Medicament delivery device, cover, and methods of medicament delivery

Abstract

A cover is provided for actuating a medicament delivery device. The cover includes a first end portion and a second end portion. The second end portion is configured to surround a delivery member of the medicament delivery device in a storage configuration. The cover also includes a wall that extends between the first end portion and the second end portion. An inner surface of the wall at least partially defines an interior volume and is configured to move an actuator of the medicament delivery device when the delivery member is positioned outside of the interior volume and the medicament delivery device is moved within the interior volume of the cover.

Description

Attorney Docket No. INMD-196 / 01WO   MEDICAMENT DELIVERY DEVICE, COVER, AND METHODS OF MEDICAMENT DELIVERY Cross Reference to Related Application

[0001] This application claims priority from U.S. Provisional Application Serial No. 63 / 546,453, filed October 30, 2023, the contents of which are incorporated herein in their entirety for all purposes. Background

[0002] The embodiments described herein relate to medicament delivery systems. More particularly, the embodiments described herein relate to systems and methods for actuating a medicament delivery device.

[0003] Known treatments for certain medical conditions include the introduction of a therapeutic dose of a medicament to a patient via a medicament delivery device. For example, both dry powder inhalers and nasal delivery devices can be used to deliver a medicament in a powdered form (e.g., spray dried or lyophilized) to the respiratory tract of the patient. Known medicament delivery devices include a cap that covers the delivery member (e.g., a mouthpiece, a nostril piece, or a needle). The cap can protect the user from a sharp hazard and the delivery member from damage, obstruction, and / or contamination.

[0004] With some known medicament delivery devices, the delivery of the therapeutic dose involves actuating the medicament delivery device by moving an actuator, such as a button or lever to prepare the dose for delivery. For example, some single-dose dry powder inhalers use a capsule that contains a single therapeutic dose of the medicament. Prior to use, the capsule containing the single dose of the medicament is placed within the inhaler body. An actuator is then moved (e.g., a button is pressed) to pierce or otherwise rupture the capsule. The medicament can then be drawn from the medicament delivery device and into the user’s lungs by an inhalation. Accordingly, in some known medicament delivery devices, the actuator is covered by the cap to preclude an unintended actuation of the medicament delivery device and the resultant waste of any medicament contained therein. 1  Attorney Docket No. INMD-196 / 01WO

[0005] To move some known actuators of the medicament delivery devices requires a certain degree of manual dexterity that can be lacking in certain patients. For example, patients experiencing scleroderma or rheumatoid arthritis may have diminished manual dexterity and may be unable to reliably apply sufficient force in a coordinated manner to the actuators of the medicament delivery device to move the actuators to allow the dispensing of the medicament. This can, in turn, preclude the usability to receive the therapeutic dose of the medicament.

[0006] Thus, a need exists for new and improved systems and methods for covering a portion of a medicament delivery device, e.g., a dry powder inhaler, for actuating the medicament delivery device, and for delivering a dose of the medicament. Summary

[0007] This summary introduces certain aspects of the embodiments described herein to provide a basic understanding. This summary is not an extensive overview of the inventive subject matter, and it is not intended to identify key or critical elements or to delineate the scope of the inventive subject matter.

[0008] In some embodiments, the present disclosure is directed to a cover such as for a medicament delivery device. The cover includes a first end portion and a second end portion. The second end portion is configured to surround a delivery member of the medicament delivery device on a condition that the cover is coupled to the medicament delivery device in a storage configuration. The cover also includes a wall that extends between the first end portion and the second end portion. An inner surface of the wall at least partially defines an interior volume. The inner surface of the wall is configured to move an actuator of the medicament delivery device on a condition that the delivery member of the medicament delivery device is positioned outside of the interior volume and that the medicament delivery device is moved within the interior volume of the cover.

[0009] In some embodiments, an outer surface of the second end portion is configured to engage a support surface such that a longitudinal axis of the cover is maintained orthogonal to the support surface. 2  Attorney Docket No. INMD-196 / 01WO

[0010] In some embodiments, the outer surface of the second end portion is one of planar or concave.

[0011] In some embodiments, a ratio of a surface area of the outer surface of the second end portion to a longitudinal length of the cover is in a range of 8:1 to 15:1.

[0012] In some embodiments, the first end portion defines an opening into the interior volume. A ratio of a major axis of the outer surface of the second end portion to a major axis of the opening is in a range of 1:1.2 to 1:1.5.

[0013] In some embodiments, the inner surface of the wall includes a ramped portion configured to move the actuator.

[0014] In some embodiments, the actuator is a first actuator, and the ramped portion is a first ramped portion. The inner surface of the wall includes a second ramped portion configured to move a second actuator of the medicament delivery device on a condition that the delivery member of the medicament delivery device is positioned outside of the interior volume and that the medicament delivery device is moved within the interior volume of the cover.

[0015] In some embodiments,  the inner surface of the wall includes a rib portion. The rib portion extends radially inward from the inner surface of the wall. The rib portion is configured to slidingly engage the actuator to move the actuator.

[0016] In some embodiments, the rib portion has a maximal width that is at least five percent and less than 15 percent of a maximal width of the actuator of the medicament delivery device.

[0017] In some embodiments, the inner surface of the wall includes a shoulder. The shoulder extends radially inward from the inner surface of the wall. The shoulder is positioned to limit a longitudinal movement of the medicament delivery device within the interior volume toward the second end portion on the condition that the delivery member of the medicament delivery device is positioned outside of the interior volume. 3  Attorney Docket No. INMD-196 / 01WO

[0018] In some embodiments, the first end portion is configured to cover the actuator on the condition that the cover is coupled to the medicament delivery device in a storage configuration.

[0019] In some embodiments, the actuator is coupled to a body member of the medicament delivery device. The actuator is configured to move relative to the body member of the medicament delivery device as the medicament delivery device is moved within the interior volume of the cover.

[0020] In some embodiments, the actuator is configured to move radially inward relative to the body member of the medicament delivery device as the medicament delivery device is moved within the interior volume of the cover.

[0021] In some embodiments, the first end portion defines an opening into the interior volume. The opening is sized to receive a base of the medicament delivery device.

[0022] In some embodiments, the base is positioned between the second end portion of the cover and the delivery member of the medicament delivery device on a condition that the medicament delivery device is in an actuated configuration.

[0023] In some embodiments, the first end portion of the cover surrounds the base on the condition that the delivery member is positioned outside the interior volume.

[0024] In some embodiments, the medicament delivery device is an inhaler, and the delivery member of the medicament delivery device is a mouthpiece.

[0025] In some embodiments, the medicament delivery device is an intranasal delivery device, and the delivery member of the medicament delivery device is a nozzle.

[0026] In some embodiments, the medicament delivery device is an injector, and the delivery member of the medicament delivery device is a needle.

[0027] In some embodiments, the present disclosure is directed to a method for enabling a medicament delivery device and / or delivering a medicament contained therein. The method includes removing a body member of the medicament delivery device from within an interior 4  Attorney Docket No. INMD-196 / 01WO   volume of a cover to expose a delivery member. The body member and the delivery member are removed via an opening defined at a first end portion of the cover. The method also includes placing a second end portion of the cover onto a support surface such that the opening of the cover is exposed and placing a base of the body member within the interior volume while maintaining the delivery member outside of the interior volume. Additionally, the method includes moving the body member within the interior volume such that an actuator of the medicament delivery device is moved to enable the medicament delivery device. The medicament delivery device in one embodiment, is a dry powder inhaler (DPI). In a further embodiment, the DPI is capsule-based.

[0028] In some embodiments, placing the second end portion of the cover onto the support surface includes placing a support interface of an outer surface of the second end portion onto the support surface thereby causing a longitudinal axis of the cover to be orthogonal to the support surface.

[0029] In some embodiments, removing the body member of the medicament delivery device from within the interior volume includes separating the cover from the medicament delivery device.

[0030] In some embodiments, moving the body member within the interior volume includes  applying a force to at least one of the delivery member or the body member in a longitudinal direction toward the support surface.

[0031] In some embodiments, the application of the force moves the actuator into contact with a ramped portion of the cover. The ramped portion moves the actuator relative to the body member to enable the medicament delivery device.

[0032] In some embodiments, the application of the force moves the actuator slidingly along a rib portion of the cover.

[0033] In some embodiments, the method includes maintaining the force applied to at least one of the delivery member or the body member until the base of the body member contacts a shoulder of the cover within the interior volume. The shoulder limits movement of the medicament delivery device within the interior volume toward the second end portion. 5  Attorney Docket No. INMD-196 / 01WO

[0034] In some embodiments the medicament delivery device is an inhaler, and the delivery member of the inhaler is a mouthpiece. In a further embodiment, the inhaler is a DPI. In even a further embodiment, the DPI is a capsule-based DPI.

[0035] In some embodiments, the method includes positioning a medicament container within the body member of the medicament delivery device prior to placing the base of the body member within the interior volume. The medicament container, in one embodiment, is a capsule. In a further embodiment, the capsule comprises a dry powder composition comprising an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt of a compound of Formula (I) or (II).

[0036] In some embodiments the method includes inhaling on the mouthpiece, after the dry powder inhaler is enabled, to deliver the dry powder composition in aerosolized form to the lungs of a patient in need of treatment.

[0037] In some embodiments, the present disclosure is directed to a medicament delivery system. The medicament delivery system includes a medicament delivery device that has a body member, a delivery member coupled to the body member, and an actuator that is movably coupled to the body member. The medicament delivery system also includes a medicament container assembly configured to be positioned within the body member. The medicament container assembly includes a therapeutic dose of compound of Formula (I) or (II), present in a dry powder composition. The dry powder composition in embodiments described herein comprises a compound of Formula (I) or (II). In a preferred embodiment, the compound present in the dry powder composition is treprostinil palmitil. Additionally, the medicament delivery system includes a cover that has a first end portion, a second end portion, and a wall extending between the first end portion and the second end portion. The second end portion is configured to surround the delivery member of the medicament delivery device on a condition that the cover is coupled to the medicament delivery device in a storage configuration. An inner surface of the wall at least partially defines an interior volume. The inner surface of the wall is configured to move the actuator of the medicament delivery device on a condition that the delivery member of the medicament delivery device is positioned outside of the interior volume and that the medicament delivery device is moved within the interior volume of the cover. 6  Attorney Docket No. INMD-196 / 01WO

[0038] In some embodiments, a method for treating pulmonary hypertension includes removing a body member of a dry powder inhaler from within an interior volume of a cover to expose a mouthpiece. The body member and the mouthpiece are removed via an opening defined by the cover. A base of the body member is moved through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a medicament container within the dry powder inhaler. The medicament container contains a dry powder composition comprising an effective amount of a compound of Formula (I):   or anacceptable salt thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. The method further includes inhaling on the mouthpiece, after moving the base, to deliver an aerosolized mixture of the dry powder composition to the lungs of a patient in need of treatment. In a further embodiment, R1is hexadecyl. In even a further embodiment, the compound of Formula (I) is treprostinil palmitil.

[0039] In some embodiments, the medicament container is a capsule and the method includes loading, before the moving the base of the body member, the capsule into the dry powder inhaler.

[0040] In some embodiments, the opening is defined at a first end portion of the cover and the method further includes placing, before the moving a base of the body member through the opening and within the interior volume, a second end portion of the cover onto a support surface such that the opening of the cover is exposed.

[0041] In some embodiments, the dry powder composition comprises treprostinil palmitil. In some embodiments, the treprostinil palmitil is a crystal Form I. In other embodiments, the treprostinil palmitil is a crystal Form II. 7  Attorney Docket No. INMD-196 / 01WO

[0042] In some embodiments, the inhaling on the mouthpiece includes completing 1 to 5 inhalations (i.e., puffs).

[0043] In some embodiments, the base of dry powder inhaler is at first end of the dry powder inhaler and the mouthpiece is at a second end of the dry powder inhaler.

[0044] In some embodiments, a method for delivering a dry powder composition to the lungs of a patient in need of treatment includes removing a body member of a dry powder inhaler from within an interior volume of a cover to expose a mouthpiece. The body member and the mouthpiece are removed via an opening defined by the cover. The body member is moved through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a medicament container within the dry powder inhaler. The medicament container contains the dry powder composition. The moving is performed while maintaining the mouthpiece outside of the interior volume. The method further includes inhaling on the mouthpiece, after moving the base, to deliver an aerosolized mixture of the dry powder composition to the lungs of the patient in need of treatment.

[0045] In some embodiments, the medicament container is a capsule comprising a compound of Formula (I)  or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. In a further embodiment, R1is hexadecyl. In even a further embodiment, the compound of Formula (I) is treprostinil palmitil.

[0046] In some embodiments, the method further comprises loading, before the moving the body member through the opening and within the interior volume, the capsule into the dry powder inhaler. 8  Attorney Docket No. INMD-196 / 01WO

[0047] In some embodiments, a method for treating pulmonary hypertension in a patient in need of treatment includes performing the following operations once daily during an administration period: (a) Removing a body member of a dry powder inhaler from within an interior volume of a cover to expose a mouthpiece. The body member and the mouthpiece are removed via an opening defined by the cover. (b) Moving a base of the body member through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a medicament container within the dry powder inhaler. The medicament container contains a dry powder composition. (c) Inhaling on the mouthpiece, after moving the base, to deliver the dry powder composition in aerosolized form to the lungs of the patient. The dry powder composition comprises an effective amount of a compound of Formula (I):    or an acceptable salt thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. The administration period comprises (i) a titration period and (ii) a maintenance period. During the titration period, the dry powder composition comprises a starting dose of about 80-160 μg of the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, and the starting dose is titrated to a maximum tolerated dose (MTD) of 1280 μg or less. During the maintenance period, the MTD is present in the dry powder composition. In some embodiments, R1is hexadecyl. In a further embodiment, the compound of Formula (I) is treprostinil palmitil. Brief Description of the Drawings

[0048] FIG.1 is a perspective view of a medicament delivery system in a storage configuration in which a medicament delivery device is received by a cover, according to an embodiment.

[0049] FIG.2 is a perspective view of the cover of FIG.1. 9  Attorney Docket No. INMD-196 / 01WO

[0050] FIG.3 is a cross-sectional view of the cover of FIG.1 taken at line x1-x1 in FIG.2.

[0051] FIG.4 is a cross-sectional view of the cover of FIG.1 taken at line x2-x2 in FIG.2.

[0052] FIG. 5 is a cross-sectional view of the medicament delivery system of FIG. 1 in the storage configuration taken at line x3-x3.

[0053] FIG. 6 is a perspective view of the medicament delivery system in a ready configuration.

[0054] FIG. 7 is a cross-sectional view of the medicament delivery system of FIG. 6 in the ready configuration taken at line x4-x4.

[0055] FIG.8 is a cross-sectional view of the medicament delivery system of FIG.6 taken at line x5-x5.

[0056] FIG.9 is a perspective view of the medicament delivery system in a partially actuated configuration.

[0057] FIG.10 is a cross-sectional view of the medicament delivery system of FIG.9 taken at line x6-x6.

[0058] FIG. 11 is a perspective view of the medicament delivery system in an actuated configuration.

[0059] FIG.12 is a cross-sectional view of the medicament delivery system of FIG.9 taken at line x7-x7.

[0060] FIG.13 is an illustration of the medicament delivery system transitioning from a stored configuration to an actuated configuration with the cover made transparent for clarity.

[0061] FIG.14 is an illustration of the medicament delivery system being used to deliver a dry powder in aerosolized form, according to an embodiment. 10  Attorney Docket No. INMD-196 / 01WO

[0062] FIG. 15 is a flow chart of a method for enabling a medicament delivery device and optionally delivering a medicament, according to an embodiment.

[0063] FIG. 16 is a flow chart of a method of delivering a medicament, according to an embodiment Detailed Description

[0064] Generally, the present disclosure is directed to a dual-purpose cover that protects the delivery member (e.g., a mouthpiece, a nasal piece, or a needle) of the medicament delivery device in a storage configuration and can also be used to actuate the medicament delivery device in the absence of the user having a degree of manual dexterity.

[0065] As described herein, the cover is shaped to surround the delivery member of the medicament delivery device in a storage configuration to protect the delivery member and / or the user. For example, the cover can be shaped to surround the mouthpiece of a single-dose, dry powder inhaler to protect the mouthpiece from damage, obstruction, and / or contamination. Additionally, the cover is shaped so that once it is removed from the inhaler, it can be inverted and placed open side up on a table or other support surface. The base of the inhaler can then be placed into the cover with the mouthpiece exposed. With the base positioned within the cover, the buttons that must be pressed to actuate the inhaler are also within the cover and the inhaler is supported by the contact between the cover and the table. The user can then push down on the inhaler causing the base of the inhaler to move further into the cover in the direction of the table. Due to the shape of the cover, the movement of the inhaler within the cover causes the buttons to move, thereby actuating the inhaler to enable delivery of the medicament. The user can then draw the medicament from within the inhaler via an inhalation. It should be appreciated that pressing down on the inhaler requires significantly less manual dexterity than is required to press on the actuation buttons directly. Accordingly, the use of the cover to actuate the inhaler facilitates access to the medicament by those experiencing a loss of manual dexterity.

[0066] In one aspect, a method for treating pulmonary hypertension (PH) in a patient in need thereof is described herein. The method includes administering an effective amount of one of the dry powder compositions disclosed herein to the lungs of the patient via a dry powder inhaler 11  Attorney Docket No. INMD-196 / 01WO   (DPI), once daily during an administration period. The dry powder composition comprises a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. The administering comprises removing a body member of the dry powder inhaler from within an interior volume of a cover to expose a mouthpiece. The body member and the mouthpiece are removed via an opening defined by the cover. The body member is moved through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a capsule within the dry powder inhaler that contains the dry powder composition. The method further includes inhaling on the mouthpiece to (i) aerosolize the dry powder composition via the DPI to provide an aerosolized dry powder composition, and (ii) administer the aerosolized dry powder composition to the lungs of the patient by the DPI.

[0067] The World Health Organization (WHO) has classified PH into five groups. Group 1 PH includes pulmonary arterial hypertension (PAH), idiopathic pulmonary arterial hypertension (IPAH), familial pulmonary arterial hypertension (FPAH), and pulmonary arterial hypertension associated with other diseases (APAH). For example, pulmonary arterial hypertension associated with collagen vascular disease (e.g., scleroderma), congenital shunts between the systemic and pulmonary circulation, portal hypertension and / or HIV infection are included in group 1 PH. Group 2 PH includes pulmonary hypertension associated with left heart disease, e.g., atrial or ventricular disease, or valvular disease (e.g., mitral stenosis). WHO group 3 pulmonary hypertension is characterized as pulmonary hypertension associated with lung diseases, e.g., chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and / or hypoxemia. Group 4 pulmonary hypertension is pulmonary hypertension due to chronic thrombotic and / or embolic disease. Group 4 PH is also referred to as chronic thromboembolic pulmonary hypertension. Group 4 PH patients experience blocked or narrowed blood vessels due to blood clots. Group 5 PH is the “miscellaneous” category, and includes PH caused by blood disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis) and / or metabolic disorders (e.g., thyroid disease, glycogen storage disease).

[0068] The methods provided herein can be used to treat group 1, group 2, group 3, group 4 or group 5 PH patients, as characterized by the WHO. For example, in some embodiments, the pulmonary hypertension treated is chronic thromboembolic pulmonary hypertension. In some embodiments, the pulmonary hypertension is group 1 PH, as characterized by the WHO. In a 12  Attorney Docket No. INMD-196 / 01WO   further embodiment, the method provided herein is a method for treating treated is pulmonary arterial hypertension (PAH). In a further embodiment, the PAH is class I PAH, class II PAH, class III PAH, or class IV PAH, as characterized by the New York Heart Association (NYHA). Accordingly, in some embodiments, the PAH is class I PAH; in other embodiments, the PAH is class II PAH; in additional embodiments, the PAH is class III PAH; in yet further embodiments, the PAH is class III PAH, as each class is characterized by the NYHA.

[0069] As used herein, the term “treating” includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (3) relieving the condition (e.g., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). In some embodiments, “treating” refers to inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof). In some embodiments, “treating” refers to relieving the condition (for example, by causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant as compared to the state or condition of the same patient before the treatment, or as compared to the state or condition of an untreated control patient, or the benefit is at least perceptible to the patient or to the physician.

[0070] “Effective amount” means an amount of a dry powder composition of the present disclosure that is sufficient to result in the desired therapeutic response. The “effective amount” is the amount of the compound of Formula (I) or (II) that is administered in a single dosing session.

[0071] As used herein, the term “about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10 percent of that referenced numeric indication. For example, the language “about 50” covers the range of 45 to 55. Similarly, the language “about 5” covers the range of 4.5 to 5.5. 13  Attorney Docket No. INMD-196 / 01WO

[0072] Further, specific words chosen to describe one or more embodiments and optional elements or features are not intended to limit the invention. For example, spatially relative terms— such as “beneath”, “below”, “lower”, “above”, “upper”, “proximal”, “distal”, and the like—may be used to describe the relationship of one element or feature to another element or feature as illustrated in the figures. These spatially relative terms are intended to encompass different positions (i.e., translational placements) and orientations (i.e., rotational placements) of a device in use or operation in addition to the position and orientation shown in the figures. For example, if a device in the figures is turned over, elements described as “below” or “beneath” other elements or features would then be “above” or “over” the other elements or features. Thus, the term “below” can encompass both positions and orientations of above and below. A device may be otherwise oriented (e.g., rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Likewise, descriptions of movement along (translation) and around (rotation) various axes includes various spatial device positions and orientations.

[0073] Similarly, geometric terms, such as “parallel”, “perpendicular”, “round”, or “square”, are not intended to require absolute mathematical precision, unless the context indicates otherwise. Instead, such geometric terms allow for variations due to manufacturing or equivalent functions. For example, if an element is described as “round” or “generally round,” a component that is not precisely circular (e.g., one that is slightly oblong or is a many-sided polygon) is still encompassed by this description.

[0074] In addition, the singular forms “a”, “an”, and “the” are intended to include the plural forms as well, unless the context indicates otherwise. The terms “comprises”, “includes”, “has”, and the like specify the presence of stated features, steps, operations, elements, components, etc. but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, or groups.

[0075] FIGS. 1-13 depict a medicament delivery system 1000 according to an embodiment. The medicament delivery system 1000 includes a dual-purpose cover 1100 and a medicament delivery device 1200. The medicament delivery device 1200 includes a body member 1230, a delivery member 1210 (FIG.5) coupled to the body member 1230, and at least one actuator 1220 that is movably coupled to the body member 1230. The actuator 1220 includes a piercing member 14  Attorney Docket No. INMD-196 / 01WO   or puncturer that pierces a medicament container assembly 1250 (see FIG. 12) when moved to prepare the medicament delivery device to deliver the medicament. Although the medicament delivery device 1200 is shown as having two opposing actuators 1220, in other embodiments a medicament delivery device may only have one actuator. The cover 1100 is shaped to protect the delivery member 1210 on a condition that the cover 1100 is coupled to the medicament delivery device 1200 in a storage configuration, such as depicted in FIGS.1 and 5. Specifically, the cover 1100 includes an internal protrusion that matingly fits within the delivery member 1210 to limit or prevent ingress of contaminants into the delivery member 1210. In other embodiments, the cover can include a structure that matingly surrounds the delivery member to limit or prevent ingress of contaminants into the delivery member. For example, in some embodiments, the medicament delivery device can be an injector and cover can include a needle guard that covers the needle.

[0076] Insofar as the cover 1100 is a dual-purpose cover, the cover 1100 is also shaped for use in actuating the medicament delivery device 1200 as described herein. In some embodiments, the medicament delivery system 1000 also includes a medicament container assembly 1250 (FIG.7) that is configured to be positioned within the body member 1230 of the medicament delivery device 1200. The medicament container assembly 1250 can be of any suitable form and include any suitable medicament. For example, in some embodiments the medicament container assembly 1250 can be a capsule or blister containing a therapeutic dose of a dry powder composition, such as a treprostinil prodrug or any other formulations as described herein. In other embodiments, the medicament container assembly can include multiple doses (e.g., a set of blisters with a puncturable foil seal) containing any of the formulations described herein.

[0077] The cover 1100 defines a longitudinal axis ALO (FIG.3), a first lateral axis ALA1 (FIG. 3), and a second lateral axis ALA2(FIG. 4). In some embodiments, the cover 1100 can have a longitudinal length extending along the longitudinal axis ALO, a width extending along the first lateral axis ALA1, and / or a thickness extending along the second lateral axis ALA2. The cover 1100 includes a first end portion 1110, a second end portion 1130, and a wall 1150 that extends between the first end portion 1110 and the second end portion 1130. As depicted in FIGS.1 and 5, the first end portion 1110 is configured to cover the actuator 1220 of the medicament delivery device 1200 on a condition that the cover 1100 is coupled to the medicament delivery device 1200 in the storage configuration. Accordingly, in the storage configuration, the cover 1100 precludes the applying 15  Attorney Docket No. INMD-196 / 01WO   of a force to the actuator 1220, thereby precluding the inadvertent or premature actuation of the medicament delivery device 1200. The storage configuration of the medicament delivery system 1000 is, for example, depicted in FIGS.1 and 5.

[0078] As depicted by the cross-sectional view of FIG.5, the second end portion 1130 of the cover 1100 is configured to surround the delivery member 1210 of the medicament delivery device 1200 on a condition that the cover 1100 is coupled to the medicament delivery device 1200 in the storage configuration. In the storage configuration, the second end portion 1130 of the cover 1100 isolates the delivery member 1210 from a volume surrounding the medicament delivery system 1000. Accordingly, in the storage configuration, the second end portion 1130 protects the delivery member 1210 inserted therein from damage, obstruction, and / or contamination. Further, the second end portion 1130 also precludes the delivery of the medicament to the user via the delivery member 1210 on a condition that the delivery member 1210 is inserted therein.

[0079] The wall 1150 extends between the first end portion 1110 and the second end portion 1130 to form the cover 1100 as a substantially hollow body (i.e., that defines an interior volume). The wall 1150 surrounds the longitudinal axis ALO defined by the cover 1100. The wall 1150 includes an outer surface 1151 separated from an inner surface 1152 by a wall thickness. The inner surface 1152 of the wall 1150 at least partially defines an interior volume 1170 (FIG.2) of the cover 1100. The inner surface 1152 of the wall 1150 is also configured (e.g., shaped or formed) to move the actuator 1220 of the medicament delivery device 1200 on a condition that the delivery member 1210 of the medicament delivery device 1200 is positioned outside the interior volume 1170 (e.g., is removed from the second end portion 1130 as depicted in FIGS. 6-12) and that another portion the medicament delivery device 1200 is moved within the interior volume 1170. In other words, the inner surface 1152 of the wall 1150 is shaped to engage the actuator 1220 so that a movement of the body member 1230 of the medicament delivery device 1200 along the longitudinal axis ALO results in a force applied to the actuator 1220. The actuator 1220 can then move in response to the force applied by the cover 1100 to actuate the medicament delivery device 1200. Said another way, the engagement between the actuator 1220 and the inner surface 1152 of the wall 1150 can result in a movement of the actuator along the first lateral axis ALA1 (e.g., radially inward) in response to the movement of the body member 1230 along the longitudinal axis ALO. 16  Attorney Docket No. INMD-196 / 01WO

[0080] In some embodiments, a portion of the outer surface 1151 of the wall 1150 at the second end portion 1130 is configured to engage a support surface SS (FIGS.7, 10, and 12). Said another way, the outer surface 1151 of the second end portion 1130 can define a support interface 1134 that is shaped to engage the support surface SS. The support surface SS can, for example, be a table, a counter or other similar structure having sufficient strength and rigidity to resist a force applied to the medicament delivery device 1200 toward the support surface SS. The outer surface 1151 of the second end portion 1130 can be configured such that the longitudinal axis ALOof the cover 1100 is maintained orthogonal to the support surface SS (i.e., maintained orthogonal to a substantially planar support surface SS), such as depicted in FIG. 7. Being orthogonal to the support surface, the longitudinal axis ALOcan, for example, be in a substantially vertical orientation. In some embodiments, the outer surface 1151 of the second end portion 1130 positioned to engage the support surface SS is substantially planar and orthogonal to the longitudinal axis ALO. However, in some embodiments, the portion of outer surface 1151 of the second end portion 1130 positioned to engage the support surface SS is generally concave.

[0081] In some embodiments, the outer surface 1151 of the second end portion 1130 positioned to engage the support surface SS is sized to maintain the stability of the medicament delivery device 1200 relative to the support surface SS on a condition that the medicament delivery device 1200 is received by the cover 1100 and the delivery member 1210 is positioned outside the interior volume 1170, as depicted in FIG.7. Similarly stated, the second end portion 1130 and / or the support interface 1134 can be sized and shaped to limit the likelihood that the system will tip over when the medicament delivery device 1200 is received within the cover 1100 for actuation. For example, in some embodiments, a ratio of the surface area of the outer surface 1151 of the second end portion 1130 positioned to engage the support surface SS to a longitudinal length LL of the cover 1100 is in a range of 5:1 to 20:1 (e.g.,8:1 to 15:1). In other words, the magnitude of the surface area is between five and twenty times greater than the magnitude of the longitudinal length LL to stably maintain the longitudinal axis ALOorthogonal to (e.g., extending from) the support surface SS. Said another way, a support interface 1134 defined by the outer surface 1151 can have a surface area that is proportional to the longitudinal length LL of the cover 1100. In some embodiments, the support interface 1134 defined by the outer surface 1151 can include a 17  Attorney Docket No. INMD-196 / 01WO   weight element and / or a magnetic element positioned to increase the stability of the medicament delivery system in a ready configuration, such as depicted in FIG.6 and 7.

[0082] In some embodiments, the first end portion 1110 defines an opening 1112 (FIG.2) into the interior volume 1170. Said another way, the wall 1150 at the first end portion 1110 is shaped to define the opening 1112 into the interior volume 1170. As the depicted in FIGS. 6-12, the opening 1112 is sized to receive a base 1240 of the medicament delivery device 1200 that separated from the delivery member 1210 along the longitudinal axis ALO. Accordingly, the first end portion 1110 of the cover 1100 surrounds the base 1240 on the condition that the delivery member 1210 is positioned outside the interior volume 1170 as depicted in FIG.6-12. Therefore, the base 1240 is positioned between the second end portion 1130 and the delivery member 1210 on a condition that the medicament delivery device 1200 is in an actuated configuration as depicted in FIGS.11 and 12.

[0083] As depicted in FIG.3, the length of a major axis AM1of the outer surface 1151 of the second end portion 1130 (e.g., of the support interface 1134) to a length of a major axis AM2 of the opening 1112 are proportional. For example, in some embodiments, a ratio of the length of a major axis AM1to the length of a major axis AM2is in a range of 1:0.5 to 1:2 (e.g., 1:1.2 to 1:1.5). Such a ratio establishes a limit on the maximal length of the opening 1112 relative to the support interface 1134 to ensure that the support interface 1134 has a sufficient surface area to maintain the orthogonal orientation of the longitudinal axis ALOrelative to the support surface SS. The major axis AM1of the outer surface 1151 of the second end portion 1130 and the major axis AM2of the opening 1112 can each extend parallel to the first lateral axis ALA1 and, therefore, correspond to a width of the cover 1100. A minor axis (not shown) of each of the outer surface 1151 of the second end portion 1130 and the opening 1112 can extend parallel to the second lateral axis ALA1and correspond to a thickness of the cover 1100 at the first end portion 1110 and the second end portion 1130.

[0084] In some embodiments, the inner surface 1152 of the wall 1150 includes a ramped portion 1154. The ramped portion 1154 can be a substantially planar structure intersecting both the longitudinal axis ALO and the first lateral axis ALA1 (when the planar construct is extended) and containing the second lateral axis ALA2. Said another way, the ramped portion 1154 can be an 18  Attorney Docket No. INMD-196 / 01WO   inclined plane with a separation from the longitudinal axis ALO that is at a maximum magnitude toward the first end portion 1110 and that decreases toward the second end portion 1130. In other words, the ramped portion 1154 is tapered inward along the longitudinal length of the cover 1100 in the direction of the support surface SS.

[0085] The ramped portion 1154 is configured to move the actuator 1220 of the medicament delivery device 1200. For example, the ramped portion 1154 can be configured to cause the actuator 1220 to move radially inward toward the longitudinal axis ALOin response to a longitudinal movement of the body member 1230 toward the support surface SS. The longitudinal movement of the body member 1230 toward the support surface SS is indicated by arrow AA in FIG.9 and arrow BB in FIG 11. In some embodiments, the medicament delivery device 1200 can, as depicted herein, include a first and second actuator 1220 that are identical but arranged in opposition relative to the medicament container assembly 1250 (FIG.7). Accordingly, the cover 1100 can include corresponding first and second ramped portions 1154 configured to move the actuators 1220. In some embodiments, the second end portion 1130 of the cover 1100 includes a squared elliptic cylinder formed by the wall 1150. The ramped portion 1154 can extend longitudinally from the squared elliptic cylinder and extend radially outward along the first lateral axis ALA1to define the opening 1112. Additionally, a portion of the wall 1150 orthogonal to the second lateral axis ALA2 can extend linearly from a corresponding portion of the squared elliptic cylinder.

[0086] As depicted in FIGS. 2-4, in some embodiments, the inner surface 1152 of the wall 1150 includes a rib portion 1156. The rib portion 1156 extends radially inward from the inner surface 1152 of the wall 1150. More particularly, the rib portion 1156 can extend longitudinally along the ramped portion 1154 of the inner surface 1152. The rib portion 1156 is configured to slidingly engage the actuator 1220 to move the actuator 1220 relative to the body member 1230. Said another way, on a condition that the delivery member 1210 is positioned outside the interior volume 1170, the force applied to the actuator 1220 by the ramped portion 1154 is applied via the point of contact between the actuator 1220 and the rib portion 1156. In some embodiments, the rib portion 1156 has a maximal width WM1 (FIG.8) that is less than 15 percent (e.g., greater than one percent and less than five percent or 10 percent) of the maximal width WM2of the actuator 1220. The narrowness of the rib portion 1156 relative to the maximal width WM2of the actuator 19  Attorney Docket No. INMD-196 / 01WO   1220 minimizes the friction between the medicament delivery device 1200 and the cover 1100 during actuation. As a result, the magnitude of the force applied to move the body member 1230 within the interior volume 1170 in the direction of the support surface SS is substantially equal to the magnitude of the force otherwise required to be applied directly to the actuator 1220 to actuate the medicament delivery device 1200 in the absence of the cover 1100. Additionally, the reduced friction resulting from the contact between the rib portion 1156 and the actuator 1220 precludes a requirement to separate the actuator 1220 from the ramped portion 1154 via a lubricating layer. The absence of a lubricating layer enhances the reusability of the medicament delivery system 1000.

[0087] In some embodiments, the inner surface 1152 of the wall 1150 includes a shoulder 1158 (FIG.2). The shoulder 1158 extends radially inward (e.g., toward the longitudinal axis ALO) from the inner surface 1152 of the wall 1150. As depicted in FIG.12, the shoulder 1158 is positioned to limit the longitudinal movement of the body member 1230 within the interior volume 1170 toward the second end portion 1130 on the condition that the delivery member 1210 of the medicament delivery device 1200 is positioned outside the interior volume 1170. Said another way, the longitudinal movement in response to an applied force (e.g., a downward force) of the medicament delivery device 1200 within the cover 1100 toward the support surface SS is halted upon contact between the shoulder 1158 and the base 1240 as depicted in FIG.12. The shoulder 1158 can be positioned to permit sufficient travel of the body member 1230 to move the actuator 1220 radially inward to pierce the medicament container assembly 1250, while maintaining the delivery member 1210 outside the interior volume 1170. Maintaining the delivery member 1210 outside the interior volume 1170 on a condition that the medicament delivery device 1200 is actuated, can facilitate access to the therapeutic dose of the medicament by the user.

[0088] As described herein, in some embodiments, the actuator 1220 is coupled to the body member 1230 of the medicament delivery device 1200. The actuator 1220 is configured to move relative to the body member 1230 as the medicament delivery device 1200 is moved longitudinally (e.g., toward the support surface SS) within the interior volume 1170 of the cover 1100. As depicted in FIGS. 7, 10, and 12, in some embodiments the actuator 1226 configured to move radially inward relative to the body member 1230. In some embodiments, a compressible element, such as a spring, (not shown) can be positioned between a portion of the actuator 1220 and the 20  Attorney Docket No. INMD-196 / 01WO   body member 1230 to bias the actuator 1220 radially outward when the medicament delivery device 1200 is in the storage configuration depicted in FIG.1 and the ready configuration depicted in FIG.6. However, the force applied on the actuator 1220 by the ramped portion 1154 in response to longitudinal movement of the medicament delivery device 1200 in the direction of the support surface SS is greater than the force of the compressible element and the actuator 1220 is moved radially inward as depicted in FIGS.10 and 12. As depicted in FIG.12, the radial movement of the actuator 1220 in response to the force applied by the ramped portion 1154 can puncture or otherwise rupture the medicament container assembly 1250 positioned within the body member 1230.

[0089] In some embodiments, the medicament delivery device 1200 is an inhaler, and the delivery member 1210 is a mouthpiece. The inhaler can be configured to support the inhalation of the contents of a capsule, for medical treatments. For example, the inhaler can be a reusable dry powder inhaler that can be used to deliver medicament from a single-dose capsules. However, in some embodiments, the medicament delivery device 1200 can be an intranasal device, and the delivery member 1210 can be a nozzle. In such embodiments, the cover 1100 can be configured to receive the nozzle in the storage configuration. In further embodiments, the medicament delivery device 1200 can be an injector, and the delivery member 1210 can be a needle. In such embodiments, the cover 1100 can be configured to receive the needle in the storage configuration.

[0090] In some embodiments, the medicament container assembly 1250 can include a therapeutic dose of a dry powder composition. The dry powder composition can be a dry powder composition comprising an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the dry powder composition comprises a treprostinil prodrug described in International Application Publication WO 2015 / 061720, the disclosure of which is incorporated herein by reference in its entirety.

[0092] The dry powder composition includes, in some embodiments, a compound of Formula (I): 21  Attorney Docket No. INMD-196 / 01WO

[0093] or ansalt thereof, wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl.

[0094] In some embodiments of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is tetradecyl. In a further embodiment, R1is linear tetradecyl.

[0095] In some embodiments of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is pentadecyl. In a further embodiment, R1is linear pentadecyl.

[0096] In some embodiments of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is heptadecyl. In a further embodiment, R1is linear heptadecyl.

[0097] In some embodiments of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is octadecyl. In a further embodiment, R1is linear octadecyl.

[0098] In some embodiments, the compound of Formula (I) is the compound having the Chemical Abstract Services (CAS) registry number 1706528-83-7.

[0099] In some embodiments of the compound of Formula (I), R1is hexadecyl. In a further embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is a compound of Formula (II): 22  Attorney Docket No. INMD-196 / 01WO   ,

[0100]

[0101] The compound of Formula (II) is also referred to herein as C16TR or its international nonproprietary name, treprostinil palmitil (TP) (CAS registry number 1706528-83-7).

[0102] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of a compound of Formula (II).

[0103] Treprostinil palmitil, in one embodiment, is present in a crystalline form in one of the dry powder compositions and medicament containers. Crystalline forms of treprostinil palmitil are described in U.S. Patent No. 10,781,160, which is incorporated herein by reference in its entirety.

[0104] In one embodiment, the treprostinil palmitil is a crystal Form I having an X-ray powder diffraction (XRPD) pattern exhibiting peaks at two, three, four, five or all of the following 2θ reflection angles: 3.3±0.2°, 6.6±0.2°, 14.2±0.2°, 18.9±0.2°, 21.3±0.2°, and 22.5±0.2°. In another embodiment, the XRPD pattern of treprostinil palmitil crystal Form I further comprises peaks at one, two, three, four, five, six, seven, eight or all of the following 2θ reflection angles: 13.8±0.2°, 15.3±0.2°, 16.9±0.2°, 17.8±0.2°, 19.8±0.2°, 20.6±0.2°, 20.9±0.20, 24.4±0.2°, and 24.8±0.2°. In one embodiment, the treprostinil palmitil is a crystal Form I having an XRPD pattern exhibiting peaks at the 2θ reflection angles provided in Table 1.   Table 1. XRPD Data for Treprostinil Palmitil Crystal Form I.23  Attorney Docket No. INMD-196 / 01WO Table 1. XRPD Data for Treprostinil Palmitil Crystal Form I. 2Ɵ l (°) D l (Å) Rlti it it (%)Attorney Docket No. INMD-196 / 01WO   Table 1. XRPD Data for Treprostinil Palmitil Crystal Form I. 2Ɵ l (°) D l (Å) R l ti i t it (%)

[0105] d of Formula (I) is treprostp p p y g differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 52.2±1° C. and a peak maximum of approximately 54.5±1° C.

[0106] In one embodiment of a method described herein, treprostinil palmitil crystal Form II has an XRPD pattern exhibiting peaks at two, three, four, five or all of the following 2θ reflection angles: 3.4±0.2°, 6.1±0.2°, 9.4±0.2°, 20.3±0.2°, 21.6±0.2°, and 23.4±0.2°. In another embodiment, the XRPD pattern of treprostinil palmitil crystal Form II further comprises peaks at one, two, three, four, five, six, seven, eight or all the following 2θ reflection angles: 7.0±0.2°, 9.0±0.2°, 12.2±0.2°, 12.7±0.2°, 17.5±0.2°, 18.0±0.2°, 18.5±0.2°, 19.1±0.2°, and 19.4±0.2°. In one embodiment, the treprostinil palmitil is a crystal Form II having an XRPD pattern exhibiting peaks at the 2θ reflection angles provided in Table 2. Table 2. XRPD Data for Treprostinil Palmitil Crystal Form II.25  Attorney Docket No. INMD-196 / 01WO Table 2. XRPD Data for Treprostinil Palmitil Crystal Form II. 2Ɵ l (°) D l (Å) Rlti it it (%)Attorney Docket No. INMD-196 / 01WO   Table 2. XRPD Data for Treprostinil Palmitil Crystal Form II. 2Ɵ l (°) D l (Å) R l ti i t it (%)

[0107] In one embodiment of a method for treating pulmonary hypertension provided herein, the compound of Formula (I) is treprostinil palmitil crystal Form II having a DSC thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 54.6±1° C. and a peak maximum of approximately 56.9±1° C.

[0108] In embodiments described herein, the dry powder composition is present in the medicament container. In preferred embodiments, the medicament container is a capsule for use within a dry powder inhaler (DPI).

[0109] In some embodiments, the dry powder composition comprises:

[0110] (a) a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, present at from about 0.5 wt% to about 5 wt% of the total weight of the dry powder composition:

[0111] Wherein Formula (I) and (II) are defined above;

[0112] (b) from about 10 wt% to about 61 wt% of leucine, and the balance being 27  Attorney Docket No. INMD-196 / 01WO

[0113] (c) a sugar selected from the group consisting of trehalose and mannitol. The entirety of (a), (b), and (c) is 100 wt%.

[0114] In a further embodiment, the composition comprises from about 25 wt% to about 61 wt% of leucine. In even a further embodiment, the composition comprises from about 25 wt% to about 45 wt% of leucine. In some embodiments, the composition comprises from about 45 wt% to about 61 wt% of leucine.

[0115] In some embodiments, the compound of Formula (I) or (II) is present at about 0.4 wt% about 0.5 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.5 wt%, about 1.7 wt%, about 2.0 wt%, about 2.3 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 4 wt%, about 3.5 wt%, or about 5 wt% of the total weight of the dry powder composition.

[0116] In some embodiments, the leucine is present at about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or about 60 wt% of the total weight of the dry powder composition.

[0117] In some embodiments, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present from about 0.8 wt% to about 1.5 wt% of the total weight of the dry powder composition. In some embodiments, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof is present from about 2.7 wt% to about 4 wt% of the total weight of the dry powder composition. In some embodiments, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof is present from about 2.7 wt% to about 3.5 wt%, for example, from about 2.8 wt% to about 3.2 wt%, or from about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0118] In some embodiments, the leucine is present at from about 25 wt% to about 61 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 25 wt% to about 50 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 25 wt% to about 40 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 20 wt% 28  Attorney Docket No. INMD-196 / 01WO   to about 33 wt%, e.g., about 20 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, or about 33 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 25 wt% to about 33 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 27 wt% to about 33 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 27 wt% to about 31 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 27 wt% to about 30 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine is present at from about 28 wt% to about 30 wt% of the total weight of the dry powder composition.

[0119] In some embodiments, the leucine is present at about 30 wt% of the total weight of the dry powder composition.

[0120] In yet further embodiments, the leucine is present at from about 45 wt% to about 61 wt% of the total weight of the dry powder composition, for example at from about 45 wt% to about 55 wt%, or from about 50 wt% to about 55 wt%. In a further embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 3 wt% to about 4 wt% of the total weight of the dry powder composition. In even a further embodiment, R1is hexadecyl, e.g., linear hexadecyl.

[0121] In some embodiments, the sugar in the dry powder composition is trehalose. In some embodiments, the sugar in the dry powder composition is mannitol.

[0122] In some embodiments, the composition components have the weight percentages set forth in Table 3, below. In some embodiments, the composition components have the weight percentages set forth in Table 3, below, ± 5% for each component. In yet further embodiments, the composition has a leucine-to-mannitol weight ratio (“leucine : mannitol” or “leucine-to- mannitol”) set forth in Table 3. 29  Attorney Docket No. INMD-196 / 01WO   Table 3. Exemplary dry powder compositions for use within a medicament container. Leucine-to-Mannitol

[0123] In some embodiments, the dry powder composition has the components and weight percentages set forth in Table 4. 30  Attorney Docket No. INMD-196 / 01WO   Table 4. Exemplary dry powder composition. tit (% )

[0124] The leucine-to-sugar (i.e., mannitol or trehalose) weight ratio in a composition provided herein, in some embodiments, is from about 0.4-to-1 (leucine-to-mannitol or -trehalose) to about 1.7-to-1 (leucine-to-mannitol -trehalose). In a further embodiment, the composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at from about 1 wt% to about 4 wt% of the total weight of the dry powder composition. In a further embodiment, the leucine-to-sugar weight ratio is from about 0.4:1 (leucine-to-mannitol or -trehalose) to 0.9:1 (leucine-to-mannitol or -trehalose). In even a further embodiment, the leucine-to-sugar weight ratio is from about 0.4:1 (leucine-to-mannitol or -trehalose) to 0.5:1 (leucine-to-mannitol or - trehalose). In a further embodiment, the sugar is mannitol. The leucine, in some embodiments, is L-leucine.

[0125] In some embodiments, the dry powder composition is one of the dry powder compositions described in International Patent Application Publication No. 2020 / 223237, the disclosure of which is incorporated by reference herein in its entirety for all purposes.

[0126] In some embodiments, the dry powder composition is one of the dry powder compositions described in International Patent Application Publication No. 2022 / 094100, the disclosure of which is incorporated by reference herein in its entirety for all purposes.

[0127] According to some embodiments described herein, the medicament container, e.g., a dry powder capsule, comprises an effective amount of a compound of Formula (I) or (II) within a dry powder composition. The composition is delivered via the medicament delivery device to a patient in need of pulmonary hypertension treatment. Specifically, the composition is aerosolized 31  Attorney Docket No. INMD-196 / 01WO   by a medicament delivery device of the disclosure to provide an aerosolized composition to the lungs of a patient in need of treatment.

[0128] In some embodiments, the pulmonary hypertension (PH) is portopulmonary hypertension (PPH). PPH is defined by the coexistence of portal and pulmonary hypertension. The diagnosis of portopulmonary hypertension is based on hemodynamic criteria: (1) portal hypertension and / or liver disease (clinical diagnosis-ascites / varices / splenomegaly), (2) mean pulmonary artery pressure > 25 mmHg at rest, (3) pulmonary vascular resistance > 240 dynes s / cm5, (4) pulmonary artery occlusion pressure < 15mmHg or transpulmonary gradient > 12 mmHg. PPH is a serious complication of liver disease, and is present in 0.25 to 4% of patients suffering from cirrhosis. PPH is comorbid in an estimated 4-6% of those referred for a liver transplant.

[0129] In some embodiments, the pulmonary hypertension is group 3 PH, as characterized by the WHO. In further embodiments, the method provided herein is a method for treating PH associated with interstitial lung disease (PH-ILD).

[0130] In the methods for treating PH-ILD provided herein, the ILD may include one or more lung conditions. The one or more lung conditions comprise, in some embodiments, idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, hypersensitivity pneumonitis, acute interstitial pneumonitis, interstitial pneumonia (e.g., idiopathic interstitial pneumonia), connective tissue disease, sarcoidosis or asbestosis. In some embodiments, the ILD is connective tissue disease- associated interstitial lung disease (CTD-ILD). In some embodiments, the ILD is sarcoidosis. In yet further embodiments, the ILD is IPF. In additional embodiments, the ILD is an idiopathic interstitial pneumonia (IIP).

[0131] In some embodiments for treating PH-ILD provided herein, the ILD includes pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF). Pulmonary fibrosis is a respiratory disease in which scars are formed in the lung tissues, leading to serious breathing problems. Scar formation, i.e., the accumulation of excess fibrous connective tissue, leads to thickening of the walls, and causes reduced oxygen supply in the blood. As a result, pulmonary fibrosis patients 32  Attorney Docket No. INMD-196 / 01WO   suffer from perpetual shortness of breath. In some patients the specific cause of the disease can be diagnosed, but in others the probable cause cannot be determined, a condition called IPF.

[0132] The length of the administration period in any given case may depend on the nature and severity of the PH being treated and how well a patient tolerates and responds to the therapy. The treatment methods provided herein are provided as a chronic therapy, and as such, a patient is on-therapy as long as the therapy is safe and effective. Accordingly, the administration period in some embodiments, continues until a patient dies. In other embodiments, the administration period is the length of time the treatment is effective.

[0133] In some embodiments, if a patient experiences an adverse reaction to the therapy, they are provided a decreased dose during the administration period. Similarly, a patient may be titrated to a higher dose should they show a lower dose be shown to be well tolerated. In some embodiments, the uptitration takes place only after the patient has shown to tolerate a lower dose for two or more days, e.g., two days, three days, four days, five days, six days or seven days. As such, method of treatments of the disclosure, in some embodiments, comprise a titration period.

[0134] As used herein “titration period” refers to a period of time when a starting dose of a compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is administered to a patient, and the starting dose is increased (titrated) incrementally until the patient reaches their maximum tolerated dose (MTD). The incremental increase in one embodiment, is by about 80 µg to about 200 µg, for example by about 80 µg or by about 160 µg. In a preferred embodiment, the incremental increase is by about 80 µg. In a preferred embodiment, the incremental increase is by about 160 µg. In addition to a dose being increased during a titration period, a dose Y may also be decreased to a prior dose X, e.g., if the patient experiences one or more adverse events at the dose Y of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. In the embodiments described herein, a dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof is not further uptitrated once the patient is shown to tolerate a dose of 1280 µg.

[0135] In one embodiment of a method comprising a titration period, the titration period comprises an upwards dose titration. In another embodiment, the titration period comprises an upwards dose titration and a downwards dose titration. The upwards dose titration, in one 33  Attorney Docket No. INMD-196 / 01WO   embodiment, comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof by an increment of about 80-160 μg. In a further embodiment, the upwards dose titration comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, by about an 80 μg increment. In another embodiment, the upwards dose titration comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, by about a 160 μg increment.

[0136] For example, in one embodiment of the disclosure, the medicament delivery device (e.g., DPI) and medicament container (e.g., dry powder capsule) described herein comprises a dry powder composition comprising an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. A patient in need of pulmonary hypertension treatment is administered once daily in a single dosing session during a titration period, a starting dose comprising about 80-160 μg of a compound of Formula (I), wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, or a compound of Formula (II) and then titrating the starting dose during the titration period to a maximum tolerated dose (MTD) of 1280 µg or less, administered once daily in a single dosing session. In a further embodiment, R1is hexadecyl. An administration period, as used herein, can comprise both a titration period and a maintenance period, where a MTD is administered.

[0137] As such in some embodiments, an administration period comprises (i) a titration period and (ii) a maintenance period, and wherein during the titration period, the starting dose comprising about 80-160 μg of the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof is administered once daily in a single dosing session, and the starting dose is titrated to a maximum tolerated dose (MTD) of 1280 μg or less, and wherein during the maintenance period, the MTD is administered once daily in a single dosing session.

[0138] As used herein, a “maintenance period” or “maintenance dosing period” refers to a period of time where the patient is administered an effective amount of a compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, e.g., the patient’s maximum tolerated dose (MTD) once daily during a single dosing session. As provided herein, the compound is administered via a dry powder inhaler (DPI) (medicament delivery device). The 34  Attorney Docket No. INMD-196 / 01WO   compound, in one embodiment, is present in one of the dry powder compositions described herein, and can be present, in one embodiment, in a single or multiple DPI capsules (medicament containers).

[0139] In one embodiment of a method comprising a titration period, the titration period comprises an upwards dose titration. In another embodiment, the titration period comprises an upwards dose titration and a downwards dose titration. The upwards dose titration, in one embodiment, comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof by an increment of about 80-160 μg. In a further embodiment, the upwards dose titration comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, by about an 80 μg increment. In another embodiment, the upwards dose titration comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, by about a 160 μg increment.

[0140] In embodiments, the starting dose is titrated to one or more doses selected from about 160 µg, about 240 µg, about 320 µg, about 400 µg, about 450 µg, about 480 µg, about 640 µg, about 720 µg, about 800 µg, about 880 µg, about 960 µg, about 1040 µg, about 1120 µg, about 1200 µg, or about 1280 µg. In another embodiment, the starting dose is titrated by increments of about 80 µg or 160 µg until achieving a dose of about 700-1300 µg. In one embodiment, the starting dose is 80 µg. In another embodiment, the starting dose is 160 µg. In one embodiment, a dose is titrated to a higher dose after the patient has shown to tolerate the dose for two or more days.

[0141] In one embodiment of a method comprising a MTD, the MTD ranges from about 720 µg to about 1280 µg. In another embodiment, the MTD is about 720 µg, about 800 µg, about 880 µg, about 960 µg, about 1040 µg, about 1120 µg, about 1200 µg, or about 1280 µg.

[0142] In some embodiments, the administration period is about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years, about 20 years or about 30 years.

[0143] In some embodiments, the administration period for the methods provided herein is at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at 35  Attorney Docket No. INMD-196 / 01WO   least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years or at least about 10 years or at least about 20 years. The administration period, in some embodiments, is from about 30 days to about 2 years. In some embodiments, the administration period is from about 6 months to about 3 years, or from 6 months to about 4 years, or from about 6 months to about 5 years, or from about 6 months to about 6 years, or from about 6 months to about 7 years, or from about 6 months to about 8 years, or from about 1 year to about 10 years, or from about 2 years to about 10 years, or from about 6 months to about 20 years, or from about 5 years to about 20 years, or from about 10 years to about 30 years.

[0144] In some embodiments, the administration period is at least about 1 year.

[0145] In some embodiments, the administration period is at least about 5 years.

[0146] In some embodiments, the administration period is from about 1 year to about 15 years. In some embodiments, the administration period is from about 5 years to about 15 years. In some further embodiments, the administration period is from about 10 years to about 20 years. In even some embodiments, the administration period is from about 1 year to about 20 years.

[0147] In some embodiments of the disclosed methods, a patient is administered the dry powder composition once daily in a single dosing session during an administration period. In some embodiments, the administration is with food. In some embodiments, each dosing session comprises 1 to 5 inhalations (puffs) from a DPI (medicament delivery device), for example 1 inhalation (1 puff), 2 inhalations (2 puffs), 3 inhalations (3 puffs), 4 inhalations (4 puffs) or 5 inhalations (5 puffs). As used herein, a “dosing session” refers to 1 to 5 inhalations (puffs) from a DPI as required to administer from about 80 µg to about 1280 µg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The DPI, in some embodiments, is small and transportable by the patient. In some embodiments, the DPI is a single dose DPI. 36  Attorney Docket No. INMD-196 / 01WO

[0148] In order to achieve a particular dose, in some embodiments, more than one DPI capsule including the composition can be employed. For example, in the case of a 640 µg dose, two 320 µg DPI capsules can be used. Each capsule can be administered via 1 or 2 inhalations, for example.

[0149] The effective amount of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, may include a fixed dose of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The fixed dose, in some embodiments, is present in one or multiple DPI capsules. The fixed dose, in some embodiments, is a dose that is titrated (either up or down) from a prior dose. In some embodiments, the fixed dose is the same dose or substantially the same dose as a prior dose. The effective amount, in some embodiments, is the amount of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, administered during each dosing session. In some embodiments, the amount “administered” refers to the amount of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the capsule, or multiple capsules in the DPI, administered in a single dosing session. In some embodiments, the fixed dose ranges from about 80 μg to about 1280 µg of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, e.g., about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 µg, about 480 μg, about 640 µg, 675 µg, about 720 µg, about 800 µg, about 880 µg, about 960 µg, about 1040 µg, about 1120 µg, about 1200 µg, or about 1280 µg of the compound of Formula (II), a stereoisomer thereof, or pharmaceutically acceptable salt thereof. For example, if the dry powder composition is administered once daily in a single dosing session, the effective amount can be considered to be the amount of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the capsule or multiple capsules that is administered during the single dosing session. For example, in some embodiments, one or more capsules may be formulated with the dry powder composition wherein the one or more capsules have a total dose of about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 µg, about 480 μg, about 640 µg, 675 µg, about 720 µg, about 800 µg, about 880 µg, about 960 µg, about 1040 µg, about 1120 µg, about 1200 µg, or about 1280 µg of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and each of the aforementioned dosages may be an effective amount, and may also be 37  Attorney Docket No. INMD-196 / 01WO   referred to as the amount administered once daily in a single dosing session, during the administration period. As a further example, in some embodiments, the capsule comprises a dry powder composition including about 320 µg of a compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and, for purposes of this disclosure, the amount administered is 640 µg, even if takes 2 or more puffs from two capsules to administer the 640 µg. Similarly, in this example, the amount administered is 640 µg even if a residual amount of compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof remains in the DPI (e.g., if about 5%, 10%, 20%, 30%, 40%, or 50% remains in the DPI).

[0150] The dose “administered” in a single dosing session also encompasses situations where the DPI is refiled or reloaded 1 or more times (e.g., by changing the capsules) in order to achieve the desired effective amount. In such situations, “administration” refers to the total dosage in the capsules which are administered in the dosing session. For example, to administer a dosage of 240 μg of a compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, one 80 µg capsule and one 160 µg capsule may be used. The DPI may be filed with a first 80 µg capsule, and after emptying the cartridge in 1 or more puffs, a 160 µg capsule may be loaded in the DPI and emptied in 1 or more puffs. Both capsules are used in the same dosing session, and therefore the dose administered is 240 µg.

[0151] In some embodiments, the effective amount comprises an escalating dose during the administration period. In some further embodiments, the effective amount is based upon an upwards titration, based on the highest tolerated dose for the patient. In some embodiments, the patient is initially administered 80 μg. If this dose is well tolerated, the dose is uptitrated until reaching the patient’s highest tolerable dose. During the titration period, the patient stays on the same dose for a minimum number of cumulative days, e.g., 2 days, 3 days or 4 days, prior to titrating to the next higher dose. See, e.g., Figure 21 for an embodiment of dose titration. If a dose is not tolerated, the dose may be decreased to the previous dose level.

[0152] During a titration period, each patient’s dose can be uptitrated to the maximum tolerated dose for that patient. As an example, a patient, in some embodiments, starts the method of the invention with a single 80 μg DPI capsule, once-daily. If this dose is well tolerated, the dose is uptitrated until reaching the patient’s highest tolerable dose. During the Titration Period, 38  Attorney Docket No. INMD-196 / 01WO   patients stay on study drug for the minimum number of cumulative days (e.g., 2 days at 80 μg, 160 μg, or 240 μg, 3 days at 320 μg or 4 days at 400 μg or 480 μg) prior to starting the next higher dose. Study drug titration may occur slower than the above example, but not faster. Figure 21 provides an exemplary embodiment of dose titration for a patient in need of treatment. If a dose is not tolerated, the dose may be decreased to the previous dose level.

[0153] In the methods provided herein, a patient is administered a compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof (e.g., treprostinil palmitil), for an administration period. The administration period, in some embodiments, comprise a titration period and a maintenance period. In one embodiment, the administration is with food. The administration period, in one embodiment, comprises a titration period. In embodiments, during the titration period, the patient is administered a starting dose of a compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof (e.g., treprostinil palmitil), and the starting dose is titrated (e.g., incrementally increased) to an effective amount, e.g., a maximum tolerated dose. In one embodiment, the administration period comprises a maintenance period. In embodiments, during the maintenance period, the patient is administered the maximum tolerated dose once daily during a single dosing session. As discussed throughout, the maximum dose administered to patients with PH according to the methods disclosed herein is 1280 µg. Therefore, if a patient tolerates a dose of 1280 μg, then 1280 μg is considered the maximum tolerated dose. However, an individual maximum tolerated dose may be less than 1280 µg. Accordingly, in embodiments, a patient’s maximum tolerated dose is selected from the group consisting of 720 μg, 800 μg, 880 μg, 960 μg, 1040 μg, 1120 μg, 1200 μg and 1280 μg.

[0154] In embodiments of a method for treating pulmonary hypertension described herein, a patient is administered a compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, once daily in a single dosing session during a titration period, e.g., via a dry powder inhaler. In one embodiment, the titration period comprises an upwards dose titration (also referred to as a uptitration). In embodiments, the upwards titration is initiated from a starting dose and the starting dose is incrementally increased until reaching the maximum tolerated dose. In another embodiment, the titration period comprises an upwards titration and a downwards titration (also referred to as a downtitration). Down titration may occur 39  Attorney Docket No. INMD-196 / 01WO   if the patient does not tolerate the higher dose. The maximum tolerated dose, in one embodiment, is then administered to the patient for a maintenance period.

[0155] In embodiments of the method for treating PH, during the titration period, a dose X of the compound of Formula (I), or enantiomer, diastereomer or pharmaceutically acceptable salt thereof, is increased by about 80 μg to about 200 μg to a dose Y (e.g., by about 80 μg to about 160 μg or by about 80 μg), if the patient is shown to tolerate dose X. In this example, dose X may be the starting dose or any dose between the starting dose and the maximum tolerated dose, and dose Y may be the next sequential dose (e.g., a dose that is 80-160 μg higher than dose X), or dose Y may be the patient’s maximum tolerated dose. In a further embodiment, the patient is administered the dose X for about one to about seven days prior to increasing the dose to dose Y. In a further embodiment, the patient is administered a dose X for about one to about five days prior to increasing the dose to dose Y. In even a further embodiment, the patient is administered a dose X for about one to about three days prior to increasing the dose to dose Y. In embodiments when dose Y is less than the maximum tolerated dose, the maximum tolerated dose may be achieved by increasing dose X by 80-160 μg to achieve dose Y and administering dose Y for a period of time (e.g., 2-7 days), then increasing dose Y by 80-160 μg, and repeating until reaching the maximum tolerated dose.

[0156] The upwards titration, in one embodiment, comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof by increments of about 80-160 μg. In a further embodiment, the upwards dose titration, comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, by about 80 μg. In another embodiment, the upwards dose titration comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, by about 160 μg. During an upwards dose titration, in one embodiment, a patient remains on a dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, for about one to seven days, for example, one to six days prior to further incrementally increasing the dose. If a patient experiences an adverse event, then the patient is down-titrated to the prior dose, which can then be considered the maximally tolerated dose. In a preferred embodiment, the compound of Formula (I) is treprostinil palmitil. 40  Attorney Docket No. INMD-196 / 01WO

[0157] During a titration period, a patient’s dose can be gradually (in increments) uptitrated to the maximum tolerated dose for that patient. In some embodiment, the maximum tolerated dose is about 1280 μg. In another embodiment, a patient’s maximum tolerated dose is selected from the group consisting of 720 μg, 800 μg, 880 μg, 960 μg, 1040 μg, 1120 μg, 1200 μg and 1280 μg. In some embodiments, the maximum tolerated dose is 1280 µg. In some embodiments, the maximum tolerated dose is 1200 µg. In some embodiments, the maximum tolerated dose is 1120 µg. In some embodiments, the maximum tolerated dose is 1040 µg. In some embodiments, the maximum tolerated dose is 960 µg. In some embodiments, the maximum tolerated dose is 880 µg. In some embodiments, the maximum tolerated dose is 800 µg. In some embodiments, the maximum tolerated dose is 720 µg. If a patient is uptitrated to a particular dose and then experiences one or more adverse events, for example, one or more moderate or severe adverse events, the dose of the compound of Formula (I), or enantiomer, diastereomer or pharmaceutically acceptable salt thereof, is downward titrated to the prior tolerated dose.

[0158] In embodiments, the upwards titration disclosed herein improves tolerability to the compound of Formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. In embodiments, the methods disclosed herein may be used with a patient who has not previously been administered a compound of Formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is first administered a compound of Formula (I). In alternative embodiments, the methods disclosed herein may be used with a patient who resumes treatment with a compound of Formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, after previously discontinuing treatment for multiple days.

[0159] As an example of a titration period in one of the methods provided herein, a patient, in one embodiment, is initially administered a starting dose of 80 μg of a compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, once daily during a single dosing session. In a further embodiment, the compound of Formula (I) is treprostinil palmitil and is present in a dry powder composition. The 80 μg of the compound of Formula (I), in one embodiment, is present in a dry powder composition, for example, in a single DPI capsule. After administering 80 μg the dose for several days (e.g., from 2-7 days) to the patient, the dose is gradually (in increments) uptitrated until reaching the patient’s maximum tolerated dose. Uptitration, in one embodiment, comprises incrementally increasing the patient’s dose of the 41  Attorney Docket No. INMD-196 / 01WO   compound of Formula (I) by about 80 or 160 μg after a patient is shown to tolerate a prior dose for about 2-7 days.

[0160] As another example of a titration period in one of the methods provided herein, a patient, in one embodiment, is initially administered a starting dose of 160 μg of a compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, once daily during a single dosing session. In a further embodiment, the compound of Formula (I) is treprostinil palmitil and is present in a dry powder composition. The 160 μg of the compound of Formula (I), in one embodiment, is present in a dry powder composition, for example, in a single DPI capsule or multiple DPI capsules. After administering 160 μg the dose for several days (e.g., from 2-7 days) to the patient, the dose is gradually (in increments) uptitrated until reaching the patient’s maximum tolerated dose. Uptitration, in one embodiment, comprises incrementally increasing the patient’s dose of the compound of Formula (I) by about 80 or 160 μg after a patient is shown to tolerate a prior dose for about 2-7 days.

[0161] In embodiments, the maximum tolerated dose is the highest dose of the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof administered to a patient for a period of time (e.g., at least 7-14 days) that does not cause one or more adverse events unrelated to the underlying condition. During a titration period, a patient’s maximum tolerated dose does not exceed 1280 μg. In other words, the titration period ends when a patient is shown to tolerate a dose of 1280 μg. Thus, in some embodiments, the maximum tolerated dose is 1280 µg. In some embodiments, the maximum tolerated dose is 1200 µg. In some embodiments, the maximum tolerated dose is 1120 µg. In some embodiments, the maximum tolerated dose is 1040 µg. In some embodiments, the maximum tolerated dose is 960 µg. In some embodiments, the maximum tolerated dose is 880 µg. In some embodiments, the maximum tolerated dose is 800 µg. In some embodiments, the maximum tolerated dose is 720 µg.

[0162] In a further embodiment, the patient’s maximum tolerated dose is administered to the patient as a maintenance dose to treat the pulmonary hypertension in the patient. For example, in an embodiment, the 1280 μg dose is administered to the patient as a maintenance dose to treat the pulmonary hypertension in the patient. In an embodiment, 1200 µg, 1120 µg, 1040 µg, 960 µg, 880 µg, 800 µg, or 720 µg is administered to the patient as a maintenance dose to treat the pulmonary hypertension in the patient. The maintenance dose is administered to the patient once 42  Attorney Docket No. INMD-196 / 01WO   daily during a single dosing session, e.g., via a dry powder inhaler (DPI). The 1280 μg dose, in one embodiment, is present in multiple capsules for use with a capsule-based DPI.

[0163] During the titration period, patients stay on each dose of the compound of Formula (I) for a minimum number of cumulative days prior to starting the next higher dose (as a non-limiting example, 2 days at 80 μg, 160 μg, or 240 μg, 3 days at 320 μg or 4 days at 400 μg, 480 μg, 560 μg, 640 μg, 720 μg, 800 μg, 880 μg, 960 μg, 1040 μg, 1120 μg, 1200 μg or 1280 μg). After the titration period, the patient continues to administer the maximum tolerated dose (e.g., about 1280 μg), for a period of time during a maintenance treatment period.

[0164] In embodiments, during the titration period, the minimum number of cumulative days during which patient stays on the same dose of a compound of Formula (I) ranges from 2-14 days, 2-7 days or 2-10 days. In embodiments, during a titration period, the minimum number of cumulative days during which patient stays on the same dose is 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or any combination thereof, prior to titrating to the next higher dose. See, e.g., Figure 1 for non-limiting embodiments of a dose titration period / dose titration scheme.

[0165] In some embodiments, the total length of the titration period is from about 20 days to about 90 days, from about 20 days to about 80 days, from about 20 days to about 60 days, from about 20 days to about 50 days, from about 25 days to about 75 days, or from about 25 days to about 60 days. In some embodiments, the total length of the titration period is about 2 weeks to about 6 weeks, about 2 weeks to about 5 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 6 weeks, about 3 weeks to about 5 weeks, or about 3 weeks to about 4 weeks. In some embodiments, the total length of the titration period is 21 days (i.e., three weeks). In some embodiments, the total length of the titration period is at least about 25 days, at least about 29 days, at least about 30 days, at least about 31 days, at least about 32 days, at least about 33 days, at least about 35 days, at least about 37 days, at least about 39 days, at least about 41 days, at least about 43 days, at least about 45 days, at least about 47 days, at least about 49 days, at least about 51 days, at least about 53 days, at least about 55 days, at least about 57 days, at least about 58 days, at least about 59 days, or at least about 60 days.

[0166] In some embodiments, during the titration period, the dose is uptitrated in increments of from about 10 ug to about 200 μg, e.g., about 10 μg, about 15 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 43  Attorney Docket No. INMD-196 / 01WO   μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, or about 200 μg until the patient’s maximum tolerated dose is achieved. As described above, a titration period in one embodiment is terminated once a patient is shown to tolerate a dose of 1280 μg. As such, a 1280 μg dose is considered a maximum tolerated dose for the methods described herein. In another embodiment, during the titration period, the dose is uptitrated in increments of about 80 μg or about 160 μg until the patient’s maximum tolerated dose is achieved or a dose of 1280 μg is achieved. In yet another embodiment, during the titration period, the dose is uptitrated in increments of 80 μg until the patient’s maximum tolerated dose is achieved or a dose of 1280 μg is achieved. In some embodiments, during the titration period, the patient receives one or more of a 720 µg dose, an 800 µg dose, an 880 µg dose, a 960 µg dose, a 1040 µg dose, a 1120 µg dose, a 1200 µg dose, and a 1280 µg dose. In some embodiments, the maximum tolerated dose of a patient undergoing a PH treatment method is 720 µg, 800 µg, 880 µg, 960 µg, 1040 µg, 1120 µg, 1200 µg, or 1280 µg.

[0167] In embodiments, the patient is shown to tolerate a dose before titrating to a higher dose. In some embodiments, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose X for 2-14 days, 2-7 days, or 2-4 days. In some embodiments, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In one embodiment, a dose is titrated to a higher dose after the patient has shown to tolerate the dose for 2 days, 3 days, 4 days, or 5 days. In another embodiment, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 2 days, 3 days, or 4 days. In one embodiment, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 2 days. In one embodiment, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 3 days. In one embodiment, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 4 days. In one embodiment, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 5 days. In one embodiment, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 6 days. In one embodiment, a dose X is titrated to a higher dose Y after the patient has shown to tolerate the dose for 7 days. In one embodiment, if a dose Y is not tolerated, e.g., because the patient experiences one or more adverse events, the dose Y is downtitrated to the previous dose level X. 44  Attorney Docket No. INMD-196 / 01WO

[0168] In some embodiments, a patient receiving a previously effective dose of a compound of Formula (I) may over time experience disease progression, clinical worsening of PH, or reduced efficacy of the dose that was previously effective. In embodiments, clinical worsening in a patient may be indicated by one or more of hospitalization for right heart failure, heart-lung or lung transplant, or atrial septostomy. In embodiments, clinical worsening may be indicated by a combined occurrence of two or more events including a 20% decrease in 6MWD, worsening WHO / NYHA functional capacity class, and / or appearance of or worsening of signs / symptoms of right heart failure. In embodiments, these patients may have their current dose titrated to higher dose, e.g., up to a maximum tolerated dose or if a dose of 1280 μg is achieved, to 1280 µg daily. In embodiments, the previously effective dose ranges from 160-640 µg, 240-640 µg, 320-640 µg, 400-640 µg, 480-640 µg, or 560-640-640 µg of a compound of Formula (I) (e.g., treprostinil palmitil). In embodiments, the previously effective dose is 640 µg of a compound of Formula (I) (e.g., treprostinil palmitil), which was the highest dose administered in a clinical trial, and it was surprisingly observed to be well tolerated. To treat more severe cases of PH, e.g., PH-ILD, PAH or PAH that progresses after administering 640 µg, the dose of a compound of Formula (I) (e.g., treprostinil palmitil), the dose can be uptitrated to a higher dose, such as a maximum tolerated dose (MTD), e.g., an MTD of 1280 μg, whichever is less In some embodiments, the higher dose is 720 µg, 800 µg, 880 µg, 960 µg, 1040 µg, 1120 µg, 1200 µg, or 1280 µg. Is some embodiments, the dose is increased in 160 µg increments. Is some embodiments, the dose is increased in 80 µg increments.

[0169] In some embodiments, the patient treated by the disclosed methods manifests one or more of the following therapeutic responses during the administration period as compared to prior to the administration period: (1) a reduction in the pulmonary vascular resistance index (PVRI), (2) a reduction in mean pulmonary artery pressure, (3) an increase in the hypoxemia score, (4) a decrease in the oxygenation index, (5) improved right heart function, and (6) improved exercise capacity (e.g., as measured by the six-minute walk test).

[0170] 6MWT is a validated method for measuring exercise capacity and assessment of pulmonary function, and performed according to the American Thoracic Society (ATS) guidelines. See American Thoracic Society. ATS Statement: Guidelines for the six minute walk test. Am J Respir Crit Care Med.2002;166(1):111-17, incorporated herein by reference in its entirety for all 45  Attorney Docket No. INMD-196 / 01WO   purposes. In some embodiments, the 6MWT is performed at approximately the same time on a day during the administration period as on a day prior to the administration period. In some further embodiments, the same equipment is used to perform the 6MWT. In still some further embodiments, the same person administers the 6MWT.

[0171] In some embodiments, the patient’s distance walked in the 6MWT is increased during the administration period, as compared to prior to the administration period, by at least about 5 meters, at least about 10 meters, at least about 20 meters, at least about 30 meters, at least about 40 meters, or at least about 50 meters. In some embodiments, the patient’s distance walked in the 6MWT is increased during the administration period, as compared to prior to the administration period, by from about 5 meters to about 60 meters, by from about 5 meters to about 50 meters, by from about 10 meters to about 50 meters, by from about 15 meters to about 50 meters, or by from about 20 meters to about 40 meters. In some embodiments, the patient’s distance walked in the 6MWT is increased by at least about 30 meters, during the administration period, compared to prior to the administration period.

[0172] In some embodiments, the patient’s distance walked in the 6MWT is increased during the administration period, as compared to prior to the administration period, by about 1%, by about 2%, by about 3%, by about 4%, by about 5%, by about 6%, by about 7%, by about 8%, by about 9%, by about 10%, by about 11%, by about 12%, by about 13%, by about 14%, by about 15%, by about 16%, by about 17%, by about 18%, by about 19%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, by about 55%, by about 60%, by about 65%, by about 70%, by about 75%, by about 80%, by about 85%, or by about 90%. In some embodiments, the patient’s distance walked in the 6MWT is increased during the administration period, as compared to prior to the administration period, by at least about 5%, by at least about 10%, by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, or by at least about 50%. In some embodiments, the patient’s distance walked in the 6MWT is increased during the administration period, as compared to prior to the administration period, by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30%, by about 5% to about 20%, by about 10% to about 50%, by about 15% to about 50%, by about 20% to about 50%, or by about 25% to about 50%. 46  Attorney Docket No. INMD-196 / 01WO

[0173] In some embodiments for treating PH, treating comprises improving the quality of life of the patient during the administration period, compared to the quality of life of the patient prior to the administration period. The quality of life, in some embodiments, is measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Questionnaire. McCabe et al. (2013). Chest. 2013;144(2):522-30, incorporated by reference herein in its entirety for all purposes. The CAMPHOR Questionnaire is a pulmonary hypertension specific measure of health- related quality of life (QOL) consisting of 3 sections that evaluate a total of 65 items (25 relating to symptoms, 15 relating to activities, and 25 relating to QOL). The CAMPHOR scoring is negatively weighted therefore, a higher score indicates worse QOL and greater functional limitation. Symptom and QOL items are both scored out of 25 and activity items have 3 possible responses (score 0-2), giving a score out of 30. Each CAMPHOR assessment takes an average of 10 minutes. In some embodiments for treating PH, treating comprises decreasing the patient’s CAMPHOR Questionnaire score during the administration period, compared to the CAMPHOR Questionnaire score prior to the administration period. The decrease, in some embodiments, is by from 1 to about 10, from 1 to about 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3 or from 1 to 2.

[0174] In some embodiments of a method for treating PH, the method comprises increasing the patient’s saturation of peripheral capillary oxygenation (SpO2) at rest assessed by pulse oximetry during the administration period, compared to the patient’s SpO2at rest prior to the administration period.

[0175] Oxygen saturation is an indication of how much hemoglobin in the blood is bound to oxygen, and is typically provided as a percentage of oxyhemoglobin to the total hemoglobin. SpO2 is an indication of oxygen saturation in the peripheral capillaries. Exemplary methods to measure SpO2 include, but are not limited to, pulse oximetry using a pulse oximeter. In some embodiments of a method for treating PH provided herein, the method comprises increasing the patient’s SpO2 at rest during the administration period, as compared to prior to the administration period, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 47  Attorney Docket No. INMD-196 / 01WO   25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or by at least about 90%. In some embodiments, the method for treating PH comprises increasing the patient’s SpO2 at rest during the administration period, as compared to prior to the administration period, by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30%, by about 5% to about 20%, by about 10% to about 50%, by about 15% to about 50%, by about 20% to about 50%, or by about 25% to about 50%.

[0176] In some embodiments, the method for treating PH provided herein comprises improving the lung function of the patient during the administration period, as compared to the lung function of the patient prior to the administration period. The improvement in lung function in some embodiments, is measured by spirometry.

[0177] Improving the lung function of the patient, in some embodiments, comprises increasing the patient’s forced vital capacity (FVC), increasing the patient’s percent predicted forced vital capacity (ppFVC), increasing the patient’s forced expiratory volume in 1 second (FEV1), increasing the patient’s percent predicted forced expiratory volume in one second (ppFEV1), increasing the patient’s forced expiratory flow between 25% and 75% of FVC (FEF(25-75%)), increasing the patient’s total lung capacity (TLC), or increasing the patient’s lung diffusion capacity for carbon monoxide (DLCO), during the administration period, as compared to the respective value prior to the administration period.

[0178] The assessment of lung function, e.g., via FVC, ppFVC, FEV1, ppFEV1, FEF(25-75%), TLC, or DLCO measurement, in some embodiments, comprises comparing the lung function in the patient prior to the administration period, e.g., immediately prior to treatment, to a time point during the administration period the administration period, or to an average of measurements taken during the administration period.

[0179] As provided herein, in some embodiments, the method for treating PH comprises improving the lung function in the patient during the administration period, as compared to the respective value prior to the administration period, wherein the lung function is measured by spirometry. Spirometry is a physiological test that measures how an individual inhales or exhales volumes of air. The primary signal measured in spirometry may be volume or flow. For the 48  Attorney Docket No. INMD-196 / 01WO   methods described herein, pulmonary function test (PFT) by spirometry (e.g., FEV1, FVC, FEF(25- 75%), and TLC) is performed per the American Thorasic Society (ATS) / European Respiratory Society (ERS) criteria, e.g., as set forth by Miller et al. (Miller et al., “Standardization of Spirometry,” Eur. Respir. J.26:319-38 (2005), incorporated by reference herein in its entirety for all purposes). DLCO can be measured using techniques described by Modi P, Cascella M, “Diffusing Capacity Of The Lungs For Carbon Monoxide,” [Updated 2021 Mar 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: www.ncbi.nlm.nih.gov / books / NBK556149 / ; Graham et al., “2017 ERS / ATS standards for single- breath carbon monoxide uptake in the lung,” European Respiratory Journal 49:1600016 (2017); each of which is incorporated herein by reference in its entirety for all purposes.

[0180] In some embodiments, the spirometer is capable of accumulating volume for greater than or equal to 15 seconds, e.g., ≥ 20 seconds, ≥ 25 seconds, ≥ 30 seconds, ≥ 35 seconds. The spirometer in some embodiments can measure volumes of ≥ 8 L (BTPS) with an accuracy of at least ± 3% of reading or ± 0.050 L, whichever is greater, with flows between 0 and 14 L•s-1. In some embodiments, the total resistance to airflow of the spirometer at 14 L•s-1is < 1.5 cmH2O•L-1•s-1(0.15 kPa•L-1•s-1). In some embodiments, the total resistance of the spirometer is measured with any tubing, valves, pre-filter, etc. included that may be inserted between the patient and the spirometer. With respect to devices that exhibit changes in resistance due to water vapor condensation, in some embodiments, spirometer accuracy requirements are met under BTPS (body temperature, ambient pressure, saturated with water vapor) conditions for up to eight successive FVC maneuvers performed in a 10-min period without inspiration from the instrument.

[0181] With respect to the forced expiratory maneuvers described herein, in some embodiments, the range and accuracy recommendations as set forth in Table 6 of Miller et al., are met (Miller et al., “Standardization of Spirometry,” Eur. Respir. J.26:319-38 (2005), incorporated by reference herein in its entirety for all purposes).

[0182] In some embodiments, improving lung function comprises improving the forced vital capacity (FVC) of the patient, i.e., the maximal volume of air exhaled with maximally forced effort from a maximal inspiration, during the administration period, as compared to the FVC prior to the administration period. The FVC is expressed in liters at body temperature and ambient pressure 49  Attorney Docket No. INMD-196 / 01WO   saturated with water vapor (BTPS). In some embodiments, the improvement in lung function is an improvement in the percent predicted forced vital capacity (ppFVC).

[0183] “Forced vital capacity” (FVC) denotes the volume of gas which is exhaled during a forced expiration starting from a position of full inspiration and ending at complete expiration and is one measure of treatment efficacy. FVC may be expressed as a percentage of the predicted FVC (i.e., ppFVC) obtained from a normal population, based on the patient’s age, height, gender, and sometimes weight and race. In some embodiments of a method for treating PH, improving the patient’s lung function comprises increasing the patient’s FVC or ppFVC during the administration period, compared to the patient’s corresponding FVC or ppFVC prior to the administration period. The increase in FVC or ppFVC, in some embodiments, is an increase of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the increase in FVC or ppFVC is an increase of from about 1% to about 20%, from about 1% to about 15%, from about 1% to about 10%, from about 1% to about 5%, from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 5% to about 20%, from about 10% to about 50%, from about 15% to about 50%, from about 20% to about 50%, or from about 25% to about 50%. In some embodiments, increasing FVC or ppFVC is increasing pre-bronchodilator FVC or ppFVC. In some embodiments, increasing FVC or ppFVC is increasing post-bronchodilator FVC or ppFVC.

[0184] In some embodiments, the patient’s ppFVC is 80% or less prior to the administration period. In some further embodiments, the patient’s ppFVC is 70% or less prior to the administration period. In some further embodiments, the patient’s ppFVC is 60% or less prior to the administration period. In some further embodiments, the patient’s ppFVC is 50% or less prior to the administration period. In some embodiments, the patient’s ppFVC is from 30% to 80%, from 40% to 70%, or from 50% to 60%, prior to the administration period.

[0185] FVC maneuvers can be performed according to the procedures known to those of ordinary skill in the art. Briefly, the three distinct phases to the FVC maneuver are (1) maximal inspiration; (2) a “blast” of exhalation and (3) continued complete exhalation to the end of test (EOT). The maneuver can be carried out via the closed circuit method or open circuit method. In 50  Attorney Docket No. INMD-196 / 01WO   either instance, the patient inhales rapidly and completely with a pause of less than 1 second at total lung capacity (TLC). The patient then exhales maximally until no more air can be expelled while maintaining an upright posture. The exhalation begins with a “blast” of air from the lungs and then is encouraged to fully exhale. Enthusiastic coaching of the patient continues for a minimum of three maneuvers.

[0186] FEV is the volume of gas exhaled in a specified time (typically 1 second, i.e., FEV1) from the start of the forced vital capacity maneuver (Quanjer et al. (1993). Eur. Respir. J.6, Suppl. 16, pp.5-40, incorporated by reference herein in its entirety for all purposes). FEV1 may also be expressed as a percentage of the predicted FEV1(i.e., ppFEV1) obtained from a normal population, based on the patient’s gender, height, and age, and sometimes race and weight.

[0187] In some embodiments, improving the lung function of the patient comprises increasing the patient’s FEV1 or ppFEV1 during the administration period, compared to the patient’s corresponding FEV1or ppFEV1prior to the administration period. The increase in FEV1or ppFEV1, in some embodiments, is an increase of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%. In some embodiments, the increase in FEV1or ppFEV1is an increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In some embodiments, increasing the FEV1 or ppFEV1 comprises increasing by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, increasing FEV1or ppFEV1is increasing of about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0188] In some embodiments, increasing FEV1or ppFEV1is increasing in pre-bronchodilator FEV1 or ppFEV1. In some embodiments, increasing FEV1 or ppFEV1 is increasing post- bronchodilator FEV1or ppFEV1. 51  Attorney Docket No. INMD-196 / 01WO

[0189] In some embodiments, the patient’s ppFEV1 is 80% or less prior to the administration period. In some further embodiments, the patient’s ppFEV1 is 70% or less prior to the administration period. In some further embodiments, the patient’s ppFEV1is 60% or less prior to the administration period. In some further embodiments, the patient’s ppFEV1 is 50% or less prior to the administration period. In some embodiments, the patient’s pp FEV1 is from 30% to 80%, from 40% to 70%, or from 50% to 60%, prior to the administration period.

[0190] In some embodiments, improving the lung function of the patient comprises increasing the patient’s FEV1 during the administration period, compared to prior to the administration period, by from about 25 mL to about 500 mL, from about 25 mL to about 400 mL, from about 25 mL to about 300 mL, from about 25 mL to about 250 mL, from about 25 mL to about 200 mL, or from about 50 mL to about 200 mL, as compared to the patient’s FEV1 prior to the administration period. In some embodiments, increasing FEV1 is increasing pre-bronchodilator FEV1. In some embodiments, increasing FEV1is increasing post-bronchodilator FEV1.

[0191] In some embodiments, improving the lung function of the patient comprises increasing the mean forced expiratory flow between 25% and 75% of FVC (FEF(25–75%)) (also referred to as the maximum mid-expiratory flow) of the patient during the administration period, as compared to the patient’s FEF(25–75%)prior to the administration period. The FEF(25-75%)measurement is dependent on the validity of the FVC measurement and the level of expiratory effort. The FEF(25-75%)index is taken from the blow with the largest sum of FEV1and FVC.

[0192] In some embodiments, increasing the patient’s FEF(25-75%)during the administration period comprises increasing by at least about 1%, by at least about 5%, by at least about 10%, by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, or by at least about 50%. In some embodiments, increasing the patient’s FEF(25-75%) during the administration period comprises increasing by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30%, by about 5% to about 20%, by about 10% to about 50%, by about 15% to about 50%, by about 20% to about 50%, or by about 25% to about 50%. In some embodiments, increasing FEF(25–75%)is increasing pre-bronchodilator FEF(25–75%). In some embodiments, increasing FEF(25–75%) is increasing post-bronchodilator FEF(25–75%). 52  Attorney Docket No. INMD-196 / 01WO

[0193] Total lung capacity (TLC) is the sum of the vital capacity and residual volume that represents the total volume of air that can be contained in the lung. The total lung capacity (TLC) is divided into four volumes. The tidal volume (VT) is the volume inhaled or exhaled in normal quiet breathing. The inspiratory reserve volume (IRV) is the maximum volume that can be inhaled following a normal quiet inhalation. The expiratory reserve volume (ERV) is the maximum volume that can be exhaled following a normal quiet exhalation. The residual volume (RV) is the volume remaining in the lungs following a maximal exhalation. The vital capacity (VC) is the maximum volume that can be exhaled following a maximal inhalation; VC=IRV+VT+ERV. In some embodiments, improving the lung function of the patient comprises increasing the patient’s total lung capacity (TLC) during the administration period, compared to the patient’s TLC prior to the administration period. In some embodiments, increasing is by at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or by at least about 50%. In some embodiments, increasing is by from about 1% to about 50%, by from about 5% to about 50%, by from about 5% to about 40%, by from about 5% to about 30%, by from about 5% to about 20%, by from about 10% to about 50%, by from about 15% to about 50%, by from about 20% to about 50%, or by from about 25% to about 50%.

[0194] Also known as the transfer factor, lung diffusion capacity for carbon monoxide (DLCO) is a measurement to assess the lungs' ability to transfer gas from inspired air to the bloodstream. Carbon monoxide (CO) has a high affinity for hemoglobin, and it follows the same pathway as that of oxygen to finally bind with hemoglobin. Inhaled CO is used for this test due to its high affinity for hemoglobin (200 to 250 times that of oxygen). As anemia can reduce DLCO, DLCO may be adjusted for hemoglobin values. DLCO may also need to be adjusted for several other factors, such as carboxyhemoglobin, FiO. See Modi P, Cascella M, “Diffusing Capacity Of The Lungs For Carbon Monoxide,” [Updated 2021 Mar 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan, incorporated herein by reference in its entirety for all purposes. In some embodiments, improving the lung function of the patient comprises increasing the patient’s DLCO during the administration period, compared to the patient’s DLCO prior to the administration period. In some embodiments, DLCO is adjusted for hemoglobin level, i.e., improving the lung function of the patient comprises increasing the patient’s DLCO adjusted for 53  Attorney Docket No. INMD-196 / 01WO   hemoglobin during the administration period compared to the patient’s DLCO adjusted for hemoglobin prior to the administration period. In some embodiments, improving the lung function of the patient comprises increasing the patient’s DLCO percent (DLCO %) predicted during the administration period compared to the patient’s DLCO % predicted prior to the administration period. Predicted normal DLCO values may be calculated according to the equation established by Crapo et al., Am Rev Respir Dis.123(2):185-9 (1981), or according to the equation established by Miller et al., Am Rev Respir Dis. 127(3):270-7 (1983), each of which is incorporated by reference in its entirety for all purposes. In some further embodiments, the patient’s DLCO % predicted is adjusted for hemoglobin.

[0195] In some embodiments, improving lung function comprises increasing the patient’s DLCO or DLCO % predicted by at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or by at least about 50%. In some embodiments, improving lung function comprises increasing the patient’s DLCO or DLCO % predicted by from about 5% to about 50%, by from about 5% to about 40%, by from about 5% to about 30%, by from about 5% to about 20%, by from about 10% to about 50%, by from about 15% to about 50%, by from about 20% to about 50%, or by from about 25% to about 50%. In some further embodiments, the patient’s DLCO or DLCO % predicted is adjusted for hemoglobin.

[0196] In some embodiments, the patient’s DLCO % predicted is 80% or less, 70% or less, 60% or less, or 50% or less, prior to the administration period. In some further embodiments, the patient’s DLCO % predicted is adjusted for hemoglobin. In some embodiments, the patient’s DLCO % predicted is from 30% to 80%, from 40% to 70%, or from 50% to 60%, prior to the administration period. In some further embodiments, the patient’s DLCO % predicted is adjusted for hemoglobin.

[0197] In some embodiments of a method for treating PH provided herein, the method comprises increasing the length of time to clinical worsening, as compared to an untreated PH patient, or a PH patient not treated with a compound of Formula (I) or (II), wherein the clinical worsening is one selected from the group consisting of death, hospitalization due to a respiratory indication (e.g., dyspnea, and / or deterioration of lung function indicated by reductions in FVC, 54  Attorney Docket No. INMD-196 / 01WO   DLCO, and / or SpO2), 10% or greater decline in percent predicted FVC (ppFVC) relative to the patient’s ppFVC prior to the administration period on two consecutive occasions 4-14 weeks apart, lung transplantation, and 15% or greater decrease in distance walked in a 6-minute walk test (6MWT) relative to the patient’s distance walked in a 6MWT prior to the administration period on two consecutive occasions at least 24 hours apart.

[0198] In some embodiments, the length of time to clinical worsening is increased by about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks. In some embodiments, the length of time to clinical worsening is increased by at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks. In some embodiments, the length of time to clinical worsening is increased about 20 days to about 100 days, about 30 days to about 100 days, about 20 days to about 75 days, about 20 days to about 50 days, or about 20 days to about 40 days. In some embodiments, the length of time to clinical worsening is increased at least 1 month, e.g., about 1 month to about 6 months, about 1 month to about 4 months, or about 1 month to about 3 months.

[0199] In some embodiments, a method for treating PH provided herein comprises increasing the patient’s lung lobar volume and / or airway volume assessed by computerized tomography (CT) during the administration period, compared to the patient’s lung lobar volume and / or airway volume prior to the administration period. CT may be performed via chest CT scan during a breathing cycle to generate CT images at functional residual capacity (FRC) and / or total lung capacity (TLC). In some embodiments, the lung lobar volume is the volume of the lung lobar structure of the patient’s respiratory system at TLC or FRC, and the airway volume is the volume of the airway structure of the patient’s respiratory system at TLC or FRC.

[0200] In some embodiments, increasing the patient’s lung lobar volume and / or airway volume comprises increasing by at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or by at least about 50%. In some embodiments, the patient’s lung lobar volume and / or airway volume is increased by from about 5% to about 50%, by from about 5% to about 40%, by from about 5% to about 30%, by from about 5% to about 20%, by from about 55  Attorney Docket No. INMD-196 / 01WO   10% to about 50%, by from about 15% to about 50%, by from about 20% to about 50%, or by from about 25% to about 50%.

[0201] FIG.15 is a flow chart of a method 60 for enabling a medicament delivery device and optionally delivering a medicament according to an embodiment. The method 60 can, in an embodiment, be performed via a medicament delivery system, such as medicament delivery system 1000 as described herein with reference to FIGS.1-12. However, it should be appreciated that in various embodiments, aspects of the method 60 may be accomplished via additional embodiments of the medicament delivery system 1000 or components thereof as described herein. Accordingly, the method 60 may be implemented on any suitable device as described herein. Thus, the method 60 is described below with reference to the cover 1100 and the medicament delivery device 1200 as previously described, but it should be understood that the method 60 can be employed using any of the devices described herein. FIGS.13 and 14 also provide a depiction of various operations of the method 60 implemented via the medicament delivery system 1000 as described herein.

[0202] As depicted at 62, the method 60 includes removing a body member of the medicament delivery device from within an interior volume of a cover to expose a delivery member. The body member and the delivery member are removed via an opening defined at a first end portion of the cover. As depicted at 64, the method 60 includes placing a second end portion of the cover onto a support surface such that the opening of the cover is exposed. As depicted at 66, the method 60 includes placing a base of the body member within the interior volume while maintaining the delivery member outside of the interior volume. As depicted at 68, the method 60 includes moving the body member within the interior volume such that an actuator of the medicament delivery device is moved to enable the medicament delivery device.

[0203] In some embodiments, the medicament delivery device is a dry powder inhaler containing a therapeutic dose of a dry powder composition. The dry powder composition comprises an effective amount of a compound of Formula (I): 56  Attorney Docket No. INMD-196 / 01WO  a pharmaceutically acceptable salt thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. In a further embodiment, R1is hexadecyl. In even a further embodiment, the compound of Formula (I) is treprostinil palmitil.

[0204] In some embodiments, the method 60 optionally includes inhaling on the mouthpiece, after the dry powder inhaler is enabled, to deliver the dry powder composition in aerosolized form to the patient’s lungs, as depicted at 70. This can involve first placing the delivery member (e.g., the mouthpiece) into the patient’s mouth over the tongue (see e.g., FIG.14). After the patient seals their lips around the mouthpiece, the patient then inhales. The inhalation causes delivery of the dry powder composition in aerosolized form to the lungs of the patient in need of treatment.

[0205] FIG. 13 is a graphical depiction of the method 60 implemented via the medicament delivery system 1000, as described herein, to transition the medicament delivery system 1000 from a stored configuration at Step A to an actuated configuration at Step E. Step A and FIGS.1 and 5 depict the medicament delivery system 1000 in the stored configuration in which the cover 1100 is coupled to the medicament delivery device 1200. As described herein, in some embodiments, in the stored configuration illustrated by FIG.8, the delivery member 1210 and the actuator 1220 of the medicament delivery device 1200 are surrounded and protected by the cover 1100. Removing the body member 1230 of the medicament delivery device 1200 from within the interior volume 1170 of the cover 1100, as depicted by the transition from Step A to Step B, transitions the medicament delivery device 1200 from the stored configuration. The transition from Step A to Step B can include separating the cover 1100 from the medicament delivery device 1200 and inverting the cover 1100. A support interface 1134 can be placed in contact with the support surface SS to support the cover 1100 with the longitudinal axis ALO of the cover 1100 orthogonal to the support surface SS. 57  Attorney Docket No. INMD-196 / 01WO

[0206] Additionally, in some embodiments, the medicament container assembly 1250 can be positioned or loaded within the body member 1230 prior to placing the base 1240 within the interior volume 1170. For example, in some embodiments, the delivery member 1210 can be rotated relative to the body member 1230 to expose a chamber. The medicament container assembly 1250 (which can be a capsule) can then be placed into the chamber and the delivery member 1210 can be rotated back to the closed position.

[0207] Step B depicts placing the base 1240 of the body member 1230 within the interior volume 1170 while maintaining the delivery member 1210 outside the interior volume 1170. Step C and FIGS. 6-8 depict the medicament delivery system 1000 in a ready configuration. In the ready configuration, the second end portion 1130 of the cover 1100 is in contact with the support surface SS, the medicament container assembly 1250 can be inserted within the body member 1230, and the base 1240 is inserted through the opening 1112 and into the interior volume 1170. In the ready configuration, the actuator 1220 is biased radially outward and in contact with the rib portion 1156. Accordingly, the medicament container assembly 1250 is in an unpunctured or unruptured configuration.

[0208] To transition the medicament delivery system 1000 from the ready configuration of Step C to a partially actuated configuration of Step D and FIGS.9 and 10, a force F applied to the medicament delivery device 1200 (e.g., to the delivery member 1210 and / or the body member 1230) in the direction of the support surface SS. As the support surface SS resists a movement of the cover 1100 in response to the force F, the medicament delivery device 1200 moves longitudinally relative to the cover 1100 in the direction of the support surface SS. This longitudinal movement results in the ramped portion 1154, via the rib portion 1156, moving the actuator 1220 radially inward as depicted at Step D. Said another way, the application of the force F moves the actuator 1220 into contact with the ramped portion 1154 via the rib portion 1156. The ramped portion 1154 moves the actuator 1220 relative to the body member 1230 to enable the medicament delivery device 1200.

[0209] In some embodiments, the force F is maintained on the medicament delivery device 1200 at Step D to transition the medicament delivery system 1000 to the actuated configuration depicted at Step E and FIGS. 11 and 12. As depicted, the force F is maintained on the delivery 58  Attorney Docket No. INMD-196 / 01WO   member 1210 and / or the body member 1230 until the base 1240 contacts the shoulder 1158 of the cover 1100 within the interior volume. The shoulder 1158 limits movement of the medicament delivery device 1200 within the interior volume 1170 toward the second end portion 1130. In other words, the positioning of the shoulder 1158 establishes a maximum longitudinal travel (e.g., degree of insertion) of the base 1240 upon actuation of the medicament delivery device 1200. In the actuated configuration depicted at Step E and FIGS. 11 and 12 the medicament container assembly 1250 is punctured or otherwise ruptured so that the therapeutic dose of the medicament previously contained therein can be accessed (e.g., inhaled) by the user.

[0210] For example, as shown in FIG.14, in some embodiments, the delivery member of the medicament delivery device 1200 can be placed into the patient’s mouth. In some embodiments, this can be done with the cover 1100 disposed about the base of the medicament delivery device 1200, as shown in FIG.14. In this manner, the cover 1100 can include additional features (e.g., a roughened or patterned surface) to facilitate gripping and handling during placement into the patient’s mouth. In other embodiments, however, the cover 1100 can be removed from the base of the medicament delivery device 1200 prior to the delivery member being inserted into the patient’s mouth. After the patient seals their lips around the mouthpiece, the patient then inhales. The inhalation causes delivery of the dry powder composition in aerosolized form to the lungs, as shown by the arrow AA.

[0211] FIG.16 is a flow chart of a method 80 for treating pulmonary hypertension in a patient in need thereof. The method 80 can, in an embodiment, be performed via a medicament delivery system, such as medicament delivery system 1000 as described herein with reference to FIGS. 1-12. However, it should be appreciated that in various embodiments, aspects of the method 80 may be accomplished via additional embodiments of the medicament delivery system 1000 or components thereof as described herein. Accordingly, the method 80 may be implemented on any suitable device as described herein. Thus, the method 80 is described below with reference to the cover 1100 and the medicament delivery device 1200 as previously described, but it should be understood that the method 80 can be employed using any of the devices described herein.

[0212] As depicted at 81, the method 80 includes removing a body member of a dry powder inhaler from within an interior volume of a cover to expose a mouthpiece. The body member and 59  Attorney Docket No. INMD-196 / 01WO   the mouthpiece are removed via an opening defined at a first end portion of the cover. As depicted at 82, in some embodiments, the method 80 optionally includes placing a second end portion of the cover onto a support surface such that the opening of the cover is exposed. As depicted at 83, in some embodiments, the method 80 optionally loading a medicament container assembly (e.g., a capsule) into the dry powder inhaler.

[0213] As depicted at 84, a base of the body member is moved through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a medicament container within the dry powder inhaler. The medicament container contains a dry powder composition comprising an effective amount of a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. In a further embodiment, R1is hexadecyl. In even a further embodiment, the compound of Formula (I) is treprostinil palmitil.

[0214] The method 80 further includes, at 85, inhaling on the mouthpiece, after moving the base, to deliver the dry powder composition in aerosolized form to the lungs of the patient.

[0215] While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Where methods and / or schematics described above indicate certain events and / or flow patterns occurring in certain order, the ordering of certain events and / or operations may be modified. While the embodiments have been particularly shown and described, it will be understood that various changes in form and details may be made.

[0216] Although various embodiments have been described as having particular features and / or combinations of components, other embodiments are possible having a combination of any features and / or components from any of embodiments as discussed above. 60

Claims

Attorney Docket No. INMD-196 / 01WO   What is claimed is:

1. A cover, comprising: a first end portion; a second end portion, the second end portion being configured to surround a delivery member of a medicament delivery device on a condition that the cover is coupled to the medicament delivery device in a storage configuration; and a wall extending between the first end portion and the second end portion, an inner surface of the wall at least partially defining an interior volume, the inner surface of the wall being configured to move an actuator of the medicament delivery device on a condition that the delivery member of the medicament delivery device is positioned outside of the interior volume and that the medicament delivery device is moved within the interior volume of the cover.

2. The cover of claim 1, wherein: an outer surface of the second end portion is configured to engage a support surface such that a longitudinal axis of the cover is maintained orthogonal to the support surface.

3. The cover of claim 2, wherein: the outer surface of the second end portion is one of planar or concave.

4. The cover of claim 2, wherein: a ratio of a surface area of the outer surface of the second end portion to a longitudinal length of the cover is in a range of 8:1 to 15:

1.

5. The cover of claim 2, wherein: the first end portion defines an opening into the interior volume; and a ratio of a major axis of the outer surface of the second end portion to a major axis of the opening is in a range of 1:1.2 to 1:1.

5.

6. The cover of claim 1, wherein: the inner surface of the wall includes a ramped portion configured to move the actuator. 61  Attorney Docket No. INMD-196 / 01WO   7. The cover of claim 6, wherein: the actuator is a first actuator; the ramped portion is a first ramped portion; and the inner surface of the wall includes a second ramped portion configured to move a second actuator of the medicament delivery device on a condition that the delivery member of the medicament delivery device is positioned outside of the interior volume and that the medicament delivery device is moved within the interior volume of the cover.

8. The cover of claim 1, wherein: the inner surface of the wall includes a rib portion; the rib portion extends radially inward from the inner surface of the wall; and the rib portion is configured to slidingly engage the actuator to move the actuator.

9. The cover of claim 8, wherein: the rib portion has a maximal width that is at least five percent and less than 15 percent of a maximal width of the actuator of the medicament delivery device.

10. The cover of claim 1, wherein: the inner surface of the wall includes a shoulder; the shoulder extends radially inward from the inner surface of the wall; and the shoulder is positioned to limit a longitudinal movement of the medicament delivery device within the interior volume toward the second end portion on the condition that the delivery member of the medicament delivery device is positioned outside of the interior volume.

11. The cover of claim 1, wherein: the first end portion is configured to cover the actuator on the condition that the cover is coupled to the medicament delivery device in a storage configuration.

12. The cover of claim 1, wherein: the actuator is coupled to a body member of the medicament delivery device; and 62  Attorney Docket No. INMD-196 / 01WO   the actuator is configured to move relative to the body member of the medicament delivery device as the medicament delivery device is moved within the interior volume of the cover.

13. The cover of claim 12, wherein: the actuator is configured to move radially inward relative to the body member of the medicament delivery device as the medicament delivery device is moved within the interior volume of the cover.

14. The cover of claim 1, wherein: the first end portion defines an opening into the interior volume; and the opening is sized to receive a base of the medicament delivery device.

15. The cover of claim 14, wherein: the base is positioned between the second end portion of the cover and the delivery member of the medicament delivery device on a condition that the medicament delivery device is in an actuated configuration.

16. The cover of claim 14, wherein: the first end portion of the cover surrounds the base on the condition that the delivery member is positioned outside the interior volume.

17. The cover of claim 1, wherein: the medicament delivery device is an inhaler; and the delivery member of the medicament delivery device is a mouthpiece.

18. The cover of claim 1, wherein: the medicament delivery device is an intranasal delivery device; and the delivery member of the medicament delivery device is a nozzle.

19. The cover of claim 1, wherein: 63  Attorney Docket No. INMD-196 / 01WO   the medicament delivery device is an injector; and the delivery member of the medicament delivery device is a needle.

20. A method, comprising: removing a body member of a medicament delivery device from within an interior volume of a cover to expose a delivery member, the body member and the delivery member being removed via an opening defined at a first end portion of the cover; placing a second end portion of the cover onto a support surface such that the opening of the cover is exposed; placing a base of the body member within the interior volume while maintaining the delivery member outside of the interior volume; and moving the body member within the interior volume such that an actuator of the medicament delivery device is moved to enable the medicament delivery device.

21. The method of claim 20, wherein placing the second end portion of the cover onto the support surface includes: placing a support interface of an outer surface of the second end portion onto the support surface thereby causing a longitudinal axis of the cover to be orthogonal to the support surface.

22. The method of claim 20, wherein removing the body member of the medicament delivery device from within the interior volume includes: separating the cover from the medicament delivery device.

23. The method of claim 20, wherein moving the body member within the interior volume includes: applying a force to at least one of the delivery member or the body member in a longitudinal direction toward the support surface.

24. The method of claim 23, wherein: the application of the force moves the actuator into contact with a ramped portion of the cover; and 64  Attorney Docket No. INMD-196 / 01WO   the ramped portion moves the actuator relative to the body member to enable the medicament delivery device.

25. The method of claim 23, wherein: the application of the force moves the actuator slidingly along a rib portion of the cover.

26. The method of claim 23, further comprising: maintaining the force applied to at least one of the delivery member or the body member until the base of the body member contacts a shoulder of the cover within the interior volume, the shoulder limiting movement of the medicament delivery device within the interior volume toward the second end portion.

27. The method of claim 20, wherein: the medicament delivery device is an inhaler; and the delivery member of the inhaler is a mouthpiece.

28. The method of claim 27, further comprising: positioning a medicament container assembly within the body member of the medicament delivery device prior to placing the base of the body member within the interior volume.

29. The method of claim 27, wherein the inhaler is a dry powder inhaler containing a therapeutic dose of a dry powder composition, the dry powder composition comprising an effective amount of a compound of Formula (I): or anacceptable salt thereof, wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. 65  Attorney Docket No. INMD-196 / 01WO   30. The method of claim 29, wherein the dry powder composition comprises treprostinil palmitil.

31. The method of any of claims 29 or 30, further comprising: inhaling on the mouthpiece, after the dry powder inhaler is enabled, to deliver the dry powder composition in aerosolized form to a lung.

32. A medicament delivery system, comprising: a medicament delivery device having a body member, a delivery member coupled to the body member, and an actuator movably coupled to the body member; a medicament container assembly configured to be positioned within the body member, the medicament container assembly including a therapeutic dose of a dry powder composition, the dry powder composition comprising an effective amount of a compound of Formula (I): acceptable salt thereof1, wherein R is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl; and a cover having a first end portion, a second end portion, and a wall extending between the first end portion and the second end portion, wherein: the second end portion is configured to surround the delivery member of the medicament delivery device on a condition that the cover is coupled to the medicament delivery device in a storage configuration, an inner surface of the wall at least partially defines an interior volume, and the inner surface of the wall is configured to move the actuator of the medicament delivery device on a condition that the delivery member of the medicament delivery device is positioned outside of the interior volume and that the medicament delivery device is moved within the interior volume of the cover. 66  Attorney Docket No. INMD-196 / 01WO   33. The medicament delivery system of claim 32, wherein: the medicament delivery device is a dry powder inhaler; the delivery member is a mouthpiece; and the medicament container assembly is a capsule containing the dry powder composition.

34. A method for treating pulmonary hypertension in a patient in need thereof, comprising: removing a body member of a dry powder inhaler from within an interior volume of a cover to expose a mouthpiece, the body member and the mouthpiece being removed via an opening defined by the cover; moving a base of the body member through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a medicament container within the dry powder inhaler, the medicament container containing a dry powder composition comprising an effective amount of a compound of Formula (I): accept1able salt thereof, wherein R is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl; and inhaling on the mouthpiece, after moving the base, to deliver the dry powder composition in aerosolized form to the lungs of the patient.

35. The method of claim 34, wherein the medicament container is a capsule, the method further comprising: loading, before the moving a base of the body member through the opening and within the interior volume, the capsule into the dry powder inhaler.

36. The method of claim 34, wherein the opening is defined at a first end portion of the cover, the method further comprising: 67  Attorney Docket No. INMD-196 / 01WO   placing, before the moving a base of the body member through the opening and within the interior volume, a second end portion of the cover onto a support surface such that the opening of the cover is exposed.

37. The method of claim 34, wherein the dry powder composition comprises treprostinil palmitil.

38. The method of claim 37, wherein the treprostinil palmitil is a crystal Form I.

39. The method of claim 37, wherein the treprostinil palmitil is a crystal Form II.

40. The method of claim 34, wherein the inhaling on the mouthpiece includes completing 1 to 5 inhalations.

41. The method of any of claim of any of claims 34-40, wherein moving the body member within the interior volume includes: applying a force to at least one of the mouthpiece or the body member.

42. The method of claim 41, wherein: the application of the force moves the actuator into contact with a ramped portion of the cover; and the ramped portion moves the actuator relative to the body member to enable the dry powder inhaler.

43. The method of claim 41, wherein: the application of the force moves the actuator slidingly along a rib portion of the cover.

44. The method of claim 41, further comprising: maintaining the force applied to at least one of the mouthpiece or the body member until the base of the body member contacts a shoulder of the cover within the interior volume, the 68  Attorney Docket No. INMD-196 / 01WO   shoulder limiting movement of the dry powder inhaler within the interior volume toward the second end portion.

45. The method of claim 34, wherein the placing the base of the body member within the interior volume is performed while maintaining the mouthpiece outside of the interior volume.

46. The method of claim 34, wherein the base of dry powder inhaler is at first end of the dry powder inhaler and the mouthpiece is at a second end of the dry powder inhaler.

47. A method for delivering a dry powder composition to a lung of a patient, comprising: removing a body member of a dry powder inhaler from within an interior volume of a cover to expose a mouthpiece, the body member and the mouthpiece being removed via an opening defined by the cover; moving the body member through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a medicament container within the dry powder inhaler, the medicament container containing the dry powder composition, the moving being performed while maintaining the mouthpiece outside of the interior volume; and inhaling on the mouthpiece, after moving the base, to deliver the dry powder composition in aerosolized form to the lung.

48. The method of claim 47, wherein the medicament container is a capsule comprising a compound of Formula (I):acceptable salt thereof, wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. 69  Attorney Docket No. INMD-196 / 01WO   49. The method of claim 48, wherein the dry powder composition comprises treprostinil palmitil.

50. The method of claim 48, further comprising: loading, before the moving a base of the body member through the opening and within the interior volume, the capsule into the dry powder inhaler.

51. A method for treating pulmonary hypertension in a patient in need of treatment, comprising: once daily, during an administration period: (a) removing a body member of a dry powder inhaler from within an interior volume of a cover to expose a mouthpiece, the body member and the mouthpiece being removed via an opening defined by the cover; (b) moving a base of the body member through the opening and within the interior volume such that an actuator of the dry powder inhaler is moved to pierce a medicament container within the dry powder inhaler, the medicament container containing a dry powder composition; and (c) inhaling on the mouthpiece, after moving the base, to deliver the dry powder composition in aerosolized form to the lungs of the patient; wherein, the dry powder composition comprises an effective amount of a compound of Formula (I): or anacceptable salt thereof, wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, wherein the administration period comprises (i) a titration period and (ii) a maintenance period; 70  Attorney Docket No. INMD-196 / 01WO wherein during the titration period, the dry powder composition comprises a starting dose of about 80-160 μg of the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, and the starting dose is titrated to a maximum tolerated dose (MTD) of 1280 μg or less; and wherein during the maintenance period, the MTD is present in the dry powder composition.

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