze(E)’s differences from other pMDI propellants, a practical pMDI can be made using HFO-1234ze(E). One advantage of such pMDIs is HFO-1234ze(E)’s stated GWP of less than 1. However, transitioning a formulation from a traditional propellant to a low GWP propellant such as HFO- 1234ze(E) is often unpredictable, and requires careful selection of excipients and other components to create a suitable composition for pharmaceutical use.

[0011] In one embodiment, a pMDI (also referred to herein as an MDI or metered dose inhaler) is provided that includes: a metering valve; a canister; and an actuator that includes an actuator nozzle; wherein the canister includes a composition (i.e., formulation), the composition including greater than 70% by weight of propellant HFO- 1234ze(E), polyethylene glycol (PEG), and at least one API suspended in the composition to form a suspension. In some embodiments, the composition is substantially free of ethanol. In certain embodiments, the API includes a pharmaceutically acceptable formoterol salt or solvate. In some embodiments, the API includes a steroid, such as a corticosteroid. In some embodiments, the corticosteroid includes budesonide. In some embodiments, the corticosteroid includes mometasone. In some embodiments, the corticosteroid includes beclomethasone.

[0012] In one embodiment, a metered dose inhaler is provided that includes: a metering valve; a canister; and an actuator that includes an actuator nozzle; wherein the canister includes a composition, the composition including a propellant including HFO-1234ze(E), PEG, and an active pharmaceutical ingredient including a pharmaceutically acceptable salt or solvate of formoterol (e.g., formoterol fumarate) and mometasone or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutically acceptable salt or solvate of formoterol and the mometasone or a pharmaceutically acceptable salt or solvate thereof are suspended in the composition to form a suspension.

[0013] In one embodiment, a metered dose inhaler is provided that includes: a metering valve; a canister; and an actuator that includes an actuator nozzle; wherein the canister includes a composition, the composition including a propellant including HFO-1234ze(E), PEG, and an active pharmaceutical ingredient including a pharmaceutically acceptable salt or solvate of formoterol (e.g., formoterol fumarate) and budesonide or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutically acceptable salt or solvate of formoterol and the budesonide or pharmaceutically acceptable salt or solvate thereof are suspended in the composition to form a suspension. In one embodiment, a metered dose inhaler is provided that includes: a metering valve; a canister; and an actuator that includes an actuator nozzle; wherein the canister includes a composition, the composition including a propellant including HFO-1234ze(E), PEG, and an active pharmaceutical ingredient including a pharmaceutically acceptable salt or solvate of formoterol (e.g., formoterol fumarate) and beclomethasone or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutically acceptable salt or solvate of formoterol and the beclomethasone or pharmaceutically acceptable salt or solvate thereof are suspended in the composition to form a suspension.

[0014] Herein, the term “comprises” and variations thereof do not have a limiting meaning where these terms appear in the description and claims. Such terms will be understood to imply the inclusion of a stated step or element, or group of steps or elements, but not the exclusion of any other step or element, or group of steps or elements. The phrase “consisting of’ means including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present. The phrase “consisting essentially of’ means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of’ indicates that the listed elements are required or mandatory, but that other elements are optional and may, or may not, be present depending upon whether or not they materially affect the activity or action of the listed elements. Any of the elements or combinations of elements that are recited in this specification in open-ended language (e.g., comprise and derivatives thereof), are considered to additionally be recited in closed-ended language (e.g., consist and derivatives thereof) and in partially closed-ended language (e.g., consist essentially and derivatives thereof).

[0015] Herein, a composition “substantially free of’ a material refers to a composition having less than 10 wt% of the material, less than 5 wt% of the material, less than 4 wt% of the material, less than 3 wt% of the material, less than 2 wt% of the material, or less than 1% of the material. A composition that “lacks” a component does not include a detectable amount of that component.

[0016] Herein, the concentration of a component is sometimes described as a weight percentage (“wt%,” “weight %,” or “wt-%”). The weight percent of a component in a composition is relative to the weight of the entire composition. For example, a composition including 10 wt% of polyethylene glycol (PEG) may include 10 mg of PEG and 90 mg of a solvent.

[0017] As it is used herein, a “pharmaceutically acceptable” form of an API is suitable for delivery to a subject without additional processing. For example, a pre-drug form of an API would typically not be considered pharmaceutically acceptable.

[0018] The words “preferred” and “preferably” refer to embodiments of the disclosure that may afford certain benefits, under certain 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, and is not intended to exclude other embodiments from the scope of the disclosure.

[0019] Throughout this disclosure, singular forms such as “a,” “an,” and “the” are often used for convenience; singular forms are meant to include the plural unless the singular alone is explicitly specified or is clearly indicated by the context.

[0020] As used herein, the term “or” is generally employed in its usual sense including “and / or” unless the content clearly dictates otherwise.

[0021] The term “and / or” means one or all of the listed elements or a combination of any two or more of the listed elements.

[0022] The phrase “ambient conditions” as used herein, refers to an environment of room temperature (approximately 20 °C to 25 °C) and 30% to 60% relative humidity.

[0023] Also herein, all numbers are assumed to be modified by the term “about” and in certain embodiments, preferably, by the term “exactly.” As used herein in connection with a measured quantity, the term “about” refers to that variation in the measured quantity as would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used. Herein, “up to” a number (e.g., up to 50) includes the number (e.g., 50). Herein, “at least” a number (e.g., at least 50) includes the number (e.g., 50). Herein, “no more than” a number (e.g., no more than 50) includes the number (e.g., 50).

[0024] Numerical ranges, for example “between x and y” or “from x to y,” include the endpoint values of x and y. Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range as well as the endpoints (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0025] When a concentration is described as a weight percent basis (e.g., wt%, w / w%, %w / w), it refers to the weight of the component as a percentage of the weight of the total composition. For example, a sucrose solution including 10 wt% of sucrose in water may include 10 grams of sucrose in a total of 100 grams of solution.

[0026] Some terms used in this application have special meanings, as defined herein. All other terms will be known to the skilled artisan and are to be afforded the meaning that a person of skill in the art at the time of the invention would have given them.

[0027] Elements in this specification that are referred to as “common,” “commonly used,” “conventional,” “typical,” “typically,” and the like, should be understood to be common within the context of the compositions, articles, such as inhalers and pMDIs, and methods of this disclosure; this terminology is not used to mean that these features are present, much less common, in the prior art. Unless otherwise specified, only the Background section of this Application refers to the prior art.

[0028] Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0029] The present disclosure will be described with respect to embodiments and with reference to certain drawings, but 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 can be exaggerated and not drawn to scale for illustrative purposes.

[0030] The above summary of the present disclosure is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the disclosure, guidance is provided through lists of examples, which examples may 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 present disclosure should not be limited to the specific illustrative structures described herein, but rather extends at least to the structures described by the language of the claims, and the equivalents of those structures. Any of the elements that are positively recited in this specification as alternatives may be explicitly included in the claims or excluded from the claims, in any combination as desired. Although various theories and possible mechanisms may have been discussed herein, in no event should such discussions serve to limit the claimable subject matter.

[0031] Brief Description of The Drawings

[0032] The present disclosure will be described with respect to embodiments and with reference to certain drawings, but 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 can be exaggerated and not drawn to scale for illustrative purposes.

[0033] FIG. l is a cross-sectional side view of an inhaler including a canister containing a valve according to the present disclosure.

[0034] FIG. 2 is a detailed cross-sectional side view of the inhaler of FIG. 1.

[0035] FIG. 3 is a cross-sectional side view of a metering valve for an inhaler.

[0036] FIG. 4 shows data from Example 1. (A) Delivered dose of compositions including formoterol fumarate dihydrate. (B) Delivered dose of compositions including budesonide.

[0037] FIG. 5 shows data from Example 2. (A) Delivered dose of compositions including formoterol fumarate dihydrate. (B) Delivered dose of compositions including budesonide.

[0038] FIG. 6 shows data from Example 3. (A) Delivered dose of compositions including formoterol fumarate dihydrate. (B) Delivered dose of compositions including budesonide.

[0039] Detailed Description

[0040] The compositions of the present disclosure are suspensions (i.e., suspension compositions or suspension formulations). That is, the compositions include one or more APIs dispersed in the compositions (i.e., suspended in the propellant and often a suspension aid) to form suspensions. Herein, in a “suspension” the API is in a microparticulate solid form (typically micronized, but can also be size reduced by a multitude of other particle size reduction techniques) and dispersed in a propellant, often with other soluble or non-solubilized excipients to aid the suspension behavior of the particles. As it is used herein, an “excipient” may be any component of a composition other than an API or a propellant. Solvents such as water and ethanol are considered a type of excipient. Herein, a suspension is a dispersion of particles of particulate material (e.g., API) that is visible to the unaided human eye, although there may also be a small amount of solubilized particulate material within the composition. For suspension compositions, solubilization of API is generally undesirable. In embodiments, it may be desirable to minimize solubilization of an API. Solution and suspension compositions are fundamentally different pMDI composition approaches. Different factors need to be considered when undertaking the development of products using either of these composition approaches. Accordingly, it is not possible to apply the same knowledge and understanding of solution compositions to suspension compositions. Suspensions, for example, need to achieve a degree of physical stability to avoid significant separation of the physical mixture via sedimentation or creaming of the suspended particles. This can lead to poor dose to dose reproducibility. Therefore, for suspensions, the use of suspension aids to control flocculation are often used. Also, in suspensions, the resultant aerosol particle size is predominantly influenced by the geometric particle size of the microparticulate API that can change if the API particles are partially soluble in the propellant / composition, which can lead to physical instability over time, such as particle growth. Suspensions also have a potential problem with deposition of the suspended API particles on to the internal surfaces of the canister and valve, which again can cause changes to product performance over time. These problems are specific to suspensions and any teachings specific to solutions do not necessarily overcome them.

[0041] Further, the pharmaceutical properties of a suspension often vary greatly depending on the combination of API and propellant used. For example, a first API may readily form a suspension in a propellant, such as HFO-1234ze(E) without the need for any excipients, while a second API may require a particular excipient for forming a suspension in the same propellant. Similarly, an excipient may interact differently with different propellants. For example, while a composition including HFO-1234ze(E), ethanol, and an API may form a stable suspension, a composition including HFA-152a, ethanol, and the same API may result in deposition or undesired API dissolution. Thus, a person having skill in the art would understand that the performance of a particular composition cannot necessarily be predicted from performance of similar compositions including different propellants, excipients, or APIs.

[0042] It is surprisingly described herein that compositions including HFO-1234ze(E), formoterol, and a corticosteroid, such as budesonide or mometasone, formed stable suspension in the absence of ethanol when polyethylene glycol (PEG) was added. Further, suspension compositions including HFO-1234ze(E), formoterol, a corticosteroid, and ethanol surprisingly exhibited undesirable API degradation after extended storage. In particular, formoterol exhibits instability in formulations including ethanol. Uniquely, formoterol can be prepared as a suspension or solution formulation in a propellant, such as HFO-1234ze(E). In solution formulations, formoterol may be stabilized using acids. However, acid often causes corrosion of inhaler components, such as the valve or canister. Thus, there is a need for stable suspension formulations including formoterol in a propellant that do not result in undesirable degradation of the API or corrosion of inhaler components.

[0043] The various embodiments of compositions 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 fitted with a metered dose metering valve 10 (shown in its resting position). The metering valve 10 is typically affixed, i.e., crimped, onto the canister via a cap or ferrule 11 (typically made of aluminum or an aluminum alloy) which is generally provided as part of the valve assembly. Between the canister and the ferrule there may be one or more seals. In the embodiments shown in FIGS. 1 and 2 between the canister 1 and the ferrule 11 there are two seals including, e.g., an O-ring seal and a gasket seal.

[0044] As shown in FIG. 1, the canister / valve dispenser is typically provided with an actuator 5 including an appropriate patient port 6, such as a mouthpiece. For administration to the nasal cavities the patient port is generally provided in an appropriate form (e.g., smaller diameter tube, often sloping upwardly) for delivery through the nose. Actuators are generally made of a plastic material, for example polypropylene or polyethylene. As can be seen from FIG. 1, inner walls 2 of the canister and outer walls 101 of the portion(s) of the metering valve 10 located within the canister define a composition chamber 3 in which aerosol composition 4 is contained.

[0045] The valve 10 shown in FIG. 1 and 2, includes a metering chamber 12, defined in part by an inner valve body 13, through which a valve stem 14 passes. The valve stem 14, which is biased outwardly by a compression spring 15, is in sliding sealing engagement with an inner tank seal 16 and an outer diaphragm seal 17. The valve 10 also includes a second valve body 20 in the form of a bottle emptier. The inner valve body 13 (also referred to as the “primary” valve body) defines in part the metering chamber 12. The second valve body 20 (also referred to as the “secondary” valve body) defines in part a pre-metering region or chamber besides serving as a bottle emptier.

[0046] Referring to FIG. 2, aerosol composition 4 can pass from the composition chamber 3 into a pre-metering chamber 22 provided between the secondary valve body 20 and the primary valve body 13 through an annular space 21 between a flange 23 of the secondary valve body 20 and the primary valve body 13. To actuate (fire) the valve 10, the valve stem 14 is pushed inwardly relative to the canister 1 from its resting position shown in FIGS. 1 and 2, allowing composition to pass from the metering chamber 12 through a side hole 19 in the valve stem and through a stem outlet 24 to an actuator nozzle 7 then out to the patient. When the valve stem 14 is released, composition enters into the valve 10, in particular into the pre-metering chamber 22, through the annular space 21 and thence from the pre-metering chamber through a groove 18 in the valve stem past the tank seal 16 into the metering chamber 12.

[0047] FIG. 3 shows another embodiment of a metered dose aerosol metering valve 102, different from the embodiment shown in FIGS. 1 and 2, in its rest position. The valve 102 has a metering chamber 112 defined in part by a metering tank 113 through which a stem 114 is biased outwardly by spring 115. The stem 114 is made in two parts that are push fit together before being assembled into the valve 102. The stem 114 has an inner seal 116 and an outer seal 117 disposed about it and forming sealing contact with the metering tank 113. A valve body 120 crimped into a ferrule 111 retains the aforementioned components in the valve. In use, composition enters the metering chamber via orifices 121 and 118. The composition’s outward path from the metering chamber 112 when a dose is dispensed is via orifice 119.

[0048] The primary propellant of compositions (i.e., suspensions) according to the disclosure is HFO-1234ze(E), also known as trans- 1,1, 1,3 -tetrafluoropropene, trans- 1,3,3,3-tetrafluoropropene, or trans-l,3,3,3-tetrafluoroprop-l-ene. The chemical structure of 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 relative to that of the cis (Z) isomer, at ambient conditions, makes the trans isomer a far more thermodynamically suitable propellant for achieving efficient pMDI atomization. In some embodiments, the composition lacks propellants other than HFO-1234ze(E). For example, the composition may lack HFA-134a, the composition may lack HFC-227, or the composition may lack HFA-152a.

[0049] In some embodiments, the amount of HFO-1234ze(E) by weight in the composition is at least 90%, greater than 90%, at least 92%, greater than 92%, at least 95%, greater than 95%, at least 96%, greater than 96%, at least 97%, greater than 97%, at least 98%, greater than 98%, at least 99%, or greater than 99%. In some embodiments, the amount of HFO-1234ze(E) by weight is 80% to 99%, 80% to 98%, 80% to 95%, or 85% to 90%. In some embodiments, HFO-1234ze(E) is essentially the sole propellant in the composition. That is, the pharmaceutical product performance parameters, such as emitted dose and emitted particle size distribution, are not significantly different than if HFO- 1234ze(E) were the sole propellant in the composition. In some embodiments, the amount of HFO-1234ze(E) by weight of the total propellant in the composition is greater than 95%, greater than 98%, greater than 99%, greater than 99.5%, greater than 99.8%, or 100%.

[0050] The propellant HFO-1234ze(E) is very different from an alternative low GWP propellant HFA-152a. These two propellants have different physical, chemical, and thermodynamic properties such as boiling point, vapor pressure, water solubility, liquid density, surface tension, etc. The differences in these properties make replacing one propellant with another without significantly compromising or altering pMDI product performance difficult to achieve. For example, the thermodynamic differences in propellant boiling point and vapor pressure can significantly affect pMDI aerosolization efficiency and give rise to differences in primary and secondary atomization mechanisms. Liquid density differences between the propellants and suspended API particles can affect suspension behavior, such as sedimentation rate. Differences in hygroscopicity between the propellants can affect moisture uptake, which could be problematic for suspension compositions, particularly if physical stability due to moisture uptake or chemical degradation in which water is involved is likely. Chemical interactions of the different propellants with API and excipients may also be significantly different, which could affect the long-term chemical stability of the product over the intended shelf life. The two propellants interact chemically and physically with valve plastics and elastomeric components, which could give rise to differences in the types and amounts of extractables and leachables, as well as impacting mechanical valve function. The thermodynamic properties of the propellants can give rise to different droplet particle sizes due to different evaporation rates and can also result in differences in spray characteristics such as spray force, temperature, and spray duration. Historically, the transition from CFC to HFA propellants has required significant efforts to develop new approaches to reformulate and develop capable hardware to achieve appropriate pMDI product performance. That is, it was not possible to simply directly substitute one propellant for another. Changing between propellant HFA-152a to HFO-1234ze(E) in a pMDI, is equally challenging due to many of the factors highlighted above. The total amount of composition is desirably selected so that at least a portion of the propellant in the canister is present as a liquid after a predetermined number of medicinal doses have been delivered. The predetermined number of doses may be 5 to 200, 30 to 200, 60 to 200, 60 to 120, 60, 120, 200, or any other number of doses. The total amount of composition in the canister may be from 1.0 grams (g) to 30.0 g, 2.0 g to 20.0 g, or 5.0 to 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 1.1 times, greater than 1.2 times, greater than 1.3 times, greater than 1.4 times, or greater than 1.5 times the product of the predetermined number of doses and the metering volume of the metering valve. This typically ensures that the amount of each dose remains relatively constant through the life of the inhaler.

[0051] For preparation of suspension compositions, the API is preferably provided as a micronized powder. However, it should be apparent to one of ordinary skill in the art that other forms of API may be suitable for preparation of suspension compositions consistent with this disclosure.

[0052] The compositions described herein include an API including formoterol. When a composition including formoterol is discussed in this application, the term “formoterol” may refer to any disclosed form of formoterol, such as a formoterol free base, a salt of formoterol, an anhydrous formoterol or a salt thereof, or a hydrate or solvate of formoterol. In some embodiments, a composition includes a pharmaceutically acceptable salt or solvate of formoterol, such as formoterol fumarate dihydrate, and a steroid. The form of formoterol provided may be any pharmaceutically acceptable salt or solvate of formoterol. For example, the formoterol may include formoterol fumarate. Multiple enantiomers of formoterol fumarate are known to the art. In some embodiments, the formoterol fumarate is or includes the R, R enantiomer of formoterol fumarate. In some embodiments, the formoterol fumarate is in the form of a single enantiomer, preferably R, R, formoterol fumarate. Formoterol is also available as a hydrated salt or a dehydrated salt. In some embodiments, a composition includes a hydrated formoterol salt, such as formoterol fumarate dihydrate. In some embodiments, the formoterol is R,R, formoterol fumarate dihydrate.

[0053] The concentration of formoterol in the composition may be selected to provide a particular dose. In some embodiments, the composition includes formoterol, such as formoterol fumarate dihydrate, at a concentration of 0.001 wt% to 0.03 wt%. In some embodiments, the composition includes at least 0.001 wt%, at least 0.0015 wt%, at least 0.002 wt%, at least 0.0025 wt%, at least 0.003 wt%, at least 0.0035 wt%, at least 0.004 wt%, at least 0.0045 wt%, at least 0.005 wt%, at least 0.0055 wt%, at least 0.006 wt%, at least 0.0065 wt%, at least 0.007 wt%, at least 0.0075 wt%, at least 0.008 wt%, at least 0.0085 wt%, at least 0.009 wt%, at least 0.0095 wt%, at least 0.01 wt%, at least 0.015 wt%, or at least 0.02 wt% of formoterol, such as formoterol fumarate dihydrate. In some embodiments, the composition includes at most 0.03 wt%, at most 0.025 wt%, at most 0.02 wt%, or at most 0.015 wt% of formoterol, such as formoterol fumarate dihydrate. In some particular embodiments, the composition includes 0.007 wt% to 0.019 wt% of formoterol, such as 0.0069 wt%, 0.0074 wt%, 0.0087 wt%, 0.0093 wt%, 0.0173 wt%, or 0.0186 wt% of formoterol, such as formoterol fumarate dihydrate.

[0054] In some embodiments, a composition includes a steroid such as a corticosteroid. In some embodiments, the corticosteroid includes mometasone. When a composition including mometasone is discussed in this application, the term “mometasone” may refer to any disclosed form of mometasone, such as a mometasone free base, a salt of mometasone, an anhydrous mometasone or a salt thereof, or a hydrate or solvate of mometasone. Preferably, compositions of the present disclosure include mometasone furoate, although other forms may be included. The form of mometasone provided may include pharmaceutically acceptable salt or solvate of mometasone, such as mometasone furoate.

[0055] The concentration of mometasone in the compositions may be selected to provide a particular dose. In some embodiments, the composition includes mometasone, such as mometasone furoate, at a concentration of at least 0.050 wt%, at least 0.060 wt%, at least 0.070 wt%, at least 0.080 wt%, at least 0.090 wt%, at least 0.10 wt%, at least 0.11 wt%, at least 0.20 wt%, at least 0.12 wt%, at least 0.13 wt%, at least 0.14 wt%, at least 0.15 wt%, at least 0.16 wt%, at least 0.17 wt%, at least 0.18 wt%, at least 0.19 wt%, at least 0.20 wt%, at least 0.25 wt%, at least 0.30 wt%, at least 0.35 wt%, at least 0.40 wt%, at least 0.45 wt%, or at least 0.5 wt%. In some embodiments, the composition includes mometasone, such as mometasone furoate, at a concentration of at most 0.80 wt%, at most 0.75 wt%, at most 0.7 wt%, at most 0.65 wt%, at most 0.6 wt%, at most 0.55 wt%, or at most 0.5 wt%. In some embodiments, the composition includes 0.1 wt% to 0.8 wt% or 0.1 wt% to 0.5 wt%, such as 0.081 wt%, 0.102 wt%, 0.155 wt%, 0.195 wt%, 0.203 wt%, 0.303 wt%, 0.381 wt%, or 0.763 wt% of a pharmaceutically acceptable mometasone salt or solvate. In some embodiments, a metered dose inhaler may be characterized by the exactuator dose of an API. The ex-actuator dose of an API is measured as the amount of the API that passes through the nozzle, such as the actuator nozzle 7 shown in FIG. 2. Additionally or alternatively, a metered dose inhaler may be identified by the ex-valve dose of API delivered. The ex-valve dose of an API delivered is measured as the amount of the API that passes through the valve stem, such as the valve stem 14 depicted in FIG. 2. In some embodiments, a metered dose inhaler delivers an ex-actuator dose of at least 40 micrograms / actuation, at least 45 micrograms / actuation, at least 50 micrograms / actuation, at least 55 micrograms / actuation, or at least 60 micrograms / actuation of mometasone, such as mometasone furoate. In some embodiments, a metered dose inhaler delivers an exactuator dose of at most 250 micrograms / actuation, at most 225 micrograms / actuation, at most 200 micrograms / actuation, at most 150 micrograms / actuation, at most 125 micrograms / actuation, at most 100 micrograms / actuation, or at most 75 micrograms / actuation of mometasone, such as mometasone furoate. In some embodiments wherein a metered dose inhaler includes an API including mometasone, such as mometasone furoate, and formoterol, such as formoterol fumarate, the metered dose inhaler delivers an ex-actuator dose of 50 micrograms / actuation to 250 micrograms / actuation of mometasone and 4 micrograms / actuation to 6 micrograms / actuation of formoterol, such as 60 micrograms / actuation of mometasone furoate and 5.5 micrograms / actuation of formoterol fumarate, 115 micrograms / actuation of mometasone furoate and 5.5 micrograms / actuation of formoterol fumarate, or 225 micrograms / actuation of mometasone furoate and 5.5 micrograms / actuation of formoterol fumarate.

[0056] In some embodiments, a composition includes budesonide. When a composition including budesonide is discussed in this application, the term “budesonide” may refer to any disclosed form of budesonide, such as a budesonide free base, a salt of budesonide, an anhydrous budesonide or a salt thereof, or a hydrate or solvate of budesonide, unless otherwise specified. Preferably, compositions of the present disclosure include budesonide free base. The form of budesonide provided may include any pharmaceutically acceptable salt or solvate of budesonide. It is known to the art that budesonide exists in two epimer forms, 22R and 22S. In some embodiments, a composition includes 22R budesonide. In some embodiments, a composition includes 22S budesonide. In some embodiments, a composition includes both 22R budesonide and 22S budesonide. In some embodiments, the composition includes budesonide at a concentration of at least 0.03 wt%, at least 0.04 wt%, at least 0.05 wt%, at least 0.10 wt%, at least 0.11 wt%, at least 0.20 wt%, at least 0.12 wt%, at least 0.13 wt%, at least 0.14 wt%, at least 0.15 wt%, at least 0.16 wt%, at least 0.17 wt%, at least 0.18 wt%, at least 0.19 wt%, at least 0.20 wt%, at least 0.25 wt%, or at least 0.30 wt%. In some embodiments, the composition includes budesonide, such as free base budesonide, at a concentration of at most 0.7 wt%, at most 0.65 wt%, at most 0.6 wt%, at most 0.55 wt%, at most 0.5 wt%, at most 0.45 wt%, or at most 0.4 wt%. In some embodiments, the composition includes 0.05 wt% to 0.7 wt% of budesonide, such as 0.1225 wt%, 0.1544 wt%, 0.2437 wt%, 0.3070 wt%, 0.3087 wt%, or 0.6141 wt%.

[0057] In some embodiments, a metered dose inhaler delivers an ex-actuator dose of at least 70 micrograms / actuation, at least 75 micrograms / actuation, at least 80 micrograms / actuation, at least 85 micrograms / actuation, or at least 90 micrograms / actuation of budesonide. In some embodiments, a metered dose inhaler delivers an ex-actuator dose of at most 250 micrograms / actuation, at most 225 micrograms / actuation, at most 200 micrograms / actuation, at most 150 micrograms / actuation, at most 125 micrograms / actuation, or at most 100 micrograms / actuation of budesonide. In some embodiments wherein a metered dose inhaler includes an API including budesonide and formoterol, such as formoterol fumarate dihydrate, the metered dose inhaler delivers an ex-actuator dose of 80 micrograms / actuation to 200 micrograms / actuation of budesonide and 4 micrograms / actuation to 6 micrograms / actuation of formoterol, such as 91 micrograms / actuation of budesonide and 5.1 micrograms / actuation of formoterol fumarate, or 181 micrograms / actuation of budesonide and 5.1 micrograms / actuation of formoterol fumarate.

[0058] In some embodiments, a composition includes glycopyrrolate, sometimes referred to as glycopyrronium. Typically, glycopyrrolate is provided as glycopyrronium bromide. In some embodiments, a composition includes glycopyrronium bromide, budesonide, and formoterol fumarate.

[0059] In some embodiments, a composition includes at least 0.010 wt%, at least 0.011 wt%, at least 0.012 wt%, at least 0.013 wt%, at least 0.014 wt%, at least 0.015 wt%, or at least 0.018 wt% of glycopyrronium, such as glycopyrronium bromide. In some embodiments, a composition includes at most 0.05 wt%, at most 0.045 wt%, at most 0.04 wt%, at most 0.035 wt%, at most 0.03 wt%, at most 0.025 wt%, at most 0.02 wt%, at most 0.019 wt%, at most 0.018 wt%, or at most 0.017 wt% of glycopyrronium, such as glycopyrronium bromide.

[0060] In some embodiments, a metered dose inhaler delivers an ex-actuator dose of at least 5 micrograms / actuation, at least 6 micrograms / actuation, at least 7 micrograms / actuation, at least 8 micrograms / actuation, or at least 9 micrograms / actuation of glycopyrronium, such as glycopyrronium bromide. In some embodiments, a metered dose inhaler delivers an ex-actuator dose of at most 20 micrograms / actuation, at most 18 micrograms / actuation, at most 16 micrograms / actuation, at most 14 micrograms / actuation, at most 12 micrograms / actuation, or at most 10 micrograms / actuation of glycopyrronium, such as glycopyrronium bromide.

[0061] In some embodiments, a metered dose inhaler delivers glycopyrronium bromide, budesonide, and formoterol fumarate dihydrate. In some embodiments, a metered dose inhaler delivers an ex-actuator dose of 4 micrograms / actuation to 6 micrograms / actuation of formoterol fumarate dihydrate, an ex-actuator dose of 150 micrograms / actuation to 170 micrograms / actuation of budesonide, and 5 micrograms / actuation to 20 micrograms / actuation of glycopyrronium bromide.

[0062] In some embodiments, a composition includes beclomethasone. When a composition including beclomethasone is discussed in this application, the term “beclomethasone” may refer to any disclosed form of beclomethasone, such as a beclomethasone free base, a salt of beclomethasone, an anhydrous beclomethasone or a salt thereof, or a hydrate or solvate of beclomethasone, unless otherwise specified. Preferably, compositions of the present disclosure include beclomethasone free base. The form of beclomethasone provided may include any pharmaceutically acceptable salt or solvate of beclomethasone.

[0063] In some embodiments, the composition includes beclomethasone at a concentration of at least 0.03 wt%, at least 0.04 wt%, at least 0.05 wt%, at least 0.10 wt%, at least 0.11 wt%, at least 0.20 wt%, at least 0.12 wt%, at least 0.13 wt%, at least 0.14 wt%, at least 0.15 wt%, at least 0.16 wt%, at least 0.17 wt%, at least 0.18 wt%, at least 0.19 wt%, at least 0.20 wt%, at least 0.25 wt%, or at least 0.30 wt%. In some embodiments, the composition includes beclomethasone, such as free base beclomethasone, at a concentration of at most 0.7 wt%, at most 0.65 wt%, at most 0.6 wt%, at most 0.55 wt%, at most 0.5 wt%, at most 0.45 wt%, or at most 0.4 wt%. In some embodiments, the composition includes 0.05 wt% to 0.7 wt% of beclomethasone, such as 0.1225 wt%, 0.1544 wt%, 0.2437 wt%, 0.3070 wt%, 0.3087 wt%, or 0.6141 wt%. In some embodiments, a metered dose inhaler delivers an ex-actuator dose of at least 70 micrograms / actuation, at least 75 micrograms / actuation, at least 80 micrograms / actuation, at least 85 micrograms / actuation, or at least 90 micrograms / actuation of beclomethasone. In some embodiments, a metered dose inhaler delivers an ex-actuator dose of at most 250 micrograms / actuation, at most 225 micrograms / actuation, at most 200 micrograms / actuation, at most 150 micrograms / actuation, at most 125 micrograms / actuation, or at most 100 micrograms / actuation of beclomethasone. In some embodiments wherein a metered dose inhaler includes an API including beclomethasone and formoterol, such as formoterol fumarate dihydrate, the metered dose inhaler delivers an ex-actuator dose of 80 micrograms / actuation to 200 micrograms / actuation of beclomethasone and 4 micrograms / actuation to 6 micrograms / actuation of formoterol, such as 91 micrograms / actuation of beclomethasone and 5.1 micrograms / actuation of formoterol fumarate, or 181 micrograms / actuation of beclomethasone and 5.1 micrograms / actuation of formoterol fumarate.

[0064] In some embodiments, the API(s) are dispersed or suspended in the composition (i.e., as a suspension). In some embodiments wherein a combination of two or more APIs are used, all of the APIs are suspended. In some embodiments wherein a combination of two or more APIs are used, one API is suspended and one API is dissolved .Where API is present in particulate form, i.e., suspended, it will generally have a mass median aerodynamic diameter in the range of 1 micrometer to 10 micrometers, preferably 1 micrometer to 5 micrometers.

[0065] The amount of API may be determined by the required dose per actuation and the pMDI metering valve size, that is, the size of the metering chamber, which may be 5 microliters to 200 microliters, 25 microliters to 200 microliters, 25 microliters to 150 microliters, 25 microliters to 100 microliters, or 25 microliters to 65 microliters. In some embodiments, the metering chamber has a valve size of 25 microliters. In some embodiments, the metering chamber has a valve size of 50 microliters. In some embodiments, the metering chamber has a valve size of 63 microliters.

[0066] In embodiments wherein a metered dose inhaler includes a composition including formoterol and budesonide, the amount of each of formoterol and budesonide delivered per actuation may be selected to provide a desired dose. In some embodiments, a metered dose inhaler may deliver 4 micrograms to 5 micrograms of formoterol and 75 micrograms to 175 micrograms of budesonide per actuation, such as 4.5 micrograms of formoterol and 80 micrograms of budesonide per actuation, or 4.5 micrograms of formoterol and 160 micrograms of budesonide per actuation.

[0067] In embodiments wherein a metered dose inhaler includes a composition including formoterol and mometasone, the amount of each of formoterol and mometasone delivered per actuation may be selected to provide a desired dose. In some embodiments, a metered dose inhaler may deliver 4 micrograms to 6 micrograms of formoterol and 25 micrograms to 250 micrograms of mometasone per actuation, such as 6 micrograms of formoterol and 50 micrograms of mometasone per actuation, 5 micrograms of formoterol and 100 micrograms of mometasone per actuation, or 5 micrograms of formoterol and 200 micrograms of mometasone per actuation.

[0068] In some embodiments, additional components (e.g., excipients) beyond propellant and API can be added to the composition. These components may have various uses and functions, including, but not limited to, facilitating formation of a suspension, stabilizing a suspension, and / or aiding in chemical stabilization of API or other components. In particular, the compositions disclosed herein include polyethylene glycol.

[0069] Polyethylene glycol (PEG), sometimes called poly(ethylene glycol), polyethylene oxide, or polyoxy ethylene, is a polymer having the formula H(OCH2CH2)nOH. Many different sizes of PEG are available, each including a composition of PEG molecules having a generally similar average molecular weight. PEG is typically described by the average molecular weight of the chains in a preparation of PEG. In some embodiments, a composition includes PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1500, PEG 2000, PEG 2500, PEG 3000, or a combination of two or more weights of PEG. In some embodiments, a composition includes PEG having a molecular weight from 200 to 3000. In some embodiments, a composition includes PEG having a molecular weight from 400 to 2000. In some embodiments, a composition includes PEG having a molecular weight from 500 to 1000.

[0070] A preparation of PEG may have different physical properties depending on its molecular weight. For example, PEG 300 is typically a liquid at room temperature under standard pressure, while PEG 2,000 is typically a solid at room temperature under standard pressure. In some embodiments, the PEG used in a composition is a liquid at room temperature under standard pressure. In some embodiments, a composition includes PEG 300. In some of these embodiments, a composition includes 0.01 wt% to 0.4 wt% of PEG 300, such as 0.30 wt%. In some embodiments, a composition includes PEG 1000. In some of these embodiments, a composition includes 0.03 wt% to 0.15 wt% of PEG 1000, such as 0.05 wt% or 0.10 wt%. In some embodiments, a composition includes 0.05 wt%, 0.010 wt%, or 0.15 wt% of PEG 1000. The concentration of the PEG included in the composition is typically selected as to not exceed the solubility limit of the particular weight of PEG in HFO-1234ze.

[0071] The amount of PEG in a composition may be chosen to improve physical properties of a composition. In some embodiments, a composition includes at least 0.001 wt%, at least 0.005 wt%, at least 0.01 wt%, at least 0.02 wt%, at least 0.03 wt%, at least 0.04 wt%, at least 0.05 wt%, at least 0.06 wt%, at least 0.07 wt%, at least 0.08 wt%, at least 0.09 wt%, or at least 0.1 wt% of PEG. In some embodiments, a composition includes at most 0.5 wt%, at most 0.475 wt%, at most 0.45 wt%, at most 0.425 wt%, at most 0.4 wt%, at most 0.375 wt%, at most 0.35 wt%, at most 0.325 wt%, at most 0.3 wt%, at most 0.275 wt%, at most 0.25 wt%, at most 0.225 wt%, at most 0.2 wt%, at most 0.175 wt%, at most 0.15 wt%, or at most 0.125 wt% of PEG. In some embodiments, a composition includes 0.01 wt% to 0.3 wt%, such as 0.05 wt% to 0.1 wt%.

[0072] The compositions disclosed herein may additionally be described by the compounds they do not include. In some embodiments, a composition is substantially free of acids. In some embodiments, a composition lacks acid. Acids may include organic acids, such as citric acid, acetic acid, lactic acid, formic acid, oxalic acid, uric acid, malic acid, butyric acid, and folic acid.. Acids may include mineral acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid. In some embodiments, a composition includes at most 1%, at most 0.5%, at most 0.1%, at most 0.01%, or at most 0.001% of acid. In some embodiments, a composition is substantially free of excipients such as polyvinylpyrrolidone (PVP). PVP is a commonly used pharmaceutical excipient. However, as is described herein, PVP is not soluble in some propellants, such as HFO- 1234ze(E). Thus, adding PVP to a formulation including HFO-1234ze(E) may not affect the performance of the formulation. In some embodiments, a composition is substantially free of PVP. In some embodiments, a composition lacks PVP, such as PVP K25.

[0073] In some embodiments, a composition is substantially free of components other than propellant (e.g., HFO-1234ze(E)), API, and PEG. A composition may lack, for example, oleic acid, sorbitan trioleate, sorbitan monooleate, magnesium stearate.

[0074] Typically, a composition lacks solid excipient particles such as suspending particles. Suspending particles may include phospholipids. Suspending particles typically do not include an API, but may become associated with an API within a composition. Advantageously, the compositions of the present application form stable suspensions without the need for suspending particles.

[0075] In some embodiments, a composition is substantially free of a cosolvent, such as alcohol. In some embodiments, a composition is substantially free of ethanol. In some embodiments, a composition includes at most 1%, at most 0.5%, at most 0.1%, at most 0.01%, or at most 0.001% of ethanol. In some embodiments, a composition is substantially free of water. In some embodiments, a composition includes at most 0.5%, at most 0.3%, at most 0.2%, at most 0.1%, at most 0.01%, or at most 0.001% of water.

[0076] The compositions of the present disclosure include PEG. In some embodiments, a composition is substantially free of all excipients and cosolvents except for PEG. In some embodiments, a composition consists of the propellant HFO-1234ze(E), an API, and PEG. In some embodiments, a composition consists essentially of the propellant HFO- 1234ze(E), an API, and PEG.

[0077] In certain embodiments, compositions of the present disclosure preferably display chemical stability such that acceptable levels of degradation products are present in the finished product for at least 24 months, and often from 24 to 36 months under storage conditions.

[0078] Metered Dose Inhalers

[0079] Returning to FIG.l, in use, the patient actuates the inhaler 100 by pressing downwardly on the canister 1. This moves the canister 1 into the body of the actuator 5 and presses the valve stem 14 against the actuator stem socket 8 resulting in the canister metering valve 10 opening and releasing a metered dose of composition that passes through the actuator nozzle 7 and exits the mouthpiece 6 into the patient's mouth. It should be understood that other modes of actuation, such as breath-actuation, may be used as well and would operate as described with the exception that the force to depress the canister would be provided by the device, for instance by a spring or a motor-driven screw, in response to a triggering event, such as patient inhalation.

[0080] Devices that may be used with medicament compositions of the present disclosure include those described in U.S. Patent No. 6,032,836 (Hiscocks et al.), U.S. Patent No. 9,010,329 (Hansen), and U.K. Patent GB 2544128 B (Friel).

[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 in, for example, U.S. Patent Nos. 8,740,014 (Purkins et al.); 8,479,732 (Stuart et al.), and 8,814,035 (Stuart), and U.S. Patent Application Publication No. 2012 / 0234317 (Stuart), all of which are incorporated by reference in their entirety with respect to their disclosures of dose counters.

[0082] At least one of the various internal components of an inhaler, such as a metered dose inhaler, as described herein, such as one or more of the canister, valve, gaskets, seals, or O-rings, can be coated with one or more coatings. Some of these coatings provide a low surface energy. Such coatings are not always required because they are not always necessary for the successful operation of all inhalers. Thus, some metered dose inhalers do not include coated internal components.

[0083] Some coatings that can be used are described in U.S. Patent No. 8,414,956 (Jinks 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 entireties for their disclosure of coatings for inhalers and inhaler components. Other coatings, such as fluorinated ethylene propylene resins, or FEP, are also suitable. FEP is particularly suitable for use in coating canisters.

[0084] Some coating systems that can be used are described in European Patent Application No. 3661577 (Jinks et al.), European Patent No. 3146000 (Jinks et al.), and European Patent No. 3561004 (Jinks et al.). These coating systems are particularly useful for coating valves components, including one or more of valve stems, bottle emptiers, springs, and tanks. This coating system can be used with any type of inhaler and any composition described herein.

[0085] In some embodiments the actuator nozzle is sized so as to optimize the fine particle fraction (FPF) and / or respirable dose delivered of the composition within the canister. In some embodiments the cross-sectional shape of the actuator nozzle is essentially circular or circular and has a predetermined diameter. In some embodiments where the cross- sectional shape of the actuator nozzle is non-circular, for example oval, an effective diameter may be determined by taking an average over the distances spanning the opening (e.g., the average of major and minor axes of an ellipse).

[0086] In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.08 mm or greater, 0.10 mm or greater, 0.12 mm or greater, 0.15 mm or greater, 0.175 mm or greater, 0.225 mm or greater 0.3 mm or greater, or 0.4 mm or greater. In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.5 mm or less, 0.4 mm or less, 0.3 mm or less, 0.225 mm or less, 0.175 mm or less, or 0.15 mm or less. In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.12 mm to 0.5 mm, 0.12 mm to 0.4 mm, 0.12 mm to 0.3 mm, 0.12 mm to 0.225 mm, 0.12 mm to 0.175 mm, or 0.12 mm to 0.15 mm. In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.15 mm to 0.5 mm, 0.15 mm to 0.4 mm, 0.15 mm to 0.3 mm, 0.15 mm to 0.225 mm, or 0.15 mm to 0.175 mm. In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.175 mm to 0.5 mm, 0.175 mm to 0.4 mm, 0.175 mm to 0.3 mm, or 0.175 mm to 0.225 mm. In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.225 mm to 0.5 mm, 0.225 mm to 0.4 mm, or 0.225 mm to 0.3 mm. In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.3 mm to 0.5 mm or 0.3 mm to 0.4 mm. In some embodiments the exit orifice (effective diameter) of the actuator nozzle may be 0.4 mm to 0.5 mm. It may be particularly advantageous to use smaller actuator nozzle sizes as described above (e.g., diameter between 0.12 mm (120 micrometers) and 0.225 mm (225 micrometers), or between 0.175 mm (175 micrometers) and 0.225 mm (225 micrometers)) in conjunction with compositions where the API is present as a suspension. This may aid in increasing the fine particle fraction of the emitted dose.

[0087] It should be appreciated by one of ordinary skill in the art that a given actuator nozzle exit orifice may not be suitable for delivery of any composition, and that selection of a suitable actuator nozzle exit orifice for a given composition involves considerable effort.

[0088] In some embodiments, the MDI is manufactured by pressure filling. In pressure filling, the powdered medicament, optionally combined with one or more excipients (e.g., cosolvents), is placed in a suitable aerosol container (i.e., canister) capable of withstanding the vapor pressure of the propellant and fitted with a metering valve prior to filling. The propellant is then forced as a liquid through the valve into the container. In an alternate process of pressure filling, the particulate API is combined in a process vessel with propellant and optionally one or more excipients (e.g., cosolvents), and the resulting API suspension is transferred through the metering valve fitted to a suitable MDI container.

[0089] In some embodiments, the MDI is manufactured by cold filling. In cold filling, the powdered medicament, propellant which is chilled below its boiling point and, optionally, one or more excipients (e.g., co-solvents) are added to the MDI container. In addition, a metering valve is fitted to the container post filling.

[0090] For both pressure filling and cold filling processes, additional steps, such as mixing, sonication, and homogenization may be optionally employed. Embodiments

[0091] Embodiment l is a metered dose inhaler including: a metering valve; a canister; and an actuator including an actuator nozzle; wherein the canister includes a composition, the composition including: greater than 98% by weight of propellant HFO-1234ze(E); polyethylene glycol (PEG) at a concentration of 0.01 wt% to 0.3 wt%; and an active pharmaceutical ingredient (API) suspended in the composition to form a suspension, the API including: a pharmaceutically acceptable salt or solvate of formoterol; and a corticosteroid, wherein the composition is substantially free of ethanol.

[0092] Embodiment 2 is the metered dose inhaler of embodiment 1, wherein the corticosteroid includes budesonide, a pharmaceutically acceptable salt or solvate thereof or a pharmaceutically acceptable salt or solvate of mometasone, or beclomethasone or a pharmaceutically acceptable salt or solvate thereof.

[0093] Embodiment 3 is the metered dose inhaler of embodiment 2, wherein the pharmaceutically acceptable salt or solvate of mometasone includes mometasone furoate.

[0094] Embodiment 4 is the metered dose inhaler of embodiment 1, wherein the pharmaceutically acceptable salt or solvate of formoterol includes formoterol fumarate.

[0095] Embodiment 5 is a metered dose inhaler including: a metering valve; a canister; and an actuator including an actuator nozzle; wherein the canister includes a composition, the composition including: greater than 98% by weight of propellant HFO-1234ze(E);

[0096] PEG at a concentration of 0.01 wt% to 0.3 wt%; and an API suspended in the composition to form a suspension, the API including: formoterol fumarate; and budesonide, wherein the composition is substantially free of ethanol.

[0097] Embodiment 6 is the metered dose inhaler of embodiment 5, wherein the composition includes budesonide at a concentration of 0.05 wt% to 0.7 wt%.

[0098] Embodiment 7 is a metered dose inhaler including: a metering valve; a canister; and an actuator including an actuator nozzle; wherein the canister includes a composition, the composition including: greater than 98% by weight of propellant HFO-1234ze(E);

[0099] PEG at a concentration of 0.01 wt% to 0.3 wt%; and an API suspended in the composition to form a suspension, the API including: formoterol fumarate; and mometasone furoate; wherein the composition is substantially free of ethanol.

[0100] Embodiment 8 is the metered dose inhaler of embodiment 7, wherein the composition includes mometasone furoate at a concentration of 0.05 wt% to 0.8 wt%.

[0101] Embodiment 9 is a metered dose inhaler including: a metering valve; a canister; and an actuator including an actuator nozzle; wherein the canister including a composition, the composition including: greater than 98% by weight of propellant HFO-1234ze(E);

[0102] PEG at a concentration of 0.01 wt% to 0.3 wt%; and an API suspended in the composition to form a suspension, the API including: formoterol fumarate; and beclomethasone; wherein the composition is substantially free of ethanol.

[0103] Embodiment 10 is the metered dose inhaler of embodiment 9, wherein the composition includes beclomethasone at a concentration of 0.05 wt% to 0.8 wt%.

[0104] Embodiment 11 is the metered dose inhaler of any preceding embodiment, wherein formoterol fumarate includes formoterol fumarate dihydrate.

[0105] Embodiment 12 is the metered dose inhaler of any preceding embodiment, wherein the composition includes formoterol fumarate at a concentration of 0.005 wt% to 0.02 wt%.

[0106] Embodiment 13 is the metered dose inhaler of any preceding embodiment, wherein the PEG includes PEG 1000 or PEG 300.

[0107] Embodiment 14 is the metered dose inhaler of any preceding embodiment, wherein the composition includes PEG at a concentration of 0.01 wt% to 0.15 wt%.

[0108] Embodiment 15 is the metered dose inhaler of any preceding embodiment, wherein the composition includes PEG at a concentration of 0.05 wt%, 0.10 wt%, or 0.15 wt%.

[0109] Embodiment 16 is the metered dose inhaler of any preceding embodiment, wherein the metered dose inhaler delivers a dose of less than 500 micrograms of total API per actuation.

[0110] Embodiment 17 is the metered dose inhaler of any preceding embodiment, wherein the propellant includes greater than 99% of HFO-1234ze(E).

[0111] Embodiment 18 is the metered dose inhaler of any preceding embodiment, wherein the composition is substantially free of excipients other than PEG.

[0112] Embodiment 19 is the metered dose inhaler of any preceding embodiment, wherein the composition is substantially free of polyvinylpyrrolidone (PVP). Embodiment 20 is the metered dose inhaler of any preceding embodiment, wherein the composition consists essentially of HFO-1234ze(E), PEG, and the API.

[0113] Embodiment 21 is the inhaler of any preceding embodiment, wherein the metering valve includes a metering chamber having a size of 25 microliters to 200 microliters.

[0114] Embodiment 22 is the metered dose inhaler of embodiment 21, wherein the metering chamber has a size of 50 microliters or 63 microliters.

[0115] Embodiment 23 is the metered dose inhaler of any preceding embodiment, wherein the actuator nozzle includes an exit orifice effective diameter of 0.2 mm to 0.5 mm.

[0116] Embodiment 24 is the metered dose inhaler of any preceding embodiment, wherein the API further includes glycopyrronium bromide.

[0117] Embodiment 25 is the metered dose inhaler of embodiment 23, wherein the composition comprises includes bromide at a concentration of 0.010 wt% to 0.020 wt%.

[0118] Examples

[0119] Example 1

[0120] Three pMDIs compositions including budesonide (BDS) and formoterol fumarate dihydrate (FFD) were filled into PRESSPART fluorocarbon polymer (FCP) canisters, fluorinated ethylene propylene (FEP) coated canisters, or uncoated aluminum canisters. Each canister was fitted with a 63 microliter APT AR valve. Each composition is described in Table 1 below.

[0121] Table 1: Target Concentrations of HFO-1234ze Compositions Examined

[0122] Through unit delivered dose uniformity (TU-DDU) for Formulations A to C packaged in FCP-coated canisters was measured immediately after each canister was prepared. This data is presented for FFD in FIG. 4A and for BDS in FIG. 4B. The delivered dose was measured as the total of two actuations. For each unit, delivered dose was measured at beginning and end of unit life.

[0123] FEP-coated, FCP-coated, and uncoated aluminum canisters including each formulation were stored for six weeks at 40 °C and 75% relative humidity to simulate advanced aging. After six weeks, TU-DDU was measured for each canister. The TU-DDU of FFD in each canister is shown in Table 2 and FIG. 5A. The TU-DDU of BDS in each canister is shown in Table 3 and FIG. 5B.

[0124] In addition, the total ex-actuator dose was measured using aerodynamic particle size distribution (APSD) testing. APSD testing used a five-actuation method into a Next Generation Impactor (NGI) at a flow rate of 30 liters per minute (Lpm) and using a USP throat inlet. The total ex-actuator dose was calculated as the sum of drug deposition on the USP throat inlet and all stages of the NGI. The average ex-actuator dose (micrograms / actuation) from NGI testing are presented in Table 4. Ex-actuator dose was measured immediately after preparation of the canisters and was not measured following storage of the canisters.

[0125] For both TU-DDU and NGI testing, the dose delivered for the composition without PEG was found to be substantially lower than for the compositions with PEG. In addition, the relative standard deviation for FFD and BDS was found to be substantially lower for compositions with PEG.

[0126] Table 2: Formoterol Fumarate Dihydrate Delivered Dose for Various Configurations and Timepoints.

[0127] Table 3: Budesonide Delivered Dose for Various Configurations and Timepoints.

[0128] Table 4: Average Dose Delivered from NGI Testing Example 2

[0129] PVP K25 solubility in HFA-152a and HFO-1234ze(E) formulations with varying ethanol concentrations was measured using a size exclusion chromatography with UV detection at a wavelength of 213 nm. The mean PVP K25 solubility in HFO-1234ze(E) and HFA-152a with and without ethanol is shown in Table 5. Values of zero indicate that a quantifiable amount of dissolved PVP K25 was not detected.

[0130] Table 5: Mean PVP K25 Solubility in HFO-1234ze(E) and HFA-152a.

[0131] For HFO-1234ze(E) formulations, PVP K25 was insoluble at ethanol concentrations up to 2% w / w. For HFA-152a, PVP K25 was insoluble without ethanol, but the solubility increased with increasing ethanol concentration. Previous investigation of PVP solubility in HFA-227 formulations without ethanol measured the solubility to be 0.76, 0.48 and 0.33% w / w for PVP K10, PVP K24 and PVP K40, respectively (Dawson et al., 1996). Thus, the finding that PVP K25 was insoluble in HFO-1234ze(E) was surprising.

[0132] Example 3

[0133] Formulations including BDS and FFD were prepared and filled into canisters with either a 63 mcl or 50 mcl valve. Formulations included 0.05 wt%, 0.10 wt%, or 0.15 wt% PEG 1000.

[0134] Delivered dose for FFD and BDS at the beginning of each canister lifespan is shown in FIG. 6A and FIG. 6B. Formulations including 0.10 wt% PEG in canisters with 63 mcl valves were not tested at the end of canister lifespan, but were tested at the beginning of canister lifespan (FIG. 6A, FIG. 6B). From the dose delivery measurements, it was found that 0.05 wt% PEG, rather than 0.10 wt% PEG or 0.15 wt% PEG, delivered the closest dose to target whether a 50 mcl or 63 mcl valve was used.

[0135] Example 4

[0136] Formulations including BDS and FFD were prepared and filled into PRESSPART fluorocarbon polymer (FCP) canisters. Each canister was fitted with either a 50 microliter or 63 microliter APTAR valve. Each formulation / valve volume is described in Table 6 below.

[0137] Table 6: Target Concentrations of HFO-1234ze Formulations Examined

[0138] Drug delivery was tested at the beginning (BEG) and end (END) of the canister lifespan. Dose delivery across the lifespan of each canister is shown in Table 7.

[0139] Table 7: Dose delivery consistency for formulations including PEG in HFO- 1234ze(E)

[0140] From the dose delivery measurements, it was found that formulations including 0.05 wt% PEG delivered the closest dose to target whether a 50 mcl or 63 mcl valve was used. In addition, formulations including 0.05 wt% PEG, 0.10 wt% PEG, or 0.15 wt% PEG exhibited relatively consistent dose delivery over the canister lifespan.

[0141] The embodiments described above and illustrated in the figures are presented by way of example only and are not intended as a limitation upon the concepts and principles of the present disclosure. As such, it will be appreciated by one having ordinary skill in the art that various changes in the elements and their configuration and arrangement are possible without departing from the spirit and scope of the present disclosure. All references and publications cited herein are expressly incorporated herein by reference in their entirety into this disclosure. Various features and aspects of the present disclosure are set forth in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister comprises a composition, the composition comprising: greater than 98% by weight of propellant HFO-1234ze(E); polyethylene glycol (PEG) at a concentration of 0.01 wt% to 0.3 wt%; and an active pharmaceutical ingredient (API) suspended in the composition to form a suspension, the API comprising: a pharmaceutically acceptable salt or solvate of formoterol; and a corticosteroid, wherein the composition is substantially free of ethanol.

2. The metered dose inhaler of claim 1, wherein the corticosteroid comprises budesonide or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically acceptable salt or solvate of mometasone, or beclomethasone or a pharmaceutically acceptable salt or solvate thereof.

3. The metered dose inhaler of claim 2, wherein the pharmaceutically acceptable salt or solvate of mometasone comprises mometasone furoate.

4. The metered dose inhaler of claim 1, wherein the pharmaceutically acceptable salt or solvate of formoterol comprises formoterol fumarate.

5. A metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister comprises a composition, the composition comprising: greater than 98% by weight of propellant HFO-1234ze(E);PEG at a concentration of 0.01 wt% to 0.3 wt%; and an API suspended in the composition to form a suspension, the API comprising:formoterol fumarate; and budesonide, wherein the composition is substantially free of ethanol.

6. The metered dose inhaler of claim 5, wherein the composition comprises budesonide at a concentration of 0.05 wt% to 0.7 wt%.

7. A metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister comprises a composition, the composition comprising: greater than 98% by weight of propellant HFO-1234ze(E);PEG at a concentration of 0.01 wt% to 0.3 wt%; and an API suspended in the composition to form a suspension, the API comprising: formoterol fumarate; and mometasone furoate; wherein the composition is substantially free of ethanol.

8. The metered dose inhaler of claim 7, wherein the composition comprises mometasone furoate at a concentration of 0.05 wt% to 0.8 wt%.

9. A metered dose inhaler comprising: a metering valve; a canister; and an actuator comprising an actuator nozzle; wherein the canister comprises a composition, the composition comprising: greater than 98% by weight of propellant HFO-1234ze(E);PEG at a concentration of 0.01 wt% to 0.3 wt%; and an API suspended in the composition to form a suspension, the API comprising: formoterol fumarate; and beclomethasone; wherein the composition is substantially free of ethanol.

10. The metered dose inhaler of claim 9, wherein the composition comprises beclomethasone at a concentration of 0.05 wt% to 0.8 wt%.

11. The metered dose inhaler of any preceding claim, wherein formoterol fumarate comprises formoterol fumarate dihydrate.

12. The metered dose inhaler of any preceding claim, wherein the composition comprises formoterol fumarate at a concentration of 0.005 wt% to 0.02 wt%.

13. The metered dose inhaler of any preceding claim, wherein the PEG comprises PEG 1000 or PEG 300.

14. The metered dose inhaler of any preceding claim, wherein the composition comprises PEG at a concentration of 0.01 wt% to 0.15 wt%.

15. The metered dose inhaler of any preceding claim, wherein the composition comprises PEG at a concentration of 0.05 wt%, 0.10 wt%, or 0.15 wt%.

16. The metered dose inhaler of any preceding claim, wherein the metered dose inhaler delivers a dose of less than 500 micrograms of total API per actuation.

17. The metered dose inhaler of any preceding claim, wherein the propellant comprises greater than 99% of HFO-1234ze(E).

18. The metered dose inhaler of any preceding claim, wherein the composition is substantially free of excipients other than PEG.

19. The metered dose inhaler of any preceding claim, wherein the composition is substantially free of polyvinylpyrrolidone (PVP).

20. The metered dose inhaler of any preceding claim, wherein the composition consists essentially of HFO-1234ze(E), PEG, and the API.

21. The metered dose inhaler of any preceding claim, wherein the metering valve comprises a metering chamber having a size of 25 microliters to 200 microliters.

22. The metered dose inhaler of claim 21, wherein the metering chamber has a size of 50 microliters or 63 microliters.

23. The metered dose inhaler of any preceding claim, wherein the actuator nozzle comprises an exit orifice effective diameter of 0.2 mm to 0.5 mm.

24. The metered dose inhaler of any preceding claim, wherein the API further comprises glycopyrronium bromide.

25. The metered dose inhaler of claim 24, wherein the composition comprises glycopyrronium bromide at a concentration of 0.010 wt% to 0.020 wt%.

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