metered spray inhaler

Abstract

Various embodiments of a metered dose inhaler are disclosed. The inhaler includes a canister and a metering valve connected to the canister. The metering valve includes a valve housing having first and second ends, and a metering valve stem extending through the first end of the valve housing, a metering chamber, and the second end. A first portion of the metering valve stem is disposed through a diaphragm opening in a diaphragm that is at least partially disposed within the first end of the housing and forms a dynamic seal with the diaphragm, and a second portion of the metering valve stem is disposed through a tank seal opening in a tank seal that is at least partially disposed within the second end of the housing and forms a dynamic seal with the tank seal. At least one of the diaphragm or the tank seal comprises a polytetrafluoroethylene material.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 430,761, filed December 07, 2022, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Delivery of aerosolized medications to the respiratory tract for the treatment of respiratory and other diseases can be accomplished using, for example, pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), or nebulizers. pMDIs are familiar to many patients suffering from asthma or chronic obstructive pulmonary disease (COPD). pMDI devices can include an aluminum container sealed with a metering valve that contains a pharmaceutical formulation. Typically, the pharmaceutical formulation is a solution and / or suspension of one or more pharmaceutical compounds in a liquefied hydrofluoroalkane (HFA) propellant.

[0003] In a pulmonary pMDI, the sealed container may be provided to the patient within an actuator, i.e., a generally L-shaped plastic part that includes a generally vertical tube that surrounds the container and a generally horizontal tube that forms the patient portion (e.g., mouthpiece or nosepiece) that may define an inhalation (or inspiration) orifice.

[0004] The container typically comprises a metering valve crimped onto a metal canister of an appropriate size. The metal canister is typically made of aluminum and has a wall thickness of about 0.5 mm. The container typically holds a formulation comprising a liquid propellant, a drug, cosolvents, and excipients. To prevent loss of the formulation (mainly the liquid propellant), the metering valve comprises a rubber component that forms a seal.

[0005] Historically, the propellants in most pMDIs were chlorofluorocarbons (CFCs). However, environmental concerns in the 1990s led to the replacement of CFCs with hydrofluoroalkanes (HFAs) as the most commonly used propellants in pMDIs. HFAs do not cause ozone depletion but have a reported high global warming potential (GWP), which is a measure of the future radiative impact of emitting a substance compared to emitting an equivalent amount of carbon dioxide (CO). The two most commonly used HFA propellants in pMDIs are HFA134a (CF3CH2F) and HFA227 (CF3CHFCHF3), which have 100-year GWP values ​​of 1300-1430 and 3220-3350, respectively. Summary of the Invention

[0006] In general, the present disclosure relates to a metered dose inhaler that includes a canister and a metering valve connected to the canister. The metering valve can include a diaphragm that includes an opening, with a first portion of the metering valve stem positioned to pass through the opening and form a dynamic seal with the diaphragm. The metering valve can further include a reservoir seal that includes an opening, with a second portion of the metering valve stem positioned to pass through the opening and form a dynamic seal with the reservoir seal. In one or more embodiments, at least one of the diaphragm or the reservoir seal comprises a polytetrafluoroethylene (PTFE) material. The metered dose inhaler can also include a gasket positioned between the ferrule of the metering valve and the canister. In one or more embodiments, the gasket can comprise a PTFE material.

[0007] In one aspect, the present disclosure provides a metered dose inhaler comprising: a container having a reservoir containing a formulation comprising a propellant, the propellant comprising at least one of a hydrofluoroalkane (HFA) or a hydrofluoroolefin (HFO), and at least one active pharmaceutical ingredient; and a metering valve connected to the container. The metering valve includes a valve housing having a first end and a second end, the valve housing defining a metering chamber between the first and second ends of the housing, the metering chamber adapted to receive the formulation from the reservoir. The metering valve further includes a metering valve stem extending through a first end of the valve housing, a metering chamber, and a second end of the valve housing, a diaphragm at least partially disposed within the first end of the valve housing and including an opening, wherein a first portion of the metering valve stem is disposed through the diaphragm opening to form a dynamic seal with the diaphragm, and a tank seal at least partially disposed within the second end of the valve housing and including an opening, wherein a second portion of the metering valve stem is disposed through the tank seal opening to form a dynamic seal with the tank seal, wherein at least one of the diaphragm or the tank seal consists essentially of polytetrafluoroethylene (PTFE).

[0008] In another aspect, the present disclosure provides a metered dose inhaler comprising: a container including a reservoir containing a formulation including a propellant, the propellant including at least one of an HFA or an HFO, and at least one active pharmaceutical ingredient; and a metering valve connected to the container. The metering valve includes a valve housing having a first end and a second end disposed within the reservoir, the valve housing defining a metering chamber between the first and second ends of the valve housing, the metering chamber adapted to receive the formulation from the reservoir. The metering valve further includes a metering valve stem extending through a first end of the valve housing, a metering chamber, and a second end of the valve housing; a diaphragm at least partially disposed within the first end of the valve housing and including an opening, wherein a first portion of the metering valve stem is disposed through the diaphragm opening to form a dynamic seal with the diaphragm; and a tank seal at least partially disposed within the second end of the valve housing and including an opening, wherein a second portion of the metering valve stem is disposed through the tank seal opening to form a dynamic seal with the tank seal. At least one of the diaphragm or the tank seal consists essentially of polytetrafluoroethylene (PTFE). The metering valve further has a prime position in which the formulation can flow between the reservoir and the metering chamber and the diaphragm is adapted to seal the metering chamber from the outside atmosphere. The metering valve further has an actuated position in which a second portion of the metering valve stem seals against the tank seal and the second end of the valve housing to seal the metering chamber from the reservoir, thereby defining a metered amount of the formulation within the metering chamber, and the metering valve stem includes an outlet chamber that allows the formulation to flow between the metering chamber and the external atmosphere.

[0009] In another aspect, the disclosure provides a method, the method comprising: placing a formulation comprising at least one active pharmaceutical ingredient and a propellant comprising at least one of a hydrofluoroalkane (HFA) or a hydrofluoroolefin (HFO) into a reservoir of a container; connecting a metering valve to the container; and sealing at least one interface within the valve or between the container and the valve with a PTFE seal.

[0010] 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 specifically stated.

[0011] The term "comprises" and variations thereof do not have a limiting meaning when these terms appear in the description and claims. Such terms are understood to mean the inclusion of the recited step or element or group of steps or elements, but not the exclusion of any other step or element or group of steps or elements. The term "consisting of" means "comprise" and is limited to what follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the recited elements are necessary or essential, and that other elements may not be present. The term "consisting essentially of" means including any elements listed after the phrase, and is limited to other elements that do not interfere with or contribute to the activity or function specified in this disclosure for the recited elements. Thus, the phrase "consisting essentially of" indicates that the recited elements are necessary or essential, but that other elements are optional and may or may not be present depending on whether they materially affect the activity or function of the recited elements.

[0012] In this application, terms such as "a," "an," and "the" are not intended to refer only to a singular entity, but include a general class of which a specific example may be used for illustration. The terms "a," "an," and "the" are used interchangeably with the term "at least one." The phrases "at least one of" and "including at least one of," followed by a list, refer to any one of the items in the list, and any combination of two or more items in the list.

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

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

[0015] As used herein in connection with a measured quantity, the term "about" refers to the variation in the measured quantity as would be expected by one of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring equipment used. As used herein, "up to" a number (e.g., up to 50) includes that number (e.g., 50).

[0016] Also herein, the recitations of numerical ranges by endpoints include those endpoints as well as all numbers subsumed within that range (eg, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0017] These and other aspects of the present disclosure will become apparent from the following detailed description. However, the above summary should in no way be construed as a limitation on the claimed subject matter, which subject matter is defined solely by the appended claims, as may be amended during prosecution. [Brief explanation of the drawings]

[0018] Throughout this specification, reference will be made to the accompanying drawings, wherein like reference numerals indicate like elements and wherein: [Figure 1] 1 is a schematic side view of one embodiment of an inhaler.

[0019] [Figure 2] 2 is a schematic cross-sectional side view of the inhaler of FIG. 1;

[0020] [Figure 3] 2 is a schematic cross-sectional side view of the metering valve of the inhaler of FIG. 1, with the metering valve in the priming position.

[0021] [Figure 4] FIG. 4 is a schematic cross-sectional side view of the metering valve of FIG. 3 in an actuated position.

[0022] [Figure 5] 2 is a flow chart of one embodiment of a method of forming the inhaler of FIG. 1. DETAILED DESCRIPTION OF THE INVENTION

[0023] In general, the present disclosure relates to a metered dose inhaler that includes a canister and a metering valve connected to the canister. The metering valve can include a diaphragm that includes an opening, with a first portion of the metering valve stem positioned to pass through the opening and form a dynamic seal with the diaphragm. The metering valve can further include a reservoir seal that includes an opening, with a second portion of the metering valve stem positioned to pass through the opening and form a dynamic seal with the reservoir seal. In one or more embodiments, at least one of the diaphragm or the reservoir seal comprises a polytetrafluoroethylene (PTFE) material. The metered dose inhaler can also include a gasket that is positioned between the ferrule of the metering valve and the canister. In one or more embodiments, the gasket can comprise a PTFE material.

[0024] One or more embodiments of the metered-dose inhalers described herein can offer various advantages over currently available inhalers. For example, one or more of these embodiments can include one or more seals comprising PTFE material. In a typical inhaler, one or more seals instead comprise an elastomeric material. In one or more embodiments, PTFE seals can have lower levels of leachable materials compared to elastomeric seals. These seals may not require further extraction of undesirable materials before use. PTFE seals are also less likely to expand than standard seals when exposed to propellants. Such PTFE seals can also reduce friction between the seal and the valve stem, thereby improving valve function (which can reduce or eliminate the need for silicone or other lubrication), increasing pressure and temperature resistance, and providing lower permeability compared to elastomeric seals. PTFE seals can also be used with a wider range of formulation types than elastomeric seals.

[0025] FIG. 1 is a schematic side view of one embodiment of a metered dose inhaler 10. Such inhaler 10 includes an actuator 12 and a container or canister 14. The actuator 12 has a generally elongated actuator housing 16 that receives the container 14. Such container 14 can be inserted into a container opening 18 at the top of the actuator 12. As shown in FIG. 2, a schematic cross-sectional side view of the inhaler 10, a reservoir 37 is disposed within the container 14. The reservoir 37 contains a formulation including a propellant and at least one active pharmaceutical ingredient (API) for delivery to a user via the actuator 12 and mouthpiece 22 of the housing 16, as described in further detail herein. In one or more embodiments, the mouthpiece 22 can be replaced by a nosepiece (not shown) to enable nasal delivery.

[0026] The inhaler 10 also includes a metering valve 30. As shown in FIG. 3 , the metering valve 30 includes a valve housing 60 having a first end 78 and a second end 80. The valve housing 60 defines a metering chamber 32 between the first end 78 and the second end 80 of the housing. The metering chamber 32 is adapted to receive the formulation from a reservoir 37. The metering valve 30 also includes a metering valve stem 34 extending through the first end 78, the metering chamber 32, and the second end 80 of the valve housing 60. The metering valve 30 further includes a diaphragm 36 at least partially disposed within the first end 78 of the valve housing 60. The diaphragm 36 includes an opening 38. A first portion 51 of the metering valve stem 34 is disposed through the diaphragm opening 38 to form a dynamic seal with the diaphragm. The metering valve 30 can also include a tank seal 56 at least partially disposed within the second end 80 of the valve housing 60. The tank seal 56 can include an opening 58. The second portion 52 of the metering valve stem 34 is disposed through the tank seal opening 58 to form a dynamic seal with the tank seal 56. In one or more embodiments, at least one of the diaphragm 36 or the tank seal 56 can include a polytetrafluoroethylene (PTFE) material (i.e., at least one of the diaphragm or the tank seal can be a PTFE seal). In one or more embodiments, at least one of the diaphragm or the tank seal consists essentially of polytetrafluoroethylene (PTFE).

[0027] Inhaler 10 can include any suitable inhaler. In one or more embodiments, inhaler 10 can include a pressurized metered dose inhaler (pMDI). As shown in FIG. 1 , inhaler 10 includes a container 14 that holds a formulation and a metering valve 30 connected to the container. Container 14 can include any suitable material and take any suitable shape. In one or more embodiments, one or more layers of material can be disposed over at least a portion of container 14. Such one or more layers can include any suitable material, for example, PTFE.

[0028] The container 14 is disposed within the housing 16 of the actuator 12 through a container opening 18. In one or more embodiments, at least a portion of the container 14 can extend beyond the container opening 18, as shown in FIG. 1 . The housing 16 includes a tubular sleeve portion 20 having the container opening 18 adapted to receive the container 14 and a portion defining a mouthpiece 22. While referred to herein as a mouthpiece 22, such a mouthpiece may instead be adapted to be the nosepiece of a nasal inhaler, and the present disclosure is equally applicable to nasal inhalers, even if not specifically mentioned herein. The mouthpiece 22 defines an inhalation outlet orifice (e.g., air outlet) 24. In one or more embodiments, the container 14 can include an aspiration orifice or air inlet (not shown) located in any suitable portion of the container. The actuator housing 16 can be adapted to enclose a metering valve 30 and at least a portion of the container 14. In one or more embodiments, the actuator housing 16 is adapted to enclose the metering valve 30, as shown in FIG. 2 .

[0029] The reservoir 37 disposed within the container 14 can have any suitable shape and any suitable dimensions. Furthermore, the reservoir 37 can have any suitable internal pressure of the formulation. In one or more embodiments, the pressure within the reservoir is 20 bar or less. In one or more embodiments, the pressure within the reservoir is within the range of 1-20 bar, 1-15 bar, 1-10 bar, or 1-5 bar.

[0030] The inhaler 10 may include any suitable metering valve 30. As shown in FIG. 3 , the metering valve 30 includes a valve stem 34 generally defining a longitudinal axis 2 and a valve housing 60 (i.e., a metering reservoir), with a first portion 51 of the valve stem extending through a central aperture 66 in a first end 78 of the valve housing. In one or more embodiments, the reservoir 37 and the metering valve stem 34 are aligned along the central longitudinal axis 2. The valve housing 60 includes a first end 78, a second end 80 disposed within the reservoir 37, and a wall 82 extending between the first and second ends. The valve housing 60 defines a metering chamber 32 between the first and second ends 78, 80 of the housing.

[0031] Valve housing 60 may have any suitable shape and any suitable dimensions. Additionally, metering chamber 32 defined by valve housing 60 may have any suitable shape and any suitable dimensions. In one or more embodiments, metering chamber 32 has a volume that may be between 5 microliters (μL or mcl) and 200 microliters, between 25 microliters and 200 microliters, between 25 microliters and 150 microliters, between 25 microliters and 100 microliters, between 50 microliters and 100 microliters, between 25 microliters and 65 microliters, or between 50 microliters and 65 microliters.

[0032] The metering valve stem 34 extends through the first end 78 of the valve housing 60, the metering chamber 32, and the second end 80. Such stem 34 includes a first portion 51 that extends through the first end 78 of the valve housing 60 and is exposed to the atmosphere, and a second portion 52 that extends through the second end 80 of the valve housing. The first portion 51 of the valve stem 34 extends outwardly and is in slidable sealing engagement with the diaphragm 36, while the second portion 52 of the valve stem extends inwardly and is in slidable sealing engagement with the tank seal 56.

[0033] The metering valve 30 is connected to the container 14 using any suitable technique. As shown in FIG. 3 , the metering valve 30 is connected to the container 14 by a ferrule 42, which can be connected to the container using any suitable technique. In one or more embodiments, the ferrule 42 is mechanically connected to the container 14, for example, by crimping the ferrule to the container. The ferrule 42 includes a mount 54 that is connected to the container 14 to define a reservoir 37. A gasket 72 can be disposed between the ferrule 42 and the end 15 of the container 14. The gasket 72 can be adapted to seal the reservoir 37 and the ferrule 42. Additionally, an O-ring 74 can be disposed between the ferrule 42 and the side 62 of the container 14 to further seal the reservoir 37 from the outside atmosphere.

[0034] An aperture 44 is disposed through the ferrule 42, and the opening 38 of the diaphragm 36 is aligned with the aperture of the ferrule. A first portion 51 of the valve stem 34 extends through and is slidably engaged with the opening 38 of the diaphragm 36. Thus, the diaphragm 36 forms a dynamic seal with the valve stem 34. Furthermore, the diaphragm 36 forms a dynamic seal between the metering chamber 32 and the external atmosphere. As used herein, the phrase "dynamic seal" means that a seal is maintained with a moving part when the moving part is movably coupled through the seal to substantially prevent liquid or gas from passing through the opening of the seal. In one or more embodiments, the diaphragm 36 can be sealed to the ferrule 42 using any suitable technique. The diaphragm 36 can include a spring (not shown) disposed within the diaphragm 36 or in contact with the outer surface of the diaphragm, the spring adapted to maintain the seal in contact with the ferrule 42. In one or more embodiments, the diaphragm 36 does not include a spring.

[0035] The second portion 52 of the valve stem 34 is disposed through and slidably engages an opening 58 in the tank seal 56. The second portion 52 of the valve stem 34 forms a dynamic seal with the tank seal 56. In one or more embodiments, the dynamic seal may be formed by the tank seal 56 between the metering chamber 32 and a second valve housing 68. The second portion 52 of the valve stem 34 passes through an inlet aperture 64 in a second end 80 of the valve housing 60.

[0036] The valve stem 34 is in slidable engagement with the opening 38 in the diaphragm 36. A compression spring 46 is adapted to hold the valve stem 34 in a primed position, as shown in FIG. 3 . The compression spring 46 may be disposed within a valve housing 60 between a tank seal 56 and a flange 33 disposed on the valve stem 34. The valve stem 34 further includes an orifice 48 adapted to be in fluid communication with the outlet chamber 40 disposed within the valve stem, and a channel 50 disposed within a first portion 51 of the valve stem.

[0037] In one or more embodiments, the metering valve 30 can include a second valve housing 68 (i.e., a holding cup) defining a bottle ejection mechanism. When such a second valve housing 68 is present, the formulation in the reservoir 37 can pass through a gap 84 between the valve housing 60 and the second valve housing 68, through an annular gap 76 into the holding chamber 70 (i.e., the retention chamber), and then through a channel 50 disposed in the valve stem 34 into the metering chamber 32. The second valve housing 68 can be connected to the ferrule 42 using any suitable technique. The annular gap 76 of the holding chamber 70 can be present if the inhaler 10 is adapted for use with a suspension aerosol formulation. In one or more embodiments, the second valve housing 68 can be optional if the inhaler 10 is adapted for use with a solution aerosol formulation.

[0038] As shown in FIG. 2 , the valve stem 34 protrudes from the valve housing 60 and the ferrule 42 and connects to a stem socket 26 disposed within the housing 16. The spray orifice 28 is disposed within the stem socket 26 to provide fluid communication between the valve stem 34 and the inhalation orifice 24. A user may place the mouthpiece 22 within a body cavity (e.g., the mouth) and inhale through the mouthpiece 22 while pressing downward on the container 14. This pressing force causes the container 14 to move toward the stem socket 26 relative to the valve stem 34. This relative movement separates a metered dose of pressurized formulation from the bulk formulation disposed within the reservoir 37 of the container 14 and then expels it via an outlet chamber 40 disposed within the stem 34. The expelled dose passes along a fluid pathway through the stem socket 26 and the spray orifice 28 and is directed toward the user's body cavity (e.g., at least one of the oral or nasal cavities) and the user's respiratory tract.

[0039] Operation of inhaler 10 is illustrated in Figures 3-4. In Figure 3, inhaler 10 is adapted with valve 30 in a priming position, allowing formulation to flow between reservoir 37 and metering chamber 32, with diaphragm 36 adapted to seal the metering chamber from the outside atmosphere. Annular gap 76 allows open communication between holding chamber 70 and reservoir 37, thus allowing formulation in the reservoir to enter holding chamber 70. Channel 50 in metering stem 34 allows open communication between holding chamber 70 and metering chamber 32, such that a portion of the formulation enters metering chamber 32 through inlet aperture 64. Diaphragm 36 seals central aperture 66 of valve housing 60.

[0040] 4 is a schematic cross-sectional view of a portion of inhaler 10 in an actuated position, in which formulation can flow between metering chamber 32 and the outside atmosphere. In the actuated position, metering valve stem second portion 52 seals against tank seal 56 and second end 80 of valve housing 60 to seal metering chamber 32 from reservoir 37, thereby defining a metered amount of formulation within the metering chamber. When valve stem 34 is depressed, channel 50 is moved relative to tank seal 56 such that inlet aperture 64 and tank seal opening 58 are substantially sealed, thus isolating the metered dose of formulation within metering chamber 32. Further depression of valve stem 34 allows orifice 48 to pass through aperture 44 in ferrule 42 and enter metering chamber 32, where the metered dose is exposed to ambient pressure. Rapid evaporation of the formulation's propellant can force the metered dose through orifice 48 into and through exit chamber 40. In other words, exit chamber 40 allows formulation to flow between metering chamber 32 and the outside atmosphere. It will be appreciated that other modes of actuation, such as breath actuation, can be used as well, and will operate as described, except that the force depressing the reservoir is provided by the device, for example, by a spring or motor-driven screw, in response to a triggering event, such as a patient's inhalation.

[0041] Generally, inhaler 10 can include one or more seals or gaskets (e.g., diaphragm 36) adapted to seal at least one interface between an element or component of the inhaler, or at least one interface between an element or component of the inhaler and the external atmosphere. For example, one or more seals can seal at least one interface within metering valve 30 or at least one interface between container 14 and the valve. In one or more embodiments, at least one interface can be between end 15 of container 14 and ferrule 42. In one or more embodiments, at least one interface is between metering valve stem 34 and the external atmosphere. Additionally, in one or more embodiments, at least one interface is between metering chamber 32 and reservoir 37.

[0042] In one or more embodiments, the inhaler 10 may include at least three separate seals: a diaphragm 36, a tank seal 56, and a gasket 72. In one or more embodiments, the inhaler 10 may also include an O-ring 74. The seals may include any suitable material. In one or more embodiments, each of the seals may include the same material. In one or more embodiments, one or more of the seals may include a material that is different from the material utilized in one or more additional seals. In one or more embodiments, at least one of the seals may include a PTFE material. For example, at least one of the diaphragm 36, the tank seal 56, the gasket 72, or the O-ring 74 may include PTFE. In one or more embodiments, at least one of the diaphragm 36, the tank seal 56, the gasket 72, or the O-ring 74 may consist essentially of PTFE.

[0043] Exemplary materials used to form the seals include, but are not limited to, PTFE, ethylene tetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP), polyethylene, particularly high density polyethylene or linear low density polyethylene, polyamides such as nylon, and polypropylene. Additionally, each of the seals can have any suitable hardness, for example, a hardness of about 45-80, 50-70, 50-60, or 55-60 Shore D, as measured by ASTM D 2240-15 at a standard atmosphere of 23° C. and 50% relative humidity.

[0044] As described herein, the inhaler 10 can include any suitable metering valve 30. Furthermore, the metering valve 30 can exhibit any suitable characteristics. For example, the metering valve 30 can have any suitable initial leak rate. As used herein, the phrase "initial leak rate" refers to the weight of formulation or a particular formulation component that leaves the canister per unit time when the valve is in its primed state and no labeled claimed dose has been administered. In one or more embodiments, the initial leak rate is 650 mg / yr or less. In one or more embodiments, the initial leak rate is 300 mg / yr or less.

[0045] Inhaler 10 may be configured to contain any suitable formulation disposed within reservoir 37, such as those disclosed in PCT Application No. PCT / US2022 / 042956, filed September 8, 2022, entitled "Metered Dose Inhalers and Solution Compositions," PCT Application No. PCT / US2022 / 042958, filed September 8, 2022, entitled "Metered Dose Inhalers and Suspension Compositions," and PCT Application No. PCT / US2022 / 042959, filed September 8, 2022, entitled "Propellant for Anticolinear Agents in Pressurized Metered Dose Inhalers and Suspension Compositions." The formulations may include one or more of the formulations described in PCT Application No. PCT / US2022 / 042959, filed September 8, 2022, entitled "Propellant for Anticholinergic Agents in Pressurized Metered-Dose Inhalers." In one or more embodiments, the formulation includes at least one propellant and at least one API. The formulation may include any suitable propellant. In one or more embodiments, the propellant may include at least one of a hydrofluoroalkane (HFA) or a hydrofluoroolefin (HFO). The primary propellant in compositions (i.e., formulations) according to the present disclosure is a trans-1,1 The most common fluorochemical is HFO-1234ze(E), also known as trans-1,3,3,3-tetrafluoropropene, trans-1,3,3,3-tetrafluoropropene, or trans-1,3,3,3-tetrafluoroprop-1-ene. The trans and cis isomers of HFO-1234ze have very different chemical structures. As a result, these isomers have very different physical and thermodynamic properties. At ambient temperatures, the trans (E) isomer has a significantly lower boiling point and higher vapor pressure than the cis (Z) isomer, making the trans isomer a thermodynamically much more suitable propellant for achieving efficient pMDI atomization.

[0046] In one or more embodiments, the amount of HFO-1234ze(E) in the composition is greater than 70 wt%, at least 80 wt%, greater than 80 wt%, at least 85 wt%, greater than 85 wt%, at least 90 wt%, or greater than 90 wt%. In some embodiments, the amount of HFO-1234ze(E) is 80 wt% to 99 wt%, 80 wt% to 98 wt%, 80 wt% to 95 wt%, or 85 wt% to 90 wt%. In one or more embodiments, HFO-1234ze(E) is essentially the only propellant in the composition. That is, pharmaceutical performance parameters such as emitted dose and emitted particle size distribution are not significantly different from when HFO-1234ze(E) is the only propellant in the composition. In some embodiments, the amount of HFO-1234ze(E) of the total propellant in the composition is greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight, and greater than 99.8% by weight.

[0047] The propellant HFO-1234ze(E) is very different from the alternative low-GWP propellant HFA-152a. These two propellants have different physical, chemical, and thermodynamic properties, including boiling point, vapor pressure, water solubility, liquid density, and surface tension. These differences make it difficult to replace one propellant with another without significantly impairing or altering the performance of pMDI products. For example, thermodynamic differences in propellant boiling points and vapor pressures can significantly affect the aerosolization efficiency of pMDIs and lead to differences in primary and secondary atomization mechanisms. Differences in dipole moment and polarity between propellants can affect the solubility of drug and excipients in the formulation. Differences in hygroscopicity between propellants can affect water uptake, which can be problematic for solution formulations, especially when water uptake is expected to affect physical stability or water-related chemical degradation. The chemical interactions of different propellants with drugs and excipients can also vary significantly, which can affect the long-term chemical stability of a product over its intended shelf life. The two propellants chemically and physically interact with the valve plastic and elastomeric components, which can result in differences in the type and amount of extractables and leachables, as well as affect mechanical valve function. The thermodynamic properties of the propellants can result in different droplet sizes due to different evaporation rates and can also lead to differences in spray characteristics such as atomization force, temperature, and spray duration. Historically, the transition from CFC to HFA propellants required significant effort in developing new formulations and sophisticated hardware to achieve adequate pMDI product performance. This means that simple, direct substitution of one propellant for another was not possible. Changing between the propellants HFA-152a and HFO-1234ze(E) in pMDIs is similarly challenging due to many of the factors highlighted above.

[0048] In one or more embodiments, other propellants, such as hydrofluoroalkanes including HFA-134a, HFA-227 (1,1,1,2,3,3,3-heptafluoropropane), or HFA-152a, may be included as secondary components. Further propellants that may be included as secondary components include other hydrofluoroolefins, including HFO-1234yf (2,3,3,3-tetrafluoropropene) and HFO-1234ze(Z) (i.e., cis-HFO-1234ze). Thus, in one or more embodiments, the differences between HFA-152a and HFO-1234ze(E) discussed herein can be advantageously utilized by using small amounts of HFA-152a. The amount of such secondary propellant may comprise 0.1% to 20%, 0.1% to 5%, or 0.1% to 0.5% by weight of the total composition (i.e., total formulation).

[0049] In one or more embodiments, a cosolvent is included. One particularly useful cosolvent is ethanol. In one or more embodiments, ethanol is used as a cosolvent in a solution formulation, i.e., the API is dissolved in the formulation. In one aspect, ethanol can help dissolve the API, but the API may not dissolve in the formulation in the absence of ethanol. When used in a solution formulation, ethanol can be in an amount of at least 0.5%, at least 1%, at least 2%, at least 5%, at least 10%, or at least 15% by weight of the total formulation. When used in a solution formulation, ethanol can be in an amount of up to 20% or up to 15% by weight of the total formulation.

[0050] Additionally, the formulation can include any suitable API. The API can be a drug, a vaccine, a DNA fragment, a hormone, another treatment, or a combination of any two or more APIs. In one or more embodiments, the formulation can include at least two APIs (in certain embodiments, two or three, and in certain embodiments, two) in solution.

[0051] The API may be provided in any form suitable for formulation as a solution. In one or more embodiments, the API may be provided as a solid, such as a powder or micronized powder, or as a liquid, such as a neat solution. Any suitable form of the API that is compatible with the preparation of a solution may be used in the formulations of the present disclosure.

[0052] Exemplary APIs can include those for the treatment of respiratory disorders, for example, bronchodilators such as short- or long-acting beta-agonists, anti-inflammatory agents (e.g., corticosteroids), anti-allergic agents, anti-asthmatic agents, antihistamines, TYK inhibitors, or anticholinergic agents. Exemplary APIs can include terbutaline, ipratropium, oxitropium, tiotropium, beclomethasone, flunisolide, ciclesonide, cromolyn sodium, nedocromil sodium, ketotifen, azelastine, ergotamine, cyclosporine, aclidinium, umeclidinium, glycopyrronium (i.e., glycopyrrolate), salmeterol, formoterol, procaterol, indacaterol, carmoterol, mirveterol, olodaterol, vilanterol, abesiterol, omalizumab, zileuton, insulin, pentamidine, calcitonin, leuprolide, alpha-I-antitrypsin, interferon, triamcinolone, nintedanib, a pharmaceutically acceptable salt or ester of any of the listed drugs, or a mixture of any of the listed drugs, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. For beclomethasone, an exemplary ester is the propionate.

[0053] In all embodiments, the APIs are dissolved in the formulation (i.e., as a solution). When a combination of two or more APIs is used, all of the APIs are present in solution.

[0054] In one embodiment, the formulation has beclomethasone or a pharmaceutically acceptable salt or ester thereof, more specifically beclomethasone dipropionate, as the only API.

[0055] In one embodiment, the formulation has formoterol or a pharmaceutically acceptable salt or ester thereof, more specifically formoterol fumarate, as the only API.

[0056] In one embodiment, the formulation comprises tiotropium or a pharmaceutically acceptable salt or ester thereof, more particularly tiotropium bromide, as the only API.

[0057] In one embodiment, the formulation comprises beclomethasone and formoterol or pharmaceutically acceptable salts or esters thereof, more particularly beclomethasone dipropionate and formoterol fumarate, more particularly both active ingredients dissolved in the formulation.

[0058] The amount of API can be determined by the required dose per actuation and the size of the pMDI metering valve, i.e., the size of the metering chamber 32. The metering chamber 32 can comprise any suitable volume, as further described herein. The concentration of each API is typically 0.0008% to 3.4% by weight, or 0.01% to 1.0% by weight, and sometimes 0.05% to 0.5% by weight, and therefore the pharmaceutical agent comprises a relatively small percentage of the total composition.

[0059] In certain embodiments, typical formulations of the present disclosure include the API in an amount of at least 0.001 milligram per actuation (mg / actuation), or at least 0.001 mg / actuation. In one or more embodiments, typical formulations of the present disclosure include the API in an amount of less than 0.5 mg / actuation.

[0060] In one or more embodiments, typical formulations of the present disclosure include the API in an amount of at least 1 μg / actuation, at least 10 μg / actuation, at least 50 μg / actuation, at least 100 μg / actuation, at least 150 μg / actuation, at least 200 μg / actuation, at least 300 μg / actuation, or at least 400 μg / actuation. In embodiments, typical formulations of the present disclosure include the API in an amount of less than 500 μg / actuation, up to 400 μg / actuation, up to 300 μg / actuation, or up to 200 μg / actuation. In some preferred embodiments, formulations of the present disclosure include the API in an amount of between 80 μg / actuation and 120 μg / actuation.

[0061] Any suitable technique can be utilized to form the inhaler. For example, Figure 5 is a flow chart of one method 100 of forming the inhaler 10. Although described with respect to the inhaler 10 of Figures 1-4, the method 100 can be utilized to form any suitable inhaler. At 102, the formulation is placed into the reservoir 37 of the container 14 using any suitable technique.

[0062] The metering valve 30 can be connected to the container 14 at 104 using any suitable technique. The formulation can be disposed in the reservoir before connecting the metering valve 30 to the container 14 or after connecting the metering valve to the container. In one or more embodiments, the valve stem 34 of the metering valve 30 can be disposed through an aperture 44 in a ferrule 42, and the ferrule can be connected to the end 15 of the container 14 such that the metering valve is at least partially disposed within the container 14. In one or more embodiments, the diaphragm 36 can be disposed within the ferrule 42 such that the opening 38 in the diaphragm is aligned with the aperture 44 in the ferrule, and the valve stem 34 is disposed through the opening in the diaphragm and the aperture in the ferrule.

[0063] At 106, at least one interface within the valve 30 or between the container 14 and the valve can be sealed with a seal using any suitable technique. In one or more embodiments, the seal can be a PTFE seal. Any suitable interface can be sealed utilizing a seal. In one or more embodiments, at least one interface includes the interface between the end 15 of the container 14 and the ferrule 42, which can be sealed with a gasket 72 (e.g., a PTFE gasket). Further, in one or more embodiments, at least one interface includes the interface between the metering valve stem 34 and the diaphragm 36, forming a dynamic seal between the metering valve stem and the diaphragm. Further, in one or more embodiments, at least one interface includes the interface between the metering chamber 32 of the metering valve 30 and the reservoir 37 with the tank seal 56, forming a dynamic seal between the metering valve stem and the tank seal. In such embodiments, a portion of the valve stem 34 (e.g., second portion 52) is disposed through an opening 58 in the tank seal 56. [Example]

[0064] An ethanol solution / suspension was prepared using the required concentration of the target drug. A volume of the solution / suspension was pipetted into a 16 ml canister with an internal coating of fluorinated ethylene propylene. The required amount of propellant was cold transferred into the canister. The ferrule of the metering valve was crimped onto the 16 ml canister. The metering valve was a modified Kindeva™ Spraymiser™ valve core assembly, including a valve stem, spring, outer sealing diaphragm, and inner sealing tank seal, which was fitted to the canister ferrule along with the metering tank and held in place by a valve retainer. The metering valve also contained a PTFE diaphragm made from 1 mm thick PTFE sheet (Material Q400(ET)A Actionplas, UK).

[0065] After assembly, the canisters were evaluated to determine if there were any leaks by determining weight loss. They were then stored valve-side down. After 24 hours, the canisters were tested for functionality by actuating the valve three times to assess proper functioning. After another 24 hours, the canisters were leak tested for up to seven days. After this seven-day period, the canisters were further tested for service life (Examples 1-2 and 5-6) and shot weight (Examples 3-4). After this test was completed, the canisters were again evaluated for leak rate over a seven-day period. Leakage Test

[0066] Twenty-four hours after functional testing, each canister was weighed on a five-decimal balance to determine its initial weight. They were then stored valve-side up at ambient temperature for seven days and re-weighed on the balance. Shot Weight Testing Through the Service Life of Examples 3-4

[0067] Each canister was placed in a Mark 6 actuator (available from Kindeva Drug Delivery) with an exit orifice diameter of 0.3 mm, shaken in a rotary motion for 5 seconds, and actuated once every 5 seconds for a total of 4 times. The canister was removed from the actuator and weighed. The canister was then placed in the actuator, shaken in a rotary motion for 5 seconds, actuated, and weighed. This was repeated until each canister had been actuated and weighed 120 times. The inhaler (canister and actuator) was weighed before and after each shot, and the shot weight was determined from the difference. Results are reported as the number of shots until the shot weight reached approximately steady state, the number of shots that occurred at steady state, and the mean and standard deviation of the shot weight at steady state.

[0068] Delivered Dose Testing Throughout the Service Life of Examples 1-2 and 5-6 Examples 1 and 2

[0069] Using a Mark 6 actuator (Kindeva Drug Delivery) with a 0.3 mm exit orifice diameter, the inhaler was shaken five times at the beginning (shots 1-3) and mid-life (shots 99-102), after which the delivered dose and shot weight were assessed throughout the lifespan at a flow rate of 28.3 ± 0.5 L / min into a unit spray collection apparatus (USCA) fitted with a 25 mm filter (e.g., Whatman Grade 934-AH). Samples were collected using 20 ml of diluent (75:25 methanol:water v / v), filtered through a 0.45 μm PVDF syringe filter, and analyzed by reverse-phase high-performance liquid chromatography with UV detection. The weight of each shot was determined gravimetrically. Examples 5-6

[0070] Using a Mark 6 actuator (Kindeva Drug Delivery) with a 0.4 mm exit orifice diameter, the inhaler was shaken 40 times at the beginning (shots 1-3), mid-life (shots 59-62), and end-life (shots 118-120), followed by actuation at a flow rate of 28.3 ± 0.5 L / min into a unit spray collector (USCA) fitted with a 25 mm filter (e.g., Whatman Grade 934-AH). Samples were collected using 20 ml of diluent (75:25 methanol:water v / v), filtered through a 0.45 μm PVDF syringe filter, and analyzed by reverse-phase high-performance liquid chromatography with UV detection. The weight of each shot was determined gravimetrically. Example 1

[0071] A solution of 1.5873 mg / ml beclomethasone dipropionate (Teva) was prepared in HFO-1234ze containing 8% by weight ethanol. The solution was added to three refillable 16 mL canisters. The canisters were prepared and tested as described above. Example 2

[0072] A solution of 1.5873 mg / ml beclomethasone dipropionate (Teva) was prepared in HFA-152a containing 8% by weight ethanol. The solution was added to three refillable 16 mL canisters. The canisters were prepared and tested as described above. Example 3

[0073] A placebo solution of HFO-1234ze was prepared and added to two 16 mL canisters, which were prepared and tested as described above. Example 4

[0074] A placebo solution of HFA-152a was prepared and added to two 16 mL canisters, which were prepared and tested as described above. Example 5

[0075] A suspension of 1.9126 mg / ml salbutamol sulfate (Teva API, Israel) in HFA-152a was prepared with 5% by weight ethanol. The solution was added to three refillable 16 mL canisters. The canisters were prepared and tested as described above. Example 6

[0076] A suspension of 1.9126 mg / ml salbutamol sulfate (Teva API, Israel) was prepared in HFO-1234ze containing 5% by weight ethanol. The solution was added to three refillable 16 mL canisters. The canisters were prepared and tested as described above.

[0077] The following table contains the initial start-up and end-of-life leak rate results for Examples 1-6. Note that end-of-life leak rate data was not obtained for Examples 1-2.

[0078] [Table 1]

[0079] The table below contains shot weight data over the service life of Examples 3-4 for 120 actuations.

[0080] [Table 2]

[0081] The following table contains data on mcg / actuation for Examples 1-2 and 5-6. Note that no end-of-life data was collected for Examples 1-2.

[0082] [Table 3]

[0083] The following table contains shot weight data over the service life of Examples 1-2 and 5-6. Note that no end-of-life data was collected for Examples 1-2.

[0084] [Table 4]

[0085] The data demonstrated that the use of PTFE as a sealing material produced a metering valve with low initial and end-of-life leakage rates (<175 mg / year), consistent shot weight over the life, and satisfactory delivered dose over the life for both solution and suspension formulations in HFA-152a and HFO-1234ze(Z).

[0086] The present invention is defined in the claims, however, the following non-limiting, non-exhaustive list of examples, any one or more of the features of which may be combined with any one or more features of any other example, embodiment, or aspect described herein.

[0087] Example Ex1. A metered dose inhaler comprising: a container having a reservoir containing a formulation comprising a propellant comprising at least one of a hydrofluoroalkane (HFA) or a hydrofluoroolefin (HFO) and at least one active pharmaceutical ingredient; and a metering valve connected to the container. The metering valve comprises a valve housing having a first end and a second end, the valve housing defining a metering chamber between the first end and the second end of the housing, the metering chamber adapted to receive the formulation from the reservoir. The metering valve further includes a metering valve stem extending through a first end of the valve housing, a metering chamber, and a second end of the valve housing, a diaphragm at least partially disposed within the first end of the valve housing and including an opening, wherein a first portion of the metering valve stem is disposed through the diaphragm opening to form a dynamic seal with the diaphragm, and a tank seal at least partially disposed within the second end of the valve housing and including an opening, wherein a second portion of the metering valve stem is disposed through the tank seal opening to form a dynamic seal with the tank seal, wherein at least one of the diaphragm or the tank seal consists essentially of polytetrafluoroethylene (PTFE).

[0088] Example Ex2. The inhaler of example Ex1, wherein the diaphragm does not include a spring.

[0089] Example Ex3. An inhaler according to example Ex1 or Ex2, wherein the pressure in the reservoir is less than or equal to 20 bar.

[0090] Example Ex4. The inhaler of any one of Examples Ex1-Ex3, wherein at least one of the diaphragm or tank seal has a Shore D hardness of 50-60.

[0091] Example Ex5. The inhaler of any one of Examples Ex1-Ex4, wherein the reservoir and the metering valve stem are aligned along a central longitudinal axis.

[0092] Example Ex6. The inhaler of any one of Examples Ex1-Ex5, wherein the volume of the metering chamber is about 25-100 microliters.

[0093] Example Ex7. The inhaler of any one of Examples Ex1-Ex6, further comprising an actuator having an actuator housing adapted to surround the metering valve and at least a portion of the container.

[0094] Example Ex8. The inhaler of example Ex7, further comprising a ferrule adapted to connect the metering valve to an end of the container, and a gasket disposed between the ferrule and the first end of the container.

[0095] Example Ex9. The inhaler of example Ex8, wherein the gasket consists essentially of PTFE.

[0096] Example Ex10. The inhaler of any one of Examples Ex8-Ex9, further comprising an O-ring disposed between the ferrule and a side of the canister, the O-ring consisting essentially of PTFE.

[0097] Example Ex11. The inhaler of any one of Examples Ex1-Ex10, wherein the diaphragm and tank seal each consist essentially of PTFE.

[0098] Example Ex12. The inhaler of any one of Examples Ex1-Ex11, wherein the metering valve further comprises a second valve housing disposed over the second end of the valve housing.

[0099] Example Ex13. An inhaler according to any one of Examples Ex1 to Ex12, wherein the propellant comprises HFO-1234ze(E).

[0100] Example Ex14. An inhaler according to any one of Examples Ex1 to Ex12, wherein the propellant comprises HFA-152a.

[0101] Example Ex15. The inhaler of any one of Examples Ex1-Ex14, wherein the metering valve has an initial leak rate of 650 mg / year or less.

[0102] Example Ex16. A metered dose inhaler includes a container including a reservoir containing a formulation including a propellant including at least one of an HFA or an HFO and at least one active pharmaceutical ingredient, and a metering valve connected to the container. The metering valve includes a valve housing having a first end and a second end disposed within the reservoir, the valve housing defining a metering chamber between the first end and the second end of the valve housing, the metering chamber adapted to receive the formulation from the reservoir. The metering valve further includes a metering valve stem extending through a first end of the valve housing, a metering chamber, and a second end of the valve housing; a diaphragm at least partially disposed within the first end of the valve housing and including an opening, wherein a first portion of the metering valve stem is disposed through the diaphragm opening to form a dynamic seal with the diaphragm; and a tank seal at least partially disposed within the second end of the valve housing and including an opening, wherein a second portion of the metering valve stem is disposed through the tank seal opening to form a dynamic seal with the tank seal. At least one of the diaphragm or the tank seal consists essentially of polytetrafluoroethylene (PTFE). The metering valve further has a prime position in which the formulation can flow between the reservoir and the metering chamber and the diaphragm is adapted to seal the metering chamber from the outside atmosphere. The metering valve further has an actuated position in which a second portion of the metering valve stem seals against the tank seal and the second end of the valve housing to seal the metering chamber from the reservoir, thereby defining a metered amount of the formulation within the metering chamber, and the metering valve stem includes an outlet chamber that allows the formulation to flow between the metering chamber and the external atmosphere.

[0103] Example Ex17. The inhaler of example Ex16, wherein the diaphragm does not include a spring.

[0104] Example Ex18. The inhaler of any one of Examples Ex16-Ex17, wherein the pressure in the reservoir is less than or equal to 20 bar.

[0105] Example Ex19. The inhaler of any one of Examples Ex16-Ex18, wherein at least one of the diaphragm or tank seal has a Shore D hardness of 50-60.

[0106] Example Ex20. The inhaler of any one of Examples Ex16-Ex19, wherein the volume of the metering chamber is about 25-100 microliters.

[0107] Example Ex21. The inhaler of any one of examples Ex16-Ex20, further comprising an actuator having an actuator housing adapted to surround the metering valve and at least a portion of the container.

[0108] Example Ex22. The inhaler of example Ex21, further comprising a ferrule adapted to connect the metering valve to an end of the container, and a gasket disposed between the ferrule and the first end of the container.

[0109] Example Ex23. The inhaler of example Ex22, wherein the gasket consists essentially of PTFE.

[0110] Example Ex24. The inhaler of any one of Examples Ex22-Ex23, further comprising an O-ring disposed between the ferrule and a side of the canister, the O-ring consisting essentially of PTFE.

[0111] Example Ex25. The inhaler of any one of Examples Ex16-Ex24, wherein the diaphragm and tank seal each consist essentially of PTFE.

[0112] Example Ex26. An inhaler according to any one of Examples Ex16 to Ex25, wherein the propellant comprises HFO-1234ze(E).

[0113] Example Ex27. An inhaler according to any one of Examples Ex16 to Ex25, wherein the propellant comprises HFA-152a.

[0114] Example Ex28. An inhaler according to any one of Examples Ex16 to Ex27, wherein the metering valve has an initial leak rate of 650 mg / year or less.

[0115] Example Ex29. A method comprising: placing a formulation comprising a propellant comprising at least one of a hydrofluoroalkane (HFA) or a hydrofluoroolefin (HFO) and at least one active pharmaceutical ingredient into a reservoir of a container; connecting a metering valve to the container; and sealing at least one interface within the valve or between the container and the valve with a PTFE seal.

[0116] Example Ex30. The method of example Ex29, wherein the formulation is placed in the container before connecting the metering valve to the container.

[0117] Example Ex31. The method of example Ex29, wherein the formulation is placed in the container after connecting a metering valve to the container.

[0118] Example Ex32. The method of any one of examples Ex29-Ex31, wherein connecting the metering valve to the container comprises: placing a valve stem of the metering valve through an aperture in a ferrule; and connecting the ferrule to an end of the container such that the metering valve is at least partially disposed within the container.

[0119] Example Ex33. The method of example Ex32, wherein sealing at least one interface comprises sealing the interface between the end of the container and the ferrule with a PTFE gasket.

[0120] Example Ex34. The method of example Ex33, wherein connecting the metering valve to the container further comprises placing the diaphragm within the ferrule such that the opening in the diaphragm is aligned with the aperture in the ferrule and the valve stem is positioned through the opening in the diaphragm and the aperture in the ferrule.

[0121] Example Ex35. The method of example Ex34, wherein sealing at least one interface includes sealing an interface between the metering valve stem and the diaphragm to form a dynamic seal between the metering valve stem and the diaphragm.

[0122] Example Ex36. The method of any one of examples Ex32-Ex35, wherein sealing at least one interface includes sealing an interface between a metering chamber of the metering valve and the reservoir with the tank seal to form a dynamic seal between the metering valve stem and the tank seal, wherein a portion of the valve stem is disposed through an opening in the tank seal.

[0123] All references and publications cited herein are expressly incorporated by reference in their entirety into this disclosure, except to the extent they may directly contradict this disclosure. Exemplary embodiments of the present disclosure have been described, and reference has been made to possible variations within the scope of the disclosure. These and other variations and modifications of the present disclosure will be apparent to those skilled in the art without departing from the scope of the disclosure, and it should be understood that the present disclosure is not limited to the exemplary embodiments described herein. Accordingly, the present disclosure should be limited only by the claims provided below.

Claims

1. a container comprising a reservoir containing a formulation comprising a propellant comprising at least one of a hydrofluoroalkane (HFA) or a hydrofluoroolefin (HFO) and at least one active pharmaceutical ingredient; a metering valve connected to the container; 1. A metered dose inhaler comprising: a valve housing having a first end and a second end, the valve housing defining a metering chamber between the first end and the second end of the housing, the metering chamber adapted to receive the formulation from the reservoir; a metering valve stem extending through the first end of the valve housing, a metering chamber, and a second end of the valve housing; a diaphragm at least partially disposed within the first end of the valve housing and having an opening, wherein a first portion of the metering valve stem is disposed through the diaphragm opening to form a dynamic seal with the diaphragm; a tank seal at least partially disposed within the second end of the valve housing and having an opening, wherein a second portion of the metering valve stem is disposed through the tank seal opening to form a dynamic seal with the tank seal; and Equipped with At least one of the diaphragm or the tank seal consists essentially of polytetrafluoroethylene (PTFE). Metered dose inhaler.

2. 10. The inhaler of claim 1, wherein the diaphragm does not include a spring.

3. 3. The inhaler of claim 1 or 2, wherein at least one of the diaphragm or the tank seal has a hardness of 50 to 60 Shore D.

4. An inhaler according to any one of claims 1 to 3, further comprising an actuator comprising an actuator housing adapted to surround the metering valve and at least a portion of the container.

5. a ferrule adapted to connect the metering valve to an end of the container; a gasket disposed between the ferrule and the first end of the container, the gasket consisting essentially of PTFE; The inhaler of claim 4 further comprising:

6. 6. The inhaler of claim 5, further comprising an O-ring disposed between the ferrule and a side of the container, the O-ring consisting essentially of PTFE.

7. An inhaler according to any one of claims 1 to 6, wherein the diaphragm and the tank seal each consist essentially of PTFE.

8. An inhaler according to any preceding claim, wherein the propellant comprises HFO-1234ze(E).

9. An inhaler according to any one of claims 1 to 7, wherein the propellant comprises HFA-152a.

10. a container comprising a reservoir containing a formulation comprising a propellant comprising at least one of an HFA or an HFO and at least one active pharmaceutical ingredient; a metering valve connected to the container; 1. A metered dose inhaler comprising: a valve housing having a first end and a second end disposed within the reservoir, the valve housing defining a metering chamber between the first end and the second end, the metering chamber adapted to receive the formulation from the reservoir; a metering valve stem extending through the first end of the valve housing, a metering chamber, and a second end of the valve housing; a diaphragm at least partially disposed within the first end of the valve housing and having an opening, wherein a first portion of the metering valve stem is disposed through the diaphragm opening to form a dynamic seal with the diaphragm; a tank seal at least partially disposed within the second end of the valve housing and having an opening, wherein a second portion of the metering valve stem is disposed through the tank seal opening to form a dynamic seal with the tank seal; and Equipped with at least one of the diaphragm or the tank seal consists essentially of polytetrafluoroethylene (PTFE); the metering valve further has a prime position in which the formulation can flow between the reservoir and the metering chamber and the diaphragm is adapted to seal the metering chamber from the outside atmosphere; the metering valve further has an actuated position in which the second portion of the metering valve stem seals against the tank seal and the second end of the valve housing to seal the metering chamber from the reservoir, thereby defining a metered amount of formulation within the metering chamber, and the metering valve stem includes an outlet chamber that allows the formulation to flow between the metering chamber and the external atmosphere. Metered dose inhaler.

11. 11. The inhaler of claim 10, wherein the diaphragm does not include a spring.

12. An inhaler according to claim 10 or 11, wherein at least one of the diaphragm or the tank seal has a hardness of 45 to 80 Shore D.

13. An inhaler according to any one of claims 10 to 12, further comprising an actuator comprising an actuator housing adapted to surround the metering valve and at least a portion of the canister.

14. a ferrule adapted to connect the metering valve to an end of the container; a gasket disposed between the ferrule and the first end of the container, the gasket consisting essentially of PTFE; 14. The inhaler of claim 13, further comprising:

15. 15. The inhaler of claim 14, further comprising an O-ring disposed between the ferrule and a side of the container, the O-ring consisting essentially of PTFE.

16. An inhaler according to any one of claims 10 to 15, wherein the diaphragm and the tank seal each consist essentially of PTFE.

17. An inhaler according to any one of claims 10 to 16, wherein the propellant comprises HFO-1234ze(E) or HFA-152a.

18. disposing a formulation comprising at least one active pharmaceutical ingredient and a propellant comprising at least one of a hydrofluoroalkane (HFA) or a hydrofluoroolefin (HFO) in a reservoir of the container; connecting a metering valve to said container; sealing at least one interface within the valve or between the container and the valve with a PTFE seal; A method comprising:

19. connecting the metering valve to the container; placing a valve stem of the metering valve through an aperture in a ferrule; connecting the ferrule to an end of the container such that the metering valve is at least partially disposed within the container; 20. The method of claim 18, comprising:

20. 20. The method of claim 19, wherein sealing at least one interface comprises sealing the interface between the end of the container and the ferrule with a PTFE gasket.

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