WO2025170986A1

WO2025170986A1 - Drug delivery device

Info

Publication number: WO2025170986A1
Application number: PCT/US2025/014566
Authority: WO
Inventors: Stephen Stein; Benjamin MYATT; Phil COCKS; Paul Young; Daniel Duke; Lingzhe RAO; Hui Xin ONG
Original assignee: Kindeva Drug Delivery LP
Current assignee: Kindeva Drug Delivery LP
Priority date: 2024-02-06
Filing date: 2025-02-05
Publication date: 2025-08-14
Anticipated expiration: 2026-08-06

Abstract

Metered dose inhaler device including an actuator housing (10) with a substantially hollow first portion (15) including a nozzle block, and a substantially hollow second portion (25) defining a mouthpiece and located adjacent the substantially hollow first portion. A spray orifice (45) is formed in the nozzle block (30). The spray orifice (45) defines a jet length (46) along an orifice axis. The spray orifice defines an orifice exit (49) with an orifice exit diameter (47). The jet length is at least 0.8 millimeters ("mm"). The device includes a composition including a propellant that includes 1,1-difluoroethane ("HFA-152a") or trans-1, 1,1,3-tetrafluoropropene ("HFO-1234ze(E) "), the composition located in a canister (40) disposed in the substantially hollow first portion (15). Once the composition is ejected from the orifice exit (49), the composition defines a spray pattern. The spray pattern matches that of a similar device using a propellant including 1,1,1,2,3,3,3-heptafluoropropane ("HFA-227") and a jet length less than or equal to 0.8 mm.

Description

Drug Delivery Device

Cross-Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/550,480, filed on February 6, 2024, the disclosure of which is incorporated by reference herein in its entirety.

Technological Field

[0002] The present disclosure is generally related to a drug delivery device. More particularly, the present disclosure is related to a pressurized metered dose inhaler device, (“MDI”) that uses one or more low global warming potential (“low-GWP”) propellants.

[0003] MDIs may be used, for example, to treat subjects suffering from asthma, chronic obstructive pulmonary disorder (“COPD”), bronchitis, etc. Various implementations incorporating low-GWP propellants may benefit from increased shelf life and product performance resulting, for example, from optimized propellant and solvent, and excipient combinations, while also reducing the amount of greenhouse gases in comparison to other currently used higher-GWP propellants, such as 1, 1,1,2- tetrafluoroethane (“HFA-134a,” sometimes referred to as “HFC-134a”) and 1, 1,1, 2, 3,3,3- heptafluoropropane (“HFA-227,” sometimes referred to as “HFC-227”).

Summary

[0004] The technology disclosed herein relates to an MDI that uses one or more low-GWP propellants. In one embodiment, a metered dose inhaler device may include an actuator housing. The actuator housing may include a substantially hollow first portion including a nozzle block. The actuator housing may also include a spray orifice formed in the nozzle block that is operable for dispensing a spray of metered fluid. The actuator housing may also include a substantially hollow second portion. The substantially hollow second portion may define a mouthpiece and may be located adjacent the substantially hollow first portion, such that the mouthpiece is configured to be placed within a mouth of a user. The spray orifice may define a jet length (sometimes referred to as “orifice length”) along an orifice axis. The spray orifice may define an orifice exit with an orifice exit diameter. The jet length may be at least 0.8 millimeters (“mm”). The metered dose inhaler device may further include a composition including a propellant including 1,1- difhioroethane (“HFA-152a”). The composition may be located in a canister disposed in the substantially hollow first portion. Once the composition is ejected from the orifice exit towards the mouthpiece, the composition may define a spray pattern. The spray pattern may match that of a similar metered dose inhaler device using a propellant including 1,1,1,2,3,3,3-heptafluoropropane (“HFA-227”) or 1 , 1 , 1 ,2-tetrafluoroethane (“HFA-134a”) and a jet length less than or equal to 0.8 mm.

[0005] In another embodiment, a metered dose inhaler device may include an actuator housing. The actuator housing may include a substantially hollow first portion including a nozzle block. The actuator housing may also include a spray orifice formed in the nozzle block that is operable for dispensing a spray of metered fluid. The actuator housing may also include a substantially hollow second portion. The substantially hollow second portion may define a mouthpiece and may be located adjacent the substantially hollow first portion, such that the mouthpiece is configured to be placed within a mouth of a user. The spray orifice may define a jet length along an orifice axis. The spray orifice may define an orifice exit with an orifice exit diameter. The jet length may be at least 0.8 mm. The metered dose inhaler device may further include a composition including a propellant including trans-l,l,l,3-tetrafhioropropene (“HFO-1234ze(E)”), the composition located in a canister disposed in the substantially hollow first portion. Once the composition is ejected from the orifice exit towards the mouthpiece, the composition may define a spray pattern. The spray pattern may match that of a similar metered dose inhaler device using a propellant including 1 , 1 , 1 ,2-tetrafluoroethane (“HFA-134a”) or 1,1, 1,2, 3, 3, 3 -heptafluoropropane (“HFA-227”) and a jet length less than or equal to 0.8 mm.

[0006] In another embodiment, a method of manufacturing a metered dose inhaler may include making a composition including a propellant including at least one of HFA- 152a or HFO-1234ze(E), and further including at least one of a long-acting [3- adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof. The method may further include disposing the composition into a canister for use with an actuator housing. The actuator housing may include a substantially hollow first portion having a first proximal end and a first distal end. The canister may be disposed in the substantially hollow first portion. The actuator housing may include a base portion formed at the first proximal end. The base portion may have a base plane. The actuator housing may include a nozzle block formed in the base portion. The actuator housing may include a spray orifice formed in the nozzle block that is operable for dispensing a spray of metered fluid. The actuator housing may include a substantially hollow second portion having a second proximal end and a second distal end and defining a mouthpiece. The second proximal end may be located adjacent the first proximal end and the second distal end may define an end of the mouthpiece, such that the second distal end of the mouthpiece is configured to be placed within a mouth of a user. The spray orifice may include a third proximal end and a third distal end. The third proximal end may be located towards the second proximal end and the third distal end may be located towards the second distal end. The third proximal end and the third distal end may define a jet length. The third distal end may define an orifice exit. The orifice exit may define an orifice exit diameter. The jet length may be at least 0.8 mm.

[0007] In another embodiment, a metered dose inhaler device may include an actuator housing. The actuator housing may include a substantially hollow first portion having a first proximal end and a first distal end. The actuator housing may include a base portion formed at the first proximal end, the base portion having a base plane. The actuator housing may include a nozzle block formed in the base portion. The actuator housing may include a spray orifice formed in the nozzle block that is operable for dispensing a spray of metered fluid. The actuator housing may include a substantially hollow second portion having a second proximal end and a second distal end. The substantially hollow second portion may define a mouthpiece. The second proximal end may be located adjacent the first proximal end and the second distal end may define an end of the mouthpiece. The substantially hollow second portion may define a roof section and a floor section each extending from the second proximal end to the second distal end of the mouthpiece. The mouthpiece may extend away from the second proximal end such that the second distal end of the mouthpiece is configured to be placed within a mouth of a user. The spray orifice may include a third proximal end and a third distal end. The third proximal end may be located towards the second proximal end and the third distal end may be located towards the second distal end. The third proximal end and the third distal end may define a jet length. The third distal end may define an orifice exit. The orifice exit may define an orifice exit diameter. The jet length may be at least 0.8 mm. The metered dose inhaler device may further include a composition including a propellant including at least one of HFA-152a or HFO-1234ze(E). The composition may be disposed in a canister disposed in the substantially hollow first portion. Once the composition is ejected from the orifice exit towards the mouthpiece, the composition may define a spray pattern. The spray pattern may define a width, diameter, and/or area of the spray in a plane that is roughly perpendicular to the direction of the mouthpiece exit. The plane may be at least 2.5 mm and less than or equal to 3 mm at a distance of 10 mm from the second distal end. The spray pattern may be defined at a single or multiple distances from the mouthpiece exit.

[0008] Using low-GWP propellants with existing MDIs may result in spray plumes with spray patterns that differ from the spray patterns from MDIs using current propellants. Different spray patterns can result in different drug delivery profiles. Modifying spray patterns for medication deposition may result in better or more effective treatment to the subject. Furthermore, it may be desirable to develop MDIs with low- GWP propellants that match the plume properties of existing MDIs that use higher GWP propellants (e.g., HFA-227, HFA-134a, etc.).

[0009] The above summary is not intended to describe each embodiment or every implementation. Rather, a more complete understanding of illustrative embodiments will become apparent and appreciated by reference to the following Detailed Description and claims in view of the accompanying figures of the drawing. Brief Description of the Drawings

[0010] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0011] Figure 1 is a schematic side view of an example metered dose inhaler device placed in a subject’s mouth.

[0012] Figure 2 is a schematic section side view of an example nozzle block consistent with various embodiments.

[0013] Figure 3 is an enlarged schematic section view of Figure 2.

[0014] Figure 4A illustrates example spray targeting angles and orifice half cone angles for placebo formulations with various propellants.

[0015] Figure 4B illustrates example mouthpiece droplet size for placebo formulations with various propellants.

[0016] Figure 5A illustrates mean spray width of spray pattern after the spray exits the mouthpiece for placebo and drug suspension formulations using various propellants.

[0017] Figure 5B illustrates the area in which mean spray width of Figure 5 A was measured.

[0018] Figure 5C illustrates a raw image of an MDI spray.

[0019] Figure 6 illustrates shot-to-shot repeatability of the spray pattern based on various propellants.

[0020] Figure 7A illustrates percentage change in average light extinction for various propellants.

[0021] Figure 7B illustrates percentage change in temporal stability of the spray with addition of suspended particles for various propellants.

[0022] Figure 8A illustrates a bespoke testing apparatus.

[0023] Figure 8B illustrates spray width for various propellants as measured using the apparatus of Figure 8A. [0024] Figure 9 illustrates percentage increase in spray width as a function of percentage increase in jet length for various propellants, as measured using the apparatus of Figure 8A.

[0025] Figure 10 illustrates a summary of linear regression results from Figure 9.

[0026] Figure 11 A illustrates spray profdes for one propellant at various jet lengths.

[0027] Figure 1 IB illustrates probability density functions for a spray center of mass for each of the spray profiles of Figure 11A.

[0028] Figure 12A illustrates spray pattern area for various propellants at a distance of 3 cm from a distal end of a mouthpiece.

[0029] Figure 12B illustrates spray pattern area for the propellants of Figure 12A at a distance of 6 cm from the distal end of the mouthpiece.

[0030] Figure 13 A illustrates spray pattern area for various propellants at a distance of 3 cm from a distal end of a mouthpiece.

[0031] Figure 13B illustrates spray pattern area for the propellants of Figure 12A at a distance of 6 cm from the distal end of the mouthpiece.

[0032] Figure 14 illustrates a method of manufacturing an MDI as described herein.

[0033] The present technology may be more completely understood and appreciated in consideration of the following detailed description of various embodiments in connection with the accompanying drawings.

[0034] The figures are rendered primarily for clarity and, as a result, are not necessarily drawn to scale. Schematic representations may not be drawn to scale.

Moreover, various structure/components, including but not limited to housings, canisters, and the like, may be shown schematically or removed from some or all of the views to better illustrate aspects of the depicted embodiments, or where inclusion of such structure/components is not necessary to an understanding of the various exemplary embodiments described herein. The lack of illustration/description of such structure/components in a particular figure is, however, not to be interpreted as limiting the scope of the various embodiments in any way. Detailed Description

[0035] The present invention will be described with respect to particular 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 may for illustrative purposes be exaggerated and not drawn to scale.

[0036] It is noted that the terms “have,” “include,” “comprise,” and variations thereof, do not have a limiting meaning, and are used in their open-ended sense to generally mean “including, but not limited to,” where the terms appear in the accompanying description and claims. Further, “a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably herein. Moreover, it will be understood that the terms “vertical,” “horizontal,” “top,” “bottom,” “above,” “below,” “left,” “right,” etc. as used herein may refer to particular orientations of the figures and these terms are not limitations to the specific embodiments described herein.

[0037] All headings provided herein are for the convenience of the reader and should not be used to limit the meaning of any text that follows the heading, unless so specified. Moreover, unless otherwise indicated, all numbers expressing quantities, and all terms expressing directi on/orientati on (e.g., vertical, horizontal, parallel, perpendicular, etc.) in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0038] The term “and/or” (if used) means one or all of the listed elements or a combination of any two or more of the listed elements. The term “i.e ” is used as an abbreviation for the Latin phrase id est and means “that is.” The term “e.g.” is used as an abbreviation for the Latin phrase exempli gratia and means “for example.” The term “substantially” means equal or about equal (e.g., within 10%), and in terms of planes means exactly parallel/perpendicular or about parallel/perpendicular (e.g., within 5 degrees).

[0039] As illustrated in FIG. 1, MDI actuators generally include a canister-retaining or tubular first (housing) portion and a tubular second (mouthpiece) portion, the tubular second portion being angled with respect to an axis extending through the tubular first portion. At a closed bottom end of the tubular first portion sits a nozzle block (FIG. 2) that includes a sump and a spray orifice. At the bottom of the actuator on an external face, a thumb grip may be provided for a subject, or user, using the MDI. The tubular second portion may have a circular, elliptical, or oblong cross-section.

[0040] In normal operation of an MDI device (an MDI actuator housing and a canister of a composition including a medicament), a plume of medicament is produced from the orifice into the tubular mouthpiece portion and is inhaled by a subject through the tubular mouthpiece portion. However, as described above, there tends to be substantial and undesirable deposition of the medicament in the buccal cavity when the medicament is dispensed from a conventional device.

[0041] The term “spray axis” as used herein refers to an imaginary line or ray that originates from a center of the orifice and extends to or through the end face of the mouthpiece. In some embodiments described herein, the spray axis extends to or through a center of the end face of the mouthpiece. A spray can be directed as a plume aligned along the spray axis.

[0042] Experiments were conducted to show that use of low-GWP propellants changes the plume shape and spray pattern, as compared to other currently used hydrofluorocarbon (“HFC”) or hydrofluoroalkane (“HF A”) propellants (e.g., HFA-134a, HFA-227). Spray pattern can be used to provide comparison between two MDI products (a Reference product and a Test product) as described elsewhere (e.g., FDA Draft Guidance (Recommended June 2015): Guidance for Industry (Draft), Budesonide; Formoterol Fumarate Dihydrate, Inhalation Metered Aerosol.). Spray pattern testing is often performed at two different distances from the actuator orifice. The selected distances may be at least 3 cm apart and based on the range of 3 cm to 7 cm from the actuator mouthpiece (when comparing a Test product to a Reference product, the distance for the measurements of the Test product may need to be adjusted if the distance from the orifice exit to the end of the actuator mouthpiece differs for the two products).

[0043] Two general approaches are used for determining, or measuring, spray pattern. Impaction-based techniques measure spray pattern by actuating an MDI and directing the spray towards a surface (e.g. a thin-layer chromatography plate), assigning the boundary of the spray visually, identifying a central point of the pattern, and determining a minimum (Dmin) and a maximum (Dmax) dimension of the spray pattern passing through the central point (Baxter et al., Spray Pattern and Plume Geometry Testing and Methodology: An IPAC-RS Working Group Overview, AAPS PharmSciTech vol. 23, article 145, published online 18 May 2022). The outputs from spray pattern measurements using an impaction-based method are typically Dmin, Dmax and an ovality ratio (which is the ratio of Dmax divided by Dmin).

[0044] The second general approach includes laser-based spray pattern measurements. Laser-based measurements utilize a laser sheet positioned to intersect the spray through its cross section, perpendicular to its nominal flow. A camera is positioned such that it can capture an image sequence of the spray passing through the laser sheet that is acquired by a computer. Laser-based measurements often characterize the spray pattern in terms of an area and ovality ratio, and optionally, Dmin and Dmax. Instruments used for laser-based spray pattern measurements include, for example, the Spray VIEW® (Proveris Scientific, Hudson, MA) and Envision Pharma R&D System (Oxford Lasers, Oxford, UK).

[0045] Using either of the above approaches to measure spray pattern, potential differences in spray pattern between two identical (or similar) MDI devices delivering the same medicament with different propellants may be analyzed. For example, low-GWP propellants may be compared with currently used higher GWP HFC propellants (e.g., HFA-134a, HFA-227). Then, MDIs using low-GWP propellants may be optimized to modulate the spray pattern to match the spray pattern of an identical (or similar) MDI using higher GWP HFC propellant(s). [0046] The spray pattern of one MDI can be considered to “match” the spray pattern of another MDI if a comparison utilizing the population bioequivalence (“PBE”) statistical analysis demonstrates the products to be bioequivalent at one or more distances for at least one of the area and ovality (if a laser-based spray pattern measurement technique is used) or for at least one of the Dmax and ovality (if an impaction-based spray pattern measurement technique is used). Alternately, the spray pattern of one MDI can be considered to match that of another MDI if the geometric mean of the one product (Test) divided by the geometric mean of the other product (Reference) is between 0.90 and 1.11 at one or more distances between 3 cm and 7 cm for at least one of the area and ovality (if a laser-based spray pattern measurement technique is used) or for at least one of the Dmax and ovality (if an impaction-based spray pattern measurement technique is used). Alternately, the spray pattern of one MDI can be considered to match that of another MDI if the geometric mean of the one product (Test) divided by the geometric mean of the other product (Reference) is between 0.85 and 1.18 at one or more distances between 3 cm and 7 cm for at least one of the area and ovality (if a laser-based spray pattern measurement technique is used) or for at least one of the Dmax and ovality (if an impaction-based spray pattern measurement technique is used).

[0047] An MDI is considered to be “similar” (e.g., identical or similar) to that of another MDI (e.g., where the similar MDIs are using different propellants) if the first MDI contains the same medicament as the second MDI, and the target delivered dose of each medicament is within 10 % of one another based on the product labelling. The “delivered dose” represents the mass of medicament(s) that is delivered out of the mouthpiece when the MDI is actuated and is often measured at a flow rate of 28.3 or 30 liters per minute (1pm).

[0048] As mentioned above, experiments using both the laser-based spray pattern measurement technique and the impaction-based spray pattern measurement technique were conducted using a conventional MDI actuator housing to demonstrate that spray pattern using low-GWP propellants are different than spray patterns using common HFC propellants. Next, experiments using both techniques were conducted to optimize an MDI to match the spray pattern using low-GWP propellants to the spray pattern of a conventional MDI using common HFC propellants. The MDI optimized for low-GWP propellants included an orifice with a jet length of at least 0.8 mm and less than or equal to 2 mm. The conventional MDI using common HFC propellants, by contrast, included an orifice with a jet length of less than or equal to 0.8 mm.

[0049] Figure 1 illustrates a schematic side view of a conventional MDI actuator housing 10 that includes a substantially hollow tubular first portion 15 having a first axis 20 that extends therethrough and a substantially hollow tubular second portion 25 placed in a subject’s mouth. The substantially hollow tubular first portion 15 has an open or distal end 15c and a closed or proximal end 15b, the closed or proximal end being located at a bottom or lower end of the substantially hollow tubular first portion 15 and forming a base portion as shown in the Figure. On an external surface of the closed or proximal end 15b of the substantially hollow tubular first portion 15, a thumb grip 50 may be provided in the base portion that is substantially perpendicular to the first axis 20. In one or more embodiments, the substantially hollow tubular first portion 15 may include ribs positioned on an interior surface of the substantially hollow tubular first portion. The ribs may advantageously assist in aligning a canister 40 within the substantially hollow tubular first portion 15. The ribs may be substantially parallel to the first axis 20. The ribs may be substantially parallel to a second axis 55 (described further herein). In one or more embodiments, the actuator housing 10 may include a dose counter located within the substantially hollow tubular first portion 15. A dose counter may advantageously provide the correct total number of prescribed doses.

[0050] Within the closed or proximal end 15b sits a nozzle block 30 (illustrated in Figure 2). As illustrated in Figure 2, the nozzle block 30 includes an actuator seat (or “stem socket”) 35 that defines the positioning of a canister valve stem 21 after it is inserted into the nozzle block. The actuator seat 35 is in fluid communication with a sump region 60 and an orifice (or “actuator nozzle”) 45.

[0051] Returning to Figure 1, the substantially hollow tubular second portion 25 (i.e., tubular mouthpiece portion) includes a proximal end 25b which adjoins the closed or proximal end 15b of the substantially hollow tubular first portion 15, and is connected to the base portion. The substantially hollow tubular second portion 25 may define a mouthpiece configured to be placed within a mouth of a user. The substantially hollow tubular second portion 25 may be located adjacent to the substantially hollow tubular first portion 15. The substantially hollow tubular second portion 25 also has an open or distal end 25c that includes a mouthpiece end face 70, and the tubular second portion 25 extends away from its proximal end 25b in a direction towards its distal end 25c and is substantially aligned with the second axis 55 that extends from a center of the orifice (not shown) to a center of a mouthpiece end face. In this embodiment, the spray is directed from the orifice 45 in the direction of the second axis 55 as indicated by the arrow 11. In one or more embodiments, the spray may be directed from the orifice 45 towards the distal end 25c in a direction that is not along the second axis 55 (e.g., the spray may be directed at an angle relative to the second axis 55). The mouthpiece end face 70 defines a mouthpiece face plane, which may be substantially parallel with the first axis 20 and substantially perpendicular to a plane in which second axis 55 lies. In one embodiment, the mouthpiece face plane is also substantially perpendicular to a plane in which the base portion lies. In alternative embodiments, an obtuse angle (e.g., 105 degrees) may be formed between the first axis 20 and the second axis 55 facing towards the subject (Figure 1), and the mouthpiece face plane may not be substantially parallel with the first axis 20, nor substantially perpendicular to the plane in which the axis of the mouthpiece portion 25 lies.

[0052] The canister 40 may extend beyond the open or distal end 15c of the substantially hollow tubular first portion 15. Downward pressure on the upper end of the canister 40 activates a valve to release a predetermined amount of a medicament to generate a spray that is directed through the substantially hollow tubular second portion 25 in the direction of the second axis 55.

[0053] Returning to Figure 2, a section side view of the nozzle block 30 consistent with various embodiments is illustrated. A schematic of the canister 40 containing a medicament may be disposed, mounted, or inserted, within the actuator housing 10 so that a canister valve stem 21 is located within the nozzle block 30, and in particular, within the actuator seat 35. As described above, an upper end of the canister 40 extends beyond the open or distal end 15c of the substantially hollow tubular first portion 15 (Figure 1). Downward pressure on the upper end of the canister 40 activates a valve associated with the canister valve stem 21 to release a predetermined amount of medicament into the sump region 60 and through the orifice 45 to generate a spray that is directed through the tubular second portion 25 in the direction along the second axis 55. The schematic canister 40 may not be drawn to scale.

[0054] It will be appreciated that the resulting spray of medicament will be in the form of a plume. Consequently, an angle of the orifice 45 formed with the second axis 55 may be selected to project the plume such that it isn’t directed toward a roof section 26 or a floor section 27 (Figure 1) of the substantially hollow tubular second portion 25.

[0055] Figure 3 is an enlarged section view of the nozzle block 30 of Figure 2. The orifice 45 defines a jet length 46 and an orifice diameter 47. The orifice 45 includes an orifice entrance 48 and an orifice exit 49. As described above, the jet length 46 and orifice diameter 47 may be optimized for use with low-GWP propellants (e.g., to match the spray pattern using low-GWP propellants to the spray pattern using current higher GWP HFC propellants like HFA-134a and HFA-227).

[0056] As described above, low-GWP propellants have different physicochemical properties to higher-GWP HFC propellants. One of the many factors influenced by propellant choice is spray pattern and plume geometry. Changes in the targeting angle and spreading rate of the spray can influence mouthpiece and throat deposition as well as aerosol properties. Solution compositions vary in respect to their stability and shot-to- shot repeatability depending on the propellant(s) and cosolvent(s) included in the formulation. Suspension compositions similarly exhibit variable properties depending on which propellant(s) and cosolvent(s) are included. The presence of suspended particles varies spray pattern significantly with low-GWP propellants when compared to a control (higher GWP HFC propellants) in matched MDI hardware.

[0057] However, propellants are each very different, even among low-GWP propellants. For example, the propellant HFO-1234ze(E) is very different from the 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 MDI product performance difficult to achieve. For example, the thermodynamic differences in propellant boiling point and vapor pressure can significantly affect MDI aerosolization efficiency and give rise to differences in primary and secondary atomization mechanisms. Differences in dipole moment and polarity between the propellants can affect the solubility of drugs and excipients in the composition. Differences in hygroscopicity between the propellants can affect moisture uptake, which could be problematic for solution 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 drug 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, it was not possible to simply directly substitute one propellant in an MDI for another (e.g., chlorofluorocarbons and hydrofluorocarbons). Changing between propellant HFA-152a to HFO-1234ze(E) in an MDI is equally challenging due to many of the factors highlighted above.

[0058] Figure 4A illustrates example spray targeting angles and orifice half cone angles based on propellant. Figure 4B illustrates example mouthpiece droplet size statistics based on propellant. For Figures 4A and 4B, a fixed Kindeva (Woodbury, MN) actuator with 0.4 mm orifice exit diameter was used. Part of the mouthpiece was removed to enable optical access to the orifice exit. Kindeva aluminum canisters with Bespak 50 microliter (“uL”) valves were weighed with 2 milligram per milliliter (“mg/mL”) (±0.25%) salbutamol sulfate (“SS”) medicament. The canisters were pressure filled with one of the following propellants: 1 ,1 ,1 ,2-tetrafluoroethane (“HFA-134a”), an HFC propellant, 1,1 -difluoroethane (“HFA-152a”), a low-GWP HFC propellant, or trans- 1,1,1,3-tetrafluoropropene (“HFO-1234ze(E)”), a low-GWP hydrofluoroolefin (“HFO”) propellant.

[0059] The unit was shaken using a custom pneumatic actuator prior to each shot being fired to ensure substantially homogenous composition. A high-speed imaging system (Photron SA-Z) and custom LED light (Luminus Devices, USA) were used to capture images of the spray at up to 140 kilohertz (“kHz”) at a fixed magnification of 31 micrometers per pixel (“um/pixel”). N=16 replicates were collected per composition at n=15000 images per spray. A Malvern SprayTec laser diffraction droplet sizer was used to measure initial aerosol size, with the beam placed immediately at the mouthpiece exit. A fixed flow of 28 Standard Liters Per Minute (“SLPM”) at 50% humidity was used in all tests.

[0060] The effect of propellant on (Figure 4A) spray targeting angle and orifice exit half cone angle, and (Figure 4B) mouthpiece exit droplet size statistics for all propellants are illustrated. Error bars indicate 95% confidence intervals. Addition of 2 mg/mL SS suspension generates a statistically significant change in targeting angle, with low-GWP propellants HFA-152a and HFO-1234ze(E) being less affected than HFC propellant HFA-134a. The underlying reasons for the differences in the effect of suspensions on low-GWP propellants can be better understood through analysis of the high-speed imaging (results in Figures 5A and 5B).

[0061] Figure 5A illustrates mean spray width of spray pattern after the spray exits the mouthpiece for various propellants within the region indicated by the larger box in Figure 5B. Figure 5C illustrates a raw image of a spray pattern. Figure 5 A shows the effect of propellant on spray width. The addition of a suspended drug in the propellant (e g., SS) reduces plume width for low-GWP propellants while increasing the width of the HFC HFA-134a propellant.

[0062] Figure 6 illustrates shot-to-shot repeatability of the spray pattern based on various propellants. Figure 6 shows how the shot-to-shot repeatability of the plume varies between propellant only placebos (top row) and propellants containing suspended particles (bottom row). HFC propellant HFA-134a shows a significant increase in shot- to-shot variability (bottom left) with low-GWP propellants less affected. In one or more embodiments, the shot-to-shot variability of HFA-134a may be defined as less than or equal to 5% variability in spray pattern (e.g., Dmin, Dmax) over 50 shots, 100 shots, 200 shots, 300 shots, etc. Differences in average light extinction and temporal standard deviation (stability) are more subtle; these are represented in Figures 7A and 7B.

[0063] Figure 7A illustrates percentage change in average light extinction for various propellants. Figure 7B illustrates percentage change in temporal stability of the spray with addition of suspended particles for various propellants. The difference between the suspension and the propellant-only placebo statistics have been calculated, accounting for change in targeting angle and virtual origin to align the plumes. The low- GWP propellant plumes behave similarly, while HFC propellant HF A- 134a again shows a significant increase in light extinction when the particles in suspension are added.

[0064] The addition of suspended particles to MDI compositions creates additional nucleation sites for vapor bubbles to form, enhancing the rate of flash-evaporation both inside and outside the actuator orifice but also driving increased shot-to-shot variability. Unlike solution compositions, where the Atmospheric Pressure Ionization (“API”) plays little role in spray physics due to the dominance of the cosolvent, suspensions can drive significant shifts in spray morphology, which can alter spreading rate and aerosol size. These shifts are markedly reduced for low-GWP propellants HFA-152a and HFO- 1234ze(E). This may be explained by changes in Jakob number, the ratio of sensible to latent heat. The Jakob number is 23% and 12% lower for low-GWP propellants HFA- 152a and HFO-1234ze(E) respectively relative to HFC propellant HFA-134a. Both low- GWP propellants flash-evaporate less aggressively than HFC propellant HFA-134a due to their lower Jakob value. The influence of suspended particles on nucleation processes that enhance pre-existing flashing behavior is reduced. These effects need to be accounted for in actuator orifice and mouthpiece design for low-GWP MDI products, especially in respect of mouthpiece and throat drug deposition, even if aerodynamic particle size distributions at respirable scales are comparable.

[0065] As discussed herein, spray structure and development may influence the performance of pressurized MDIs. Spray atomization can play a pivotal role in determining droplet size and distribution. The spray pattern affects droplet deposition, potentially altering the delivered dosage. Orifice configuration, which determines the initial conditions for the spray, can be an important design parameter in determining MDI spray development. With the transition from high-GWP HFC propellants to low-GWP propellants such as HFA-152a and HFO-1234ze(E), manipulation of the MDI orifice provides an alternative route to in-vitro bioequivalence with respect to factors such as plume pattern, geometry, and velocity. The influence of jet length-to-diameter ratio may be a controlling parameter for MDI sprays pattern across current and novel propellants.

[0066] Figure 8A illustrates a bespoke testing apparatus used to acquire the data illustrated in Figures 8B, 9, 10, 11A, and 1 IB. This testing apparatus utilized a modular pMDI actuator (Figure 8A(b)) to vary the jet length while holding all other actuator and composition parameters constant. The actuator included a Polyether ether ketone (“PEEK”) plastic body and side panels (Figure 8A(c)), which replicate the thermal and geometric characteristics of a conventional Kindeva actuator. A removable orifice plate manufactured from polycarbonate (3Dxtech, USA) via a micro-injection molding machine (Babyplast 6/1 OP, Spain) featured a custom nozzle orifice exit crafted using a Roland Micro-CNC machine with specialized drill bits. The orifice design was consistent across five nozzle orifices, maintaining a 0.3 mm orifice exit diameter (single hole), a 60 degree exit cone with a depth of 1.3 mm, and a flat 1.0 mm exit surface. Jet lengths ranged from 0.4 to 1.2 mm in intervals of 0.2 mm. Aerosols including Kindeva aluminum canisters crimped with 50 microliter Bespak valves were pressure filled with placebo compositions of HFC propellants HFA-134a or HFA-227, or with low-GWP propellants HFA-152a or HFO-1234ze(E), using a Pamasol (Laboratory Plant 2016/100). Pneumatic aerosol actuation was synchronized with a high-speed imaging system. Figure 8A(a) illustrates the simplified setup of the optical system. A high-speed camera (Photron SA- Z) and custom LED system (Luminus Devices, USA) were used to capture back- illuminated images of the transient spray development at a framerate of 50 kHz, an exposure time of 350 nanoseconds (“ns”), and a spatial resolution of 31 micrometers/pixel. The data were conditioned to extract quasi-steady-state statistics for spray width and light extinction. [0067] Figure 8B illustrates spray patterns for various propellants as measured using the apparatus of Figure 8A. Spray width of the spray pattern was found to increase with shorter jet lengths. This may be attributed to the role of jet length on the thermodynamic state of the composition as it exits the orifice. Longer jet lengths permit greater in-nozzle vaporization, expansion, lower two-phase mixture densities (due to low liquid volume fraction) and higher velocities for the same vapor pressure. A shorter jet length facilitates a larger volume fraction of liquid propellant at the orifice exit, inducing more aggressive flash evaporation after the orifice exit, which consequently drives broader droplet dispersion as the vaporization is unbounded.

[0068] As shown in FIG. 8B, the line for HFC propellant HFA-227at a jet length of 0.8 mm is similar to the line for low-GWP propellant HFA-152a at a jet length of 1.2 mm. This is surprising, at least because the densities of the propellant vapor (e.g. at ambient conditions) for the two propellants are very different. For example, the liquid density of HFA-152a (at 20 degrees Celsius and 1 atmospheric pressure) is about 0.91 grams per milliliter (“g/ml”). The liquid density of HFA-227 (at 20 degrees Celsius and 1 atmospheric pressure) is about 1.41 g/ml. The liquid density of HFO-1234ze(E) (at 20 degrees Celsius and 1 atmospheric pressure) is about 1.29 g/ml. The liquid density of HFA-134a (at 20 degrees Celsius and 1 atmospheric pressure) is about 1.23 g/ml.

[0069] To further explore the potential of jet length as a controlling parameter for spray performance, an empirical model was developed to predict the percentage change in spray width (“W”) relative to the reference case (“Wref,” the 0.8 mm jet length), as a function of the corresponding change in jet length (“L”) relative to the reference case (“Lref’). The results are summarized in Figures 9 and 10. Figure 9 illustrates percentage increase in spray width as a function of percentage increase in jet length for various propellants, as measured using the apparatus of Figure 8A. Figure 10 illustrates a summary of linear regression results from Figure 9.

[0070] This model focused on the averaged spray width within the analysis region (Figure 9 right panel), specifically corresponding to the spray section at the mouthpiece exit. A strong linear correlation was established for all propellants over a wide range of lengths (Figure 10). Interestingly, the relative change in plume width is independent of propellant choice. This underscores the efficacy of spray pattern manipulation via jet length adjustment.

[0071] Jet length variation also influences plume targeting and stability. Figure 11 A illustrates spray profiles for one propellant at various jet lengths. Figure 1 IB illustrates probability density functions for a spray center of mass for each of the spray profiles of Figure 11A.

[0072] More specifically, Figure 11A shows example spray extinction contours at a 15% extinction threshold for HFC propellant HFA-134a with jet lengths of 0.6, 0.8, and 1 mm. Reduced jet length leads to increased targeting angles. Figure 1 IB shows how this shifts the spray’s optical center of mass (“CoM”), which is defined as the geometric center of the plume in the images and can be used to assess targeting and stability. CoM changes with jet length are hypothesized to be due to nonuniform flow in the expansion chamber; longer orifices straighten the flow, have less variation in CoM, and thus have less targeting variation.

[0073] This analysis demonstrates how plume width and targeting of MDI sprays can be altered by manipulating jet length 46. The linear control observed over spray width remains unaffected by propellant choice, promising significant advantages in the design of low-GWP propellant actuators. Altering jet length 46 also impacts spray stability and targeting, so a holistic assessment of device performance including assessment of pharmaceutical performance is paramount. In one or more embodiments, modulating the spray pattern to become relatively smaller includes adjusting the jet length 46 to become relatively longer.

[0074] Additionally, a standard impaction-based technique may be used to compare an MDI using HFA-152a with a reference MDI using HFA-227 (see Baxter et al., Spray Pattern and Plume Geometry Testing and Methodology: An IPAC-RS Working Group Overview, AAPS PharmSciTech vol. 23, article 145, published online 18 May 2022). Multiple test MDI devices using formulations including budesonide, formoterol fumarate dihydrate and HFA-152a was compared to a similar (i.e., “reference”) MDI device using HFA-227. The reference MDI device included budesonide, formoterol fumarate didhyrate, 0.3 % poly(ethylene) glycol (“PEG”) and 0.001 % polyvinylpyrrolidone (“ PVP”) K25 in HFA-227, and used 50 microliter valves an actuator with an orifice exit diameter of 0.38 mm and the jet length of 0.75 mm.

[0075] A device using HFA-152a with a 0.30 mm orifice exit diameter and a 0.65 mm jet length was evaluated to match the performance of the HFA-227 reference described above, but using HFA-152a as the propellant. The HFA-152a configurations with 0.30 mm orifice exit diameter resulted in a good aerodynamic particle size distribution (APSD) match with reference MDls with an HFA-227 propellant. Thus, the match between HFA-227 with 0.38 mm orifice exit diameter and HFA-152a with a 0.30 mm orifice exit diameter may advantageously provide a matched APSD. Filled canisters from the HFA-227 reference device were paired with actuators having a 0.30 mm orifice exit diameter and a 0.65 mm jet length and were tested to provide for completeness of analysis. This configuration had a spray pattern area that was less than the HFA-152a configuration tested with a 0.30 mm orifice exit diameter and a 0.65 mm jet length.

[0076] The test device actuator was modified to include various jet lengths and orifice diameters, as illustrated in Figures 12A and 12B. Figure 12A illustrates the measured spray pattern areas at a distance of 3 cm from the distal end 25c. Figure 12B illustrates the measured spray patterns areas at a distance of 6 cm from the distal end 25c.

[0077] As illustrated in Figure 12A, at a distance of 3 cm from the distal end 25c, the test devices that used HFA-152a as the propellant and actuators with jet lengths of at least 0.8 mm more closely matched the spray pattern from the HFA-227 MDI configuration consisting of filled canisters from the reference device that were paired with actuators with a 0.30 mm orifice diameter and a 0.65 mm jet length. As the test device jet length increased, the spray pattern area decreased for each HFA-152a configuration using the 0.30 mm orifice diameter. To match the reference device (which use HFA-227 as propellant and actuators with a 0.38mm orifice diameter and 0.75 jet length) with a test device using HFA-152a, a 1.5 mm jet length may be advantageous in some embodiments (the match of geometric means may be between 0.90 and 1.11, as described further herein, and the ASPD may match as well).

[0078] As illustrated in Figure 12B, at a distance of 6 cm from the distal end 25c, the test device using HFA-152a and a jet length of 0.80 mm with an orifice exit diameter of 0.30 matched with the reference device using HFA-227 (with 0.38 mm orifice exit diameter). To more closely match a test device to the reference device at both 3 cm and 6 cm distances, a jet length between 0.8 mm and 1.5 mm may be advantageous.

[0079] In view of the above analyses, for an MDI as described herein with a jet length 46 of at least 0.8 mm and no greater than 2 mm and an orifice exit diameter of at least 0.2 mm and no greater than 0.5 mm, the composition in the canister 40 may include HFA-152a low-GWP propellant. The resultant spray pattern of the ejected composition from the orifice exit 49 may match that of a similar MDI using an HFA-227 propellant and a jet length of less than or equal to 0.8 mm.

[0080] In view of the above analyses, for an MDI as described herein with a jet length 46 of at least 0.6 mm and no greater than 2 mm and an orifice exit diameter of at least 0.2 mm and no greater than 0.5 mm, the composition in the canister 40 may include HFO-1234ze(E) low-GWP propellant. The resultant spray pattern of the ejected composition from the orifice exit 49 may match that of a similar MDI using an HFA- 134a propellant and a jet length of less than or equal to 0.8 mm.

[0081] Alternative embodiments to each of the above matched embodiments may include a jet length 46 of at least 1 mm, 1.1mm, 1.2 mm, 1.5 mm, etc., up to and including 2 mm.

[0082] In another embodiment, a test device using HFO-1234ze(E) was compared to reference device using HFA-227. The test device used a 63 microliters (“uL”) valve, and the reference devices used a 50 uL valve. The spray pattern area was measured at a distance of 3 cm from the distal end 25c, and the results are illustrated in Figure 13 A. The spray pattern was also measured at a distance of 6 cm from the distal end 25c, and the results are illustrated in Figure 13B. In both figures it may be noted that various jet lengths (“JL”) and orifice diameters (“OD”) were tested for the HFO-1234ze(E) test device. The test devices with jet lengths of at least 0.8 mm more closely matched the HFA-227 reference device.

[0083] As described herein, the spray pattern of one MDI can be considered to “match” the spray pattern of another MDI if a comparison utilizing the population bioequivalence (“PBE”) statistical analysis demonstrates the products to be bioequivalent at one or both distances for at least one of the area and ovality (if a laser-based spray pattern measurement technique is used) or for at least one of the Dmax, spray pattern area, and ovality (if an impaction-based spray pattern measurement technique is used). As illustrated in Figures 12A-13B, the area provided bioequivalence at both 3 cm and 6 cm from the distal end 25c for two different embodiments (HFA-152a matched with HFA- 227, and HFO-1234ze(E) matched with HFA-227, respectively). Alternately, the spray pattern of one MDI can be considered to match that of another MDI if the geometric mean of one product (Test) divided by the geometric mean of the other product (Reference) is between 0.90 and 1.11 at one or more distances for at least one of the area and ovality (if a laser-based spray pattern measurement technique is used) or for at least one of the Dmax and ovality (if an impaction-based spray pattern measurement technique is used). For example, to match the spray pattern of reference device using HFA-227 with a test device using HFA-152a as illustrated in Figure 12A, a 1.5 mm jet length may be advantageous because the geometric means divided as described may result in between 0.90 and 1.11 at 3 cm from the distal end 25c. Further, for example, to match the spray pattern of reference device using HFA-227 with a test device using HFA-152a as illustrated in Figure 12B, a 0.8 mm jet length may be advantageous because the geometric means divided as described may result in between 0.90 and 1.11 at 6 cm from the distal end 25c.

[0084] Matching the spray pattern may be further alternatively or additionally defined as: a spray pattern Dmin that is less than or equal to a 5% deviation of the Dmin of the similar metered dose inhaler device, and a Dmax that is less than or equal to a 5% deviation of the Dmax of the similar metered dose inhaler device.

[0085] Additionally, the jet length of the MDIs using the low-GWP propellants as described in each of the above matched embodiments may be at least 1.25 times the jet length of the similar MDI using the currently used higher-GWP HFC propellants. In alternative embodiments, the jet length of the MDIs using the low-GWP propellants as described in each of the above matched embodiments may be at least 1.2 times, 1.3 times, 1.4 times, 1.5 times, 2 times, 3 times, etc., the jet length of the similar MDI using the HFC propellants. Such relative jet lengths may advantageously provide an optimized spray pattern match.

[0086] Additionally, the orifice diameter 47 at the orifice exit 49 of the MDIs using the low-GWP propellants as described in each of the above matched embodiments may be no more than 0.90 times the orifice diameter 47 at the orifice exit 49 of the similar MDI using the higher-GWP HFC propellants. In alternative embodiments, the orifice diameter 47 at the orifice exit 49 of the MDIs using the low-GWP propellants as described in each of the above matched embodiments may be no more than 0.85, 0.80, 0.75, 0.60, 0.50, 0.40, 0.30, 0.20, 0.10, etc., times the orifice diameter 47 at the orifice exit 49 of the similar MDI using the higher-GWP HFC propellants. Such relative orifice diameters 47 at the orifice exits 49 may advantageously provide an optimized aerodynamic particle size distribution (APSD) match while simultaneously providing an optimized spray pattern match.

[0087] As described above, the canister 40 may include a composition. In one or more embodiments, the composition may include a medicament, sometimes referred to as an active pharmaceutical agent (“API”). In one or more embodiments, the medicament includes at least one of a long-acting P-adrenoreceptor agonist (“LABA”), a short-acting -adrenoreceptor agonist (“SABA”), a long-acting muscarinic antagonist (“LAMA”), a short-acting muscarinic agonist (“SAMA”), a corticosteroid, or a combination thereof. The composition may be optimized in tandem with the MDI device hardware (e.g., jet length, orifice diameter at the orifice exit) to optimize the spray pattern for medicament deposition in the subject or user. The composition may be selected such that the spray pattern for medicament deposition is similar to an MDI product that uses HFA-227 or HFA-134a as propellant(s).

[0088] The SABA may include salbutamol (sometimes referred to as albuterol), levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

[0089] The LABA may include formoterol, salmeterol, indacaterol, vilanterol or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof. [0090] The corticosteroid may include budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

[0091] The SAMA or LAMA may include umeclidinium, aclidinium, glycopyrrolate, ipratropium, tiotropium, or an acceptable salt or solvate thereof.

Particular combinations of medicaments may be of interest. In one or more embodiments, the composition may include budesonide and formoterol fumarate. In one or more embodiments, the composition may include mometasone furoate. In one or more embodiments, the composition may include formoterol fumarate.

[0092] As is described herein, the type and amount of medicament included in a composition may alter the spray pattern of the composition. Accordingly, the amount of medicament included in a composition may be selected to achieve a therapeutic delivered dose which can impact the spray pattern. The amount of a medicament included in a composition may be expressed as a concentration of medicament in the composition (e.g., the concentration of medicament in the propellant and any excipients) by weight percentage, the weight of medicament in a given volume of the composition, or the amount of medicament delivered by a drug delivery device with set physical parameters.

[0093] In one or more embodiments, a composition includes at least 3.5 micrograms (“ug”)/actuation (“act”), 4.0 ug/act, 4.5 ug/act, at least 5.0 ug/act, at least 5.5 ug/act, at least 6.0 ug/act, at least 10 ug/act, at least 25 ug/act, at least 50 ug/act, at least 75 ug/act, at least 100 ug/act, at least 125 ug/act, at least 150 ug/act, at least 160 ug/act, or at least 175 ug/act of medicament. In one or more embodiments, the composition includes at most 200 ug/act, at most 150 ug/act, 100 ug/act, 75 ug/act, 50 ug/act, or 10 ug/act of medicament. Depending on the medicament used, a different amount may provide a desirable pharmaceutical dose. The composition may include from 3 ug/act to 10 ug/act of medicament. The composition may include 150 ug/act to 180 ug of medicament.

[0094] In one embodiment, the optimized MDI may deliver about 4.5 micrograms ( “ug”) of formoterol fumarate dihydrate (a medicament) and about 80 ug of budesonide (another medicament) per actuation. [0095] In another embodiment, the optimized MDI may deliver about 4.5 ug of formoterol fumarate dihydrate and about 160 ug of budesonide per actuation.

[0096] In another embodiment, the optimized MDI may deliver about 4.5 ug of formoterol fumarate dihydrate and about 320 ug of budesonide per actuation.

[0097] In another embodiment, the optimized MDI may deliver about 5 ug of formoterol fumarate dihydrate and about 50 ug of mometasone furoate (another medicament) per actuation.

[0098] In another embodiment, the optimized MDI may deliver about 5 ug of formoterol fumarate dihydrate and about 100 ug of mometasone furoate per actuation.

[0099] In another embodiment, the optimized MDI may deliver about 5 ug of formoterol fumarate dihydrate and about 200 ug of mometasone furoate per actuation.

[00100] In another embodiment, the optimized MDI may deliver about 50 ug of mometasone furoate per actuation.

[00101] In another embodiment, the optimized MDI may deliver about 100 ug of mometasone furoate per actuation.

[00102] In another embodiment, the optimized MDI may deliver about 200 ug of mometasone furoate per actuation.

[00103] In one or more embodiments, the composition may include one or more excipients. Excipients may advantageously serve as the vehicle for a medicament or other active substance. In one or more embodiments, the one or more excipients may include water, poly(ethylene) glycol (“PEG”), polyvinylpyrrolidone (“povidone,” “PVP”), or a combination thereof. PEG may advantageously enhance stability of the composition, enhance solubility of the medicament, or improve delivery to a subject, for example. Typically, no more than 1% by weight (based on the total weight of the composition) water or PEG would be used as an excipient in a composition of the present disclosure. Typically, at least 0.01% by weight (based on the total weight of the composition) water or PEG would be used as an excipient in a composition of the present disclosure. In one or more embodiments, a composition includes at least 0.03 %, at least 0.04 %, 0.05 %, at least 0.1 %, at least 0.15 %, at least 0.2 %, at least 0.25 %, or at least 0.3 % PEG by weight. In one or more embodiments, a composition includes at most 0.5 %, at most 0.45 %, at most 0.4 %, or at most 0.35 % PEG by weight. In one or more embodiments, the PEG may include PEG-1000, PEG-300, PEG-200, PEG-500, any PEG between PEG-100 and PEG-6000, etc. In one or more embodiments, a composition includes PEG-1000, PEG-300, or both PEG-1000 and PEG-300.

[00104] In one or more embodiments, the one or more excipients may include PVP. PVP may be included to enhance stability of the composition, enhance solubility of the medicament, or improve delivery to a subject, for example. The form of PVP included in a composition may be selected to provide a desirable particle size. For example, a composition may include PVP K25 or PVP K30. In one or more embodiments, a composition includes less than or equal to 0.01 %, 0.002 %, 0.001 %, 0.0005 %, etc. of PVP by weight. Further, for example, a composition may include oleic acid. In one or more embodiments a composition includes less than or equal to 0.10%, 0.05 %, 0.01 %, 0.005 %, 0.002 %, 0.001 %, etc. of oleic acid by weight.

[00105] In some embodiments, a cosolvent is included. One particularly useful cosolvent is ethanol. In some embodiments, ethanol is used as a cosolvent in solution compositions, i.e., where the medicament is dissolved in the composition. In one aspect, the ethanol may aid in dissolving the medicament whereas the medicament may not be soluble in the composition in the absence of ethanol. In some embodiments, ethanol is used as a cosolvent in suspension formulations, i.e., where the medicament is suspended in the composition. In one aspect, the ethanol may aid in minimizing deposition of suspended medicament on the canister and valve surfaces. In one or more embodiments, the composition may include greater than or equal to 0.5 % ethanol and less than or equal to 15 % ethanol. When used in solution compositions, ethanol may be in amounts on a weight percent basis of the total composition of at least 0.5 %, at least 1 %, at least 2 %, at least 5 %, at least 10 %, at least 15 %. When used in solution compositions, ethanol may be in amounts on a weight percent basis of the total composition of up to 20 % or up to 15 %. In certain embodiments, when used in solution compositions, ethanol may be in amounts on a weight percent basis of the total composition of between 0.5 % and 20 %, between 1 % and 20 %, between 2 % and 20 %, between 2 % and 15 %, between 5 % and 15 %, between 10 % and 15 %, or between 15 % and 20 %. In some embodiments, the ethanol content is greater than 1 7%, or at least 17.5 %, on a weight percent basis of the total composition.

[00106] Some compositions may include a propellant that is substantially or entirely pure, meaning that there is only one propellant in the composition. For example, the propellant may include a substantial percentage of HFA-152a. In one or more embodiments, the propellant include at least 70 % by weight HFA-152a. In one or more embodiments, the propellant includes at least 90 %, at least 95 %, at least 99%, or 100 % by weight HFA-152a. In one or more other embodiments, the propellant includes a substantial percentage of HFO-1234ze(E). In one or more embodiments, the propellant includes at least 70 % by weight HFO-1234ze(E). In one or more embodiments, the propellant includes HFA-152a and does not include an impactful amount of any other propellant. In one or more embodiments, the propellant includes at least 90 %, at least 95 %, at least 99 %, or 100 % by weight of HFO-1234ze(E). In one or more embodiments, the propellant includes HFO-1234ze(E) and does not include an impactful amount of any other propellant. In one or more embodiments using HFA-152a, HFO-1234ze(E), or a combination thereof, the spray pattern may define a width that is at least 2.5 mm and less than or equal to 3 mm, at a distance of 10 mm from the second distal end 25c of the actuator housing 10.

[00107] As illustrated in Figure 14, a method 100 of manufacturing an MDI as described herein may include: making a composition including a propellant having at least one of HFA-152a or HFO-1234ze(E), and further including at least one of: a LABA, a SABA, a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof. Making such a composition is illustrated at box 110. The method 100 may further include disposing the composition into the canister 40 for use with the actuator housing 10 as described herein. Disposing the composition into the canister 40 is illustrated at box 120. Disposing the composition into the canister 40 may be performed before or after crimping a valve onto the canister 40. Once the composition is disposed in the canister 40, the canister may be disposed into an actuator housing such as the actuator housings described herein. Exemplary Aspects

[00108] Aspect 1. A metered dose inhaler device comprising: an actuator housing comprising: a substantially hollow first portion comprising a nozzle block; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion defining a mouthpiece and located adjacent the substantially hollow first portion, such that the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice defines a jet length along an orifice axis, and wherein the spray orifice defines an orifice exit with an orifice exit diameter, wherein the jet length is at least 0.8 millimeters (“mm”); and a composition comprising a propellant including 1 ,1 -difluoroethane (“HFA-152a”), the composition located in a canister disposed in the substantially hollow first portion, wherein, once the composition is ejected from the orifice exit towards the mouthpiece, the composition defines a spray pattern, and wherein the spray pattern matches that of a similar metered dose inhaler device using a propellant comprising 1,1,1,2,3,3,3-heptafluoropropane (“HFA-227”) or 1, 1,1,2-tetrafluoroethane (“HFA-134a”) and a jet length less than or equal to 0.8 mm.

[00109] Aspect 2. The metered dose inhaler device of aspect 1, wherein matching the spray pattern and the spray pattern of the similar metered dose inhaler device using a propellant comprising HFA-227 or HFA-134a and a jet length less than or equal to 0.8 mm is defined as: a result of dividing a geometric mean of the spray pattern of the metered dose inhaler device by a similar geometric mean of the spray pattern of the similar metered dose inhaler device, wherein the result is between 0.90 and 1.11 at one or more distances between 3 cm and 7 cm from a distal end of the mouthpiece.

[00110] Aspect 3. The metered dose inhaler device of aspect 2, wherein the geometric mean of the spray pattern comprises one or more of: a maximum dimension (“Dmax”) of the spray pattern, an area of the spray pattern, and an ovality ratio (the ratio of Dmax divided by a minimum dimension of the spray pattern (“Dmin”)).

[00111] Aspect 4. The metered dose inhaler device of any of aspects 1-3, wherein a matched spray pattern is produced when the metered dose inhaler device and the similar metered dose inhaler contain a same medicament, and a target delivered dose of each medicament is the same based on a product labelling. [00112] Aspect 5. The metered dose inhaler device of any of aspects 1-4, wherein the jet length is less than or equal to 2 mm.

[00113] Aspect 6. The metered dose inhaler device of any of aspects 1-5, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm.

[00114] Aspect 7. The metered dose inhaler device of any of aspects 1-6, wherein the jet length is at least 1.25 times the jet length of the similar metered dose inhaler device.

[00115] Aspect 8. The metered dose inhaler device of any of aspects 1-7, wherein the orifice exit diameter is not more than 0.90 times the orifice exit diameter of the similar metered dose inhaler device.

[00116] Aspect 9. The metered dose inhaler device of any of aspects 1-8, wherein the jet length is greater than or equal to 1 mm.

[00117] Aspect 10. A method of modulating the spray pattern of the metered dose inhaler device of any of aspects 1-9, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

[00118] Aspect 11. The metered dose inhaler device of any of aspects 1-10, wherein the composition further comprises a medicament comprising at least one of a long-acting P-adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof.

[00119] Aspect 12. The metered dose inhaler device of aspect 11, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof, and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

[00120] Aspect 13. The metered dose inhaler device of aspect 11, wherein the composition comprises budesonide and formoterol fumarate. [00121] Aspect 14. The metered dose inhaler device of aspect 1 1, wherein the composition comprises mometasone furoate and formoterol fumarate.

[00122] Aspect 15. The metered dose inhaler device of any of aspects 13-14, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

[00123] Aspect 16. The metered dose inhaler device of any of aspects 1- 11, wherein the propellant comprises at least 70 % by weight HFA-152a.

[00124] Aspect 17. The metered dose inhaler device of any of aspects 1- 11, wherein the composition comprises one or more excipients.

[00125] Aspect 18. The metered dose inhaler device of any of aspects 1-11, wherein the composition comprises ethanol.

[00126] Aspect 19. The metered dose inhaler device of aspect 18, wherein the composition comprises greater than or equal to 0.5 % ethanol and less than or equal to 15 % ethanol.

[00127] Aspect 20. The metered dose inhaler device of aspect 17, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.

[00128] Aspect 21. A metered dose inhaler device comprising: an actuator housing comprising: a substantially hollow first portion comprising a nozzle block; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion defining a mouthpiece and located adjacent the substantially hollow first portion, such that the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice defines a jet length along an orifice axis, and wherein the spray orifice defines an orifice exit with an orifice exit diameter, wherein the jet length is at least 0.8 millimeters (“mm”); and a composition comprising a propellant including trans-l,l,l,3-tetrafluoropropene (“HFO-1234ze(E)”), the composition located in a canister disposed in the substantially hollow first portion, wherein, once the composition is ejected from the orifice exit towards the mouthpiece, the composition defines a spray pattern, and wherein the spray pattern matches that of a similar metered dose inhaler device using a propellant comprising 1,1, 1,2, 3, 3, 3- heptafluoropropane (“HFA-227”) or 1 ,1 ,1 ,2-tetrafluoroethane (“HFA-134a”) and a jet length less than or equal to 0.8 mm.

[00129] Aspect 22. The metered dose inhaler device of aspect 21, wherein matching the spray pattern of the metered dose inhaler device and the spray pattern of the similar metered dose inhaler device using a propellant comprising HFA-227 or HFA-134a and a jet length less than or equal to 0.8 mm is defined as: a result of dividing a geometric mean of the spray pattern of the metered dose inhaler device by a similar geometric mean of the spray pattern of the similar metered dose inhaler device, wherein the result is between 0.90 and 1.11 at one or more distances between 3 cm and 7 cm from a distal end of the mouthpiece.

[00130] Aspect 23. The metered dose inhaler device of aspect 22, wherein the geometric mean of the spray pattern comprises one or more of: a maximum dimension (“Dmax”) of the spray pattern, an area of the spray pattern, and an ovality ratio (the ratio of Dmax divided by a minimum dimension of the spray pattern (“Dmin”)).

[00131] Aspect 24. The metered dose inhaler device of any of aspects 21-23, wherein a matched spray pattern is produced when the metered dose inhaler device and the similar metered dose inhaler contain a same medicament, and a target delivered dose of each medicament is the same based on a product labelling.

[00132] Aspect 25. The metered dose inhaler device of any of aspects 21-24, wherein the jet length is less than or equal to 2 mm.

[00133] Aspect 26. The metered dose inhaler device of any of aspects 21-25, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm.

[00134] Aspect 27. The metered dose inhaler device of any of aspects 21-26, wherein the jet length is at least 1.25 times the jet length of the similar metered dose inhaler device.

[00135] Aspect 28. The metered dose inhaler device of any of aspects 21-27, wherein the orifice exit diameter is not more than 0.90 times the orifice exit diameter of the similar metered dose inhaler device. [00136] Aspect 29. The metered dose inhaler device of any of aspects 21 -28, wherein the jet length is greater than or equal to 1 mm.

[00137] Aspect 30. A method of modulating the spray pattern of the metered dose inhaler device of any of aspects 21-29, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

[00138] Aspect 31. The metered dose inhaler device of any of aspects 21-30, wherein the composition further comprises at least one of a long-acting [3-adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long- acting muscarinic antagonist (“LAMA”), or a combination thereof.

[00139] Aspect 32. The metered dose inhaler device of aspect 31, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

[00140] Aspect 33. The metered dose inhaler device of aspect 31, wherein the composition comprises budesonide and formoterol fumarate.

[00141] Aspect 34. The metered dose inhaler device of aspect 31, wherein the composition comprises mometasone furoate and formoterol fumarate.

[00142] Aspect 35. The metered dose inhaler device of any of aspects 33-34, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

[00143] Aspect 36. The metered dose inhaler device of any of aspects 20- 31, wherein the propellant comprises at least 70 % by weight HFO-1234ze(E).

[00144] Aspect 37. The metered dose inhaler device of any of aspects 20- 31, wherein the composition comprises one or more excipients.

[00145] Aspect 38. The metered dose inhaler device of any of aspects 20- 31, wherein the composition comprises ethanol. [00146] Aspect 39. The metered dose inhaler device of aspect 38, wherein the composition comprises greater than or equal to 0.5 % ethanol and less than or equal to 15 % ethanol.

[00147] Aspect 40. The metered dose inhaler device of aspect 37, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.

[00148] Aspect 41. A method of manufacturing a metered dose inhaler comprising: making a composition comprising a propellant including at least one of 1,1- difluoroethane (“HFA-152a”) or trans- 1,1, 1,3 -tetrafluoropropene (“HFO-1234ze(E)”), and further comprising at least one of a long-acting P-adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof, and disposing the composition into a canister for use with an actuator housing comprising: a substantially hollow first portion having a first proximal end and a first distal end, wherein the canister is disposed in the substantially hollow first portion; a base portion formed at the first proximal end, the base portion having a base plane; a nozzle block formed in the base portion; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion having a second proximal end and a second distal end and defining a mouthpiece, the second proximal end being located adjacent the first proximal end and the second distal end defining an end of the mouthpiece, such that the second distal end of the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice comprises a third proximal end and a third distal end, the third proximal end being located towards the second proximal end and the third distal end being located towards the second distal end, the third proximal end and the third distal end defining a jet length, and the third distal end defining an orifice exit, wherein the orifice exit defines an orifice exit diameter, wherein the jet length is at least 0.8 mm.

[00149] Aspect 42. The method of aspect 41, wherein the jet length is less than or equal to 2 mm.

[00150] Aspect 43. The method of any of aspects 41-42, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm. [00151] Aspect 44. The method of any of aspects 41-43, wherein the jet length is greater than or equal to 1 mm.

[00152] Aspect 45. A method of modulating a spray pattern of the metered dose inhaler of any of aspects 41-44, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

[00153] Aspect 46. The method of aspect 41, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof, and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

[00154] Aspect 47. The method of aspect 41, wherein the composition comprises budesonide and formoterol fumarate.

[00155] Aspect 48. The method of aspect 41, wherein the composition comprises mometasone furoate and formoterol fumarate.

[00156] Aspect 49. The method of any of aspects 47-48, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

[00157] Aspect 50. The method of any of aspects 41-49, wherein the propellant comprises at least 70 % by weight HFA-152a.

[00158] Aspect 51. The method of any of aspects 41-49, wherein the propellant comprises at least 70 % by weight HFO-1234ze(E).

[00159] Aspect 52. The method of any of aspects 41-49, wherein the composition comprises one or more excipients.

[00160] Aspect 53. The method of any of aspects 41-49, wherein the composition comprises ethanol.

[00161] Aspect 54. The method of aspect 53, wherein the composition comprises greater than or equal to 0.5 % ethanol and less than or equal to 15 % ethanol. [00162] Aspect 55. The method of aspect 52, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.

[00163] Aspect 56. A metered dose inhaler device comprising: an actuator housing comprising: a substantially hollow first portion having a first proximal end and a first distal end; a base portion formed at the first proximal end, the base portion having a base plane; a nozzle block formed in the base portion; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion having a second proximal end and a second distal end and defining a mouthpiece, the second proximal end being located adjacent the first proximal end and the second distal end defining an end of the mouthpiece, the substantially hollow second portion defining a roof section and a floor section each extending from the second proximal end to the second distal end of the mouthpiece, wherein the mouthpiece extends away from the second proximal end such that the second distal end of the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice comprises a third proximal end and a third distal end, the third proximal end being located towards the second proximal end and the third distal end being located towards the second distal end, the third proximal end and the third distal end defining a jet length, and the third distal end defining an orifice exit, wherein the orifice exit defines an orifice exit diameter, wherein the jet length is at least 0.8 millimeters (“mm”); and a composition comprising a propellant including at least one of 1,1 -difluoroethane (“HFA-152a”) or trans- 1,1, 1,3- tetrafluoropropene (“HFO-1234ze(E)”), the composition located in a canister disposed in the substantially hollow first portion, wherein, once the composition is ejected from the orifice exit towards the mouthpiece, the composition defines a spray pattern, and wherein the spray pattern defines a width that is at least 2.5 mm and less than or equal to 3 mm at a distance of 10 mm from the second distal end.

[00164] Aspect 57. The metered dose inhaler device of aspect 56, wherein the jet length is less than or equal to 2 mm.

[00165] Aspect 58. The metered dose inhaler device of any of aspects 56-57, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm. [00166] Aspect 59. The metered dose inhaler device of any of aspects 56-58, wherein the jet length is greater than or equal to 1 mm.

[00167] Aspect 60. A method of modulating the spray pattern of the metered dose inhaler device of any of aspects 56-59, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

[00168] Aspect 61. The metered dose inhaler device of any of aspects 56-60, wherein the composition further comprises at least one of a long-acting [3-adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long- acting muscarinic antagonist (“LAMA”), or a combination thereof.

[00169] Aspect 62. The metered dose inhaler device of aspect 61, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof, and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

[00170] Aspect 63. The metered dose inhaler device of aspect 61, wherein the composition comprises budesonide and formoterol fumarate.

[00171] Aspect 64. The metered dose inhaler device of aspect 61, wherein the composition comprises mometasone furoate and formoterol fumarate.

[00172] Aspect 65. The metered dose inhaler device of any of aspects 63-64, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

[00173] Aspect 66. The metered dose inhaler device of any of aspects 56-65, wherein the propellant comprises at least 70 % by weight HFA-152a.

[00174] Aspect 67. The metered dose inhaler device of any of aspects 56-66, wherein the propellant comprises at least 70 % by weight HFO-1234ze(E).

[00175] Aspect 68. The metered dose inhaler device of any of aspects 56-67, wherein the composition comprises one or more excipients. [00176] Aspect 69. The metered dose inhaler device of any of aspects 56-68, wherein the composition comprises ethanol.

[00177] Aspect 70. The metered dose inhaler device of aspect 69, wherein the composition comprises greater than or equal to 0.5 % ethanol and less than or equal to 15 % ethanol.

[00178] Aspect 71. The metered dose inhaler device of aspect 68, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.

Examples

[00179] Table 1 below illustrates the configurations tested.

Table 1.

[00180] For Configurations 1 to 6, 10 spray pattern measurements were made at distances of 3 cm and 6 cm from the exit of the actuator mouthpiece using a Spray VIEW with Vero SFMDx actuator system (Proveris Scientific). The testing used 5 shakes with a 60 degree angle and 1.1 Hz frequency and a 0.0 second shake to actuation delay. The actuator profile used was:

• Actuation velocity = 50 mm/s.

• Actuation acceleration = 1000 m/s/s.

• Initial delay = 50 ms.

• Hold time = 2000 ms.

• Final delay = 50 ms.

[00181] In the preceding description and following claims, the term “and/or” means one or all of the listed elements or a combination of any two or more of the listed elements; the terms “comprises,” “comprising,” and variations thereof are to be construed as open ended — i.e., additional elements or steps are optional and may or may not be present; unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one; and the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[00182] As used herein, the word “exemplary” means to serve as an illustrative and should not be construed as preferred or advantageous over other embodiments.

[00183] In the preceding description, particular embodiments may be described in isolation for clarity. Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” “one or more 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. Thus, features described in the context of one embodiment may be combined with features described in the context of a different embodiment except where the features are necessarily mutually exclusive.

[00184] In several places throughout the above description, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

[00185] For any method disclosed herein that includes discrete steps, the steps may be performed in any feasible order. And, as appropriate, any combination of two or more steps may be performed simultaneously.

[00186] As used herein, the terms “preferred” and “preferably” refer to embodiments of the invention 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 invention.

[00187] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. All numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements.

[00188] It should be noted that, as used in this specification and the appended claims, the phrase “configured” describes a system, apparatus, or other structure that is constructed to perform a particular task or adopt a particular configuration. The word "configured" can be used interchangeably with similar words such as “arranged,” “constructed,” “manufactured,” and the like.

[00189] All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this technology pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated by reference. In the event that any inconsistency exists between the disclosure of the present application and the disclosure(s) of any document incorporated herein by reference, the disclosure of the present application shall govern.

[00190] This application is intended to cover adaptations or variations of the present subject matter. It is to be understood that the above description is intended to be illustrative, and not restrictive, and the claims are not limited to the illustrative embodiments as set forth herein.

Claims

CLAIMS What is claimed is:

1. A metered dose inhaler device comprising: an actuator housing comprising: a substantially hollow first portion comprising a nozzle block; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion defining a mouthpiece and located adjacent the substantially hollow first portion, such that the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice defines a jet length along an orifice axis, and wherein the spray orifice defines an orifice exit with an orifice exit diameter, wherein the jet length is at least 0.8 millimeters (“mm”); and a composition comprising a propellant including 1 , 1 -difluoroethane (“HFA- 152a”), the composition located in a canister disposed in the substantially hollow first portion, wherein, once the composition is ejected from the orifice exit towards the mouthpiece, the composition defines a spray pattern, and wherein the spray pattern matches that of a similar metered dose inhaler device using a propellant comprising 1,1, 1,2, 3, 3, 3 -heptafluoropropane (“HFA-227”) or 1,1,1,2-tetrafhioroethane (“HFA- 134a”) and a jet length less than or equal to 0.8 mm.

2. The metered dose inhaler device of claim 1, wherein matching the spray pattern and the spray pattern of the similar metered dose inhaler device using a propellant comprising HFA-227 or HFA-134a and a jet length less than or equal to 0.8 mm is defined as: a result of dividing a geometric mean of the spray pattern of the metered dose inhaler device by a similar geometric mean of the spray pattern of the similar metered dose inhaler device, wherein the result is between 0.90 and 1.11 at one or more distances between 3 cm and 7 cm from a distal end of the mouthpiece.

3. The metered dose inhaler device of claim 2, wherein the geometric mean of the spray pattern comprises one or more of: a maximum dimension (“Dmax”) of the spray pattern, an area of the spray pattern, and an ovality ratio (the ratio of Dmax divided by a minimum dimension of the spray pattern (“Dmin”)).

4. The metered dose inhaler device of any of claims 1-3, wherein a matched spray pattern is produced when the metered dose inhaler device and the similar metered dose inhaler contain a same medicament, and a target delivered dose of each medicament is the same based on a product labelling.

5. The metered dose inhaler device of any of claims 1-4, wherein the jet length is less than or equal to 2 mm.

6. The metered dose inhaler device of any of claims 1-5, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm.

7. The metered dose inhaler device of any of claims 1-6, wherein the jet length is at least 1.25 times the jet length of the similar metered dose inhaler device.

8. The metered dose inhaler device of any of claims 1-7, wherein the orifice exit diameter is not more than 0.90 times the orifice exit diameter of the similar metered dose inhaler device.

9. The metered dose inhaler device of any of claims 1-8, wherein the jet length is greater than or equal to 1 mm.

10. A method of modulating the spray pattern of the metered dose inhaler device of any of claims 1-9, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

11 . The metered dose inhaler device of any of claims 1-10, wherein the composition further comprises a medicament comprising at least one of a long-acting P- adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof.

12. The metered dose inhaler device of claim 11, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof, and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

13. The metered dose inhaler device of claim 11, wherein the composition comprises budesonide and formoterol fumarate.

14. The metered dose inhaler device of claim 11, wherein the composition comprises mometasone furoate and formoterol fumarate.

15. The metered dose inhaler device of any of claims 13-14, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

16. The metered dose inhaler device of any of claims 1- 11, wherein the propellant comprises at least 70 % by weight HFA-152a.

17. The metered dose inhaler device of any of claims 1- 11, wherein the composition comprises one or more excipients.

18. The metered dose inhaler device of any of claims 1-11, wherein the composition comprises ethanol.

19. The metered dose inhaler device of claim 18, wherein the composition comprises greater than or equal to 0.5 % ethanol by weight and less than or equal to 15 % ethanol by weight.

20. The metered dose inhaler device of claim 17, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.

21. A metered dose inhaler device comprising: an actuator housing comprising: a substantially hollow first portion comprising a nozzle block; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion defining a mouthpiece and located adjacent the substantially hollow first portion, such that the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice defines a jet length along an orifice axis, and wherein the spray orifice defines an orifice exit with an orifice exit diameter, wherein the jet length is at least 0.8 millimeters (“mm”); and a composition comprising a propellant including trans-1, 1,1, 3 -tetrafluoropropene (“HFO-1234ze(E)”), the composition located in a canister disposed in the substantially hollow first portion, wherein, once the composition is ejected from the orifice exit towards the mouthpiece, the composition defines a spray pattern, and wherein the spray pattern matches that of a similar metered dose inhaler device using a propellant comprising 1,1, 1,2, 3, 3, 3 -heptafluoropropane (“HFA-227”) and a jet length less than or equal to 0.8 mm.

22. The metered dose inhaler device of claim 21, wherein matching the spray pattern of the metered dose inhaler device and the spray pattern of the similar metered dose inhaler device using a propellant comprising HFA-227 and a jet length less than or equal to 0.8 mm is defined as: a result of dividing a geometric mean of the spray pattern of the metered dose inhaler device by a similar geometric mean of the spray pattern of the similar metered dose inhaler device, wherein the result is between 0.90 and 1.11 at one or more distances between 3 cm and 7 cm from a distal end of the mouthpiece.

23. The metered dose inhaler device of claim 22, wherein the geometric mean of the spray pattern comprises one or more of: a maximum dimension (“Dmax”) of the spray pattern, an area of the spray pattern, and an ovality ratio (the ratio of Dmax divided by a minimum dimension of the spray pattern (“Dmin”)).

24. The metered dose inhaler device of any of claims 21-23, wherein a matched spray pattern is produced when the metered dose inhaler device and the similar metered dose inhaler contain a same medicament, and a target delivered dose of each medicament is the same based on a product labelling.

25. The metered dose inhaler device of any of claims 21-24, wherein the jet length is less than or equal to 2 mm.

26. The metered dose inhaler device of any of claims 21-25, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm.

27. The metered dose inhaler device of any of claims 21-26, wherein the jet length is at least 1.25 times the jet length of the similar metered dose inhaler device.

28. The metered dose inhaler device of any of claims 21-27, wherein the orifice exit diameter is not more than 0.90 times the orifice exit diameter of the similar metered dose inhaler device.

29. The metered dose inhaler device of any of claims 21-28, wherein the jet length is greater than or equal to 1 mm.

30. A method of modulating the spray pattern of the metered dose inhaler device of any of claims 21-29, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

31. The metered dose inhaler device of any of claims 21-30, wherein the composition further comprises a medicament comprising at least one of a long-acting P- adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof.

32. The metered dose inhaler device of claim 31, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

33. The metered dose inhaler device of claim 31, wherein the composition comprises budesonide and formoterol fumarate.

34. The metered dose inhaler device of claim 31, wherein the composition comprises mometasone furoate and formoterol fumarate.

35. The metered dose inhaler device of any of claims 33-34, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

36. The metered dose inhaler device of any of claims 20- 31, wherein the propellant comprises at least 70 % by weight HFO-1234ze(E).

37. The metered dose inhaler device of any of claims 20- 31, wherein the composition comprises one or more excipients.

38. The metered dose inhaler device of any of claims 20- 31, wherein the composition comprises ethanol.

39. The metered dose inhaler device of claim 38, wherein the composition comprises greater than or equal to 0.5 % ethanol by weight and less than or equal to 15 % ethanol by weight.

40. The metered dose inhaler device of claim 37, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.

41. A method of manufacturing a metered dose inhaler comprising: making a composition comprising a propellant including at least one of 1,1- difluoroethane (“HFA-152a”) or trans- 1, 1, 1,3 -tetrafluoropropene (“HFO-1234ze(E)”), and further comprising at least one of a long-acting P-adrenoreceptor agonist (“LABA”), a short-acting P-adrenoreceptor agonist (“SABA”), a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof, and disposing the composition into a canister for use with an actuator housing comprising: a substantially hollow first portion having a first proximal end and a first distal end, wherein the canister is disposed in the substantially hollow first portion; a base portion formed at the first proximal end, the base portion having a base plane; a nozzle block formed in the base portion; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion having a second proximal end and a second distal end and defining a mouthpiece, the second proximal end being located adjacent the first proximal end and the second distal end defining an end of the mouthpiece, such that the second distal end of the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice comprises a third proximal end and a third distal end, the third proximal end being located towards the second proximal end and the third distal end being located towards the second distal end, the third proximal end and the third distal end defining a jet length, and the third distal end defining an orifice exit, wherein the orifice exit defines an orifice exit diameter, wherein the jet length is at least 0.8 mm.

42. The method of claim 41, wherein the jet length is less than or equal to 2 mm.

43. The method of any of claims 41-42, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm.

44. The method of any of claims 41-43, wherein the jet length is greater than or equal to 1 mm.

45. A method of modulating a spray pattern of the metered dose inhaler of any of claims 41-44, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

46. The method of claim 41, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof, and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

47. The method of claim 41, wherein the composition comprises budesonide and formoterol fumarate.

48. The method of claim 41, wherein the composition comprises mometasone furoate and formoterol fumarate.

49. The method of any of claims 47-48, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

50. The method of any of claims 41-49, wherein the propellant comprises at least 70 % by weight HFA-152a.

51. The method of any of claims 41-49, wherein the propellant comprises at least 70 % by weight HFO-1234ze(E).

52. The method of any of claims 41-49, wherein the composition comprises one or more excipients.

53. The method of any of claims 41-49, wherein the composition comprises ethanol.

54. The method of claim 53, wherein the composition comprises greater than or equal to 0.5 % ethanol by weight and less than or equal to 15 % ethanol by weight.

55. The method of claim 52, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.

56. A metered dose inhaler device comprising: an actuator housing comprising: a substantially hollow first portion having a first proximal end and a first distal end; a base portion formed at the first proximal end, the base portion having a base plane; a nozzle block formed in the base portion; a spray orifice formed in the nozzle block and operable for dispensing a spray of metered fluid; and a substantially hollow second portion having a second proximal end and a second distal end and defining a mouthpiece, the second proximal end being located adjacent the first proximal end and the second distal end defining an end of the mouthpiece, the substantially hollow second portion defining a roof section and a floor section each extending from the second proximal end to the second distal end of the mouthpiece, wherein the mouthpiece extends away from the second proximal end such that the second distal end of the mouthpiece is configured to be placed within a mouth of a user, wherein the spray orifice comprises a third proximal end and a third distal end, the third proximal end being located towards the second proximal end and the third distal end being located towards the second distal end, the third proximal end and the third distal end defining a jet length, and the third distal end defining an orifice exit, wherein the orifice exit defines an orifice exit diameter, wherein the jet length is at least 0.8 millimeters (“mm”); and a composition comprising a propellant including at least one of 1,1 -difluoroethane (“HFA-152a”) or trans- 1,1, 1,3 -tetrafluoropropene (“HFO-1234ze(E)”), the composition located in a canister disposed in the substantially hollow first portion, wherein, once the composition is ejected from the orifice exit towards the mouthpiece, the composition defines a spray pattern, and wherein the spray pattern defines a width that is at least 2.5 mm and less than or equal to 3 mm at a distance of 10 mm from the second distal end.

57. The metered dose inhaler device of claim 56, wherein the jet length is less than or equal to 2 mm.

58. The metered dose inhaler device of any of claims 56-57, wherein the orifice exit diameter is greater than or equal to 0.2 mm and less than or equal to 0.5 mm.

59. The metered dose inhaler device of any of claims 56-58, wherein the jet length is greater than or equal to 1 mm.

60. A method of modulating the spray pattern of the metered dose inhaler device of any of claims 56-59, wherein modulating the spray pattern to become relatively smaller comprises adjusting the jet length to become relatively longer.

61. The metered dose inhaler device of any of claims 56-60, wherein the composition further comprises at least one of a long-acting P-adrenoreceptor agonist (“LABA”), a short-acting -adrenoreceptor agonist (“SABA”), a corticosteroid, a long-acting muscarinic antagonist (“LAMA”), or a combination thereof.

62. The metered dose inhaler device of claim 61, wherein the SABA comprises salbutamol, levalbuterol, terbutaline, or a pharmaceutically acceptable salt or solvate thereof, and wherein the LABA comprises formoterol, salmeterol, indacaterol, vilanterol, or a pharmaceutically acceptable salt or solvate thereof, and wherein the corticosteroid comprises budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or a pharmaceutically acceptable salt or solvate thereof, or a combination thereof.

63. The metered dose inhaler device of claim 61, wherein the composition comprises budesonide and formoterol fumarate.

64. The metered dose inhaler device of claim 61, wherein the composition comprises mometasone furoate and formoterol fumarate.

65. The metered dose inhaler device of any of claims 63-64, wherein the formoterol fumarate is in the form of formoterol fumarate dihydrate.

66. The metered dose inhaler device of any of claims 56-65, wherein the propellant comprises at least 70 % by weight HFA-152a.

67. The metered dose inhaler device of any of claims 56-66, wherein the propellant comprises at least 70 % by weight HFO-1234ze(E).

68. The metered dose inhaler device of any of claims 56-67, wherein the composition comprises one or more excipients.

69. The metered dose inhaler device of any of claims 56-68, wherein the composition comprises ethanol.

70. The metered dose inhaler device of claim 69, wherein the composition comprises greater than or equal to 0.5 % ethanol by weight and less than or equal to 15 % ethanol by weight.

71. The metered dose inhaler device of claim 68, wherein the one or more excipients comprise one or more of poly(ethylene) glycol (“PEG”) or oleic acid.