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WO2025096521A1 - Dispositif d'administration de médicament, couvercle et procédés d'administration de médicament - Google Patents

Dispositif d'administration de médicament, couvercle et procédés d'administration de médicament Download PDF

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Publication number
WO2025096521A1
WO2025096521A1 PCT/US2024/053536 US2024053536W WO2025096521A1 WO 2025096521 A1 WO2025096521 A1 WO 2025096521A1 US 2024053536 W US2024053536 W US 2024053536W WO 2025096521 A1 WO2025096521 A1 WO 2025096521A1
Authority
WO
WIPO (PCT)
Prior art keywords
cover
delivery device
medicament delivery
dry powder
interior volume
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/053536
Other languages
English (en)
Inventor
Jung Soo Park
Tom FREJOWSKI
Inna Lobel
Julian D. MICKELSON
Adam Christopher Wrigley
Gerald O'brien
Fraz Ismat
Ariel Teper
Eugene Sullivan
Carlos Fernandez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Insmed Inc
Original Assignee
Insmed Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Insmed Inc filed Critical Insmed Inc
Publication of WO2025096521A1 publication Critical patent/WO2025096521A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0021—Mouthpieces therefor
    • A61M15/0025—Mouthpieces therefor with caps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A61M15/0033—Details of the piercing or cutting means
    • A61M15/0041—Details of the piercing or cutting means with movable piercing or cutting means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/08—Inhaling devices inserted into the nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
    • A61M2205/586—Ergonomic details therefor, e.g. specific ergonomics for left or right-handed users

Definitions

  • 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.
  • 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.
  • some single-dose dry powder inhalers use a capsule that contains a single therapeutic dose of the medicament.
  • the capsule containing the single 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.
  • 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.
  • 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
  • the outer surface of the second end portion is one of planar or concave.
  • 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.
  • 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.
  • the inner surface of the wall includes a ramped portion configured to move the actuator.
  • the actuator is a first actuator
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the first end portion defines an opening into the interior volume. The opening is sized to receive a base of the medicament delivery device.
  • 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.
  • the first end portion of the cover surrounds the base on the condition that the delivery member is positioned outside the interior volume.
  • the medicament delivery device is an inhaler, and the delivery member of the medicament delivery device is a mouthpiece.
  • the medicament delivery device is an intranasal delivery device, and the delivery member of the medicament delivery device is a nozzle.
  • the medicament delivery device is an injector, and the delivery member of the medicament delivery device is a needle.
  • 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).
  • the DPI is capsule-based.
  • 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.
  • removing the body member of the medicament delivery device from within the interior volume includes separating the cover from the medicament delivery device.
  • 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.
  • 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.
  • the application of the force moves the actuator slidingly along a rib portion of the cover.
  • 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]
  • the medicament delivery device is an inhaler, and the delivery member of the inhaler is a mouthpiece.
  • the inhaler is a DPI.
  • the DPI is a capsule-based DPI.
  • 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.
  • 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).
  • 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.
  • 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).
  • the compound present in the dry powder composition is treprostinil palmitil.
  • 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.
  • 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 an acceptable 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.
  • R 1 is hexadecyl.
  • the compound of Formula (I) is treprostinil palmitil.
  • 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.
  • 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.
  • the dry powder composition comprises treprostinil palmitil.
  • the treprostinil palmitil is a crystal Form I.
  • the treprostinil palmitil is a crystal Form II. 7 Attorney Docket No.
  • the inhaling on the mouthpiece includes completing 1 to 5 inhalations (i.e., puffs).
  • 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.
  • 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.
  • 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, R 1 is 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.
  • 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.
  • the dry powder composition comprises a starting dose of about 80-160 ⁇ g 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 ⁇ g or less.
  • MTD maximum tolerated dose
  • 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.
  • FIG.2 is a perspective view of the cover of FIG.1.
  • 9 Attorney Docket No. INMD-196/01WO
  • FIG.3 is a cross-sectional view of the cover of FIG.1 taken at line x1-x1 in FIG.2.
  • FIG.4 is a cross-sectional view of the cover of FIG.1 taken at line x2-x2 in FIG.2.
  • FIG. 5 is a cross-sectional view of the medicament delivery system of FIG. 1 in the storage configuration taken at line x3-x3.
  • FIG. 6 is a perspective view of the medicament delivery system in a ready configuration.
  • FIG. 7 is a cross-sectional view of the medicament delivery system of FIG. 6 in the ready configuration taken at line x 4 -x 4 .
  • FIG.8 is a cross-sectional view of the medicament delivery system of FIG.6 taken at line x 5 -x 5 .
  • FIG.9 is a perspective view of the medicament delivery system in a partially actuated configuration.
  • FIG.10 is a cross-sectional view of the medicament delivery system of FIG.9 taken at line x6-x6.
  • FIG. 11 is a perspective view of the medicament delivery system in an actuated configuration.
  • FIG.12 is a cross-sectional view of the medicament delivery system of FIG.9 taken at line x 7 -x 7 .
  • 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.
  • FIG.14 is an illustration of the medicament delivery system being used to deliver a dry powder in aerosolized form, according to an embodiment.
  • FIG. 15 is a flow chart of a method for enabling a medicament delivery device and optionally delivering a medicament, according to an embodiment.
  • FIG. 16 is a flow chart of a method of delivering a medicament, according to an embodiment Detailed Description
  • 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.
  • the delivery member e.g., a mouthpiece, a nasal piece, or a needle
  • 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.
  • 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.
  • 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.
  • 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.
  • WHO World Health Organization
  • 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).
  • 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
  • group 1 PH 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
  • 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.
  • COPD chronic obstructive pulmonary disease
  • ILD interstitial lung disease
  • Group 4 pulmonary hypertension is pulmonary hypertension due to chronic thrombotic and/
  • 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).
  • 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.
  • the pulmonary hypertension treated is chronic thromboembolic pulmonary hypertension.
  • the pulmonary hypertension is group 1 PH, as characterized by the WHO.
  • the method provided herein is a method for treating treated is pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • 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).
  • NYHA New York Heart Association
  • 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.
  • 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).
  • “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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cover can include a structure that matingly surrounds the delivery member to limit or prevent ingress of contaminants into the delivery member.
  • the medicament delivery device can be an injector and cover can include a needle guard that covers the needle.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cover 1100 defines a longitudinal axis ALO (FIG.3), a first lateral axis ALA1 (FIG. 3), and a second lateral axis A LA2 (FIG. 4).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 A LO . 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).
  • 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 A LO of 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 A LO can, for example, be in a substantially vertical orientation.
  • 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 A LO .
  • the portion of outer surface 1151 of the second end portion 1130 positioned to engage the support surface SS is generally concave.
  • 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.
  • 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.
  • 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).
  • 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 A LO orthogonal to (e.g., extending from) the support surface SS.
  • 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.
  • 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.
  • the first end portion 1110 defines an opening 1112 (FIG.2) into the interior volume 1170.
  • 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.
  • 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 A LO . 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.
  • the length of a major axis A M1 of 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.
  • a ratio of the length of a major axis A M1 to the length of a major axis A M2 is 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 A LO relative to the support surface SS.
  • the major axis A M1 of the outer surface 1151 of the second end portion 1130 and the major axis A M2 of 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 A LA1 and correspond to a thickness of the cover 1100 at the first end portion 1110 and the second end portion 1130.
  • 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 A LA2 . Said another way, the ramped portion 1154 can be an 18 Attorney Docket No.
  • the ramped portion 1154 is configured to move the actuator 1220 of the medicament delivery device 1200.
  • the ramped portion 1154 can be configured to cause the actuator 1220 to move radially inward toward the longitudinal axis A LO in response to a longitudinal movement of the body member 1230 toward the support surface SS.
  • 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 A LA1 to 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.
  • 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 W M2 of the actuator 1220.
  • the narrowness of the rib portion 1156 relative to the maximal width W M2 of 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the actuator 1226 configured to move radially inward relative to the body member 1230.
  • 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.
  • the 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.
  • 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.
  • 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.
  • 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.
  • the inhaler can be a reusable dry powder inhaler that can be used to deliver medicament from a single-dose capsules.
  • the medicament delivery device 1200 can be an intranasal device, and the delivery member 1210 can be a nozzle.
  • the cover 1100 can be configured to receive the nozzle in the storage configuration.
  • the medicament delivery device 1200 can be an injector, and the delivery member 1210 can be a needle.
  • the cover 1100 can be configured to receive the needle in the storage configuration.
  • 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.
  • 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.
  • the dry powder composition includes, in some embodiments, a compound of Formula (I): 21 Attorney Docket No.
  • R 1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl.
  • R 1 is tetradecyl.
  • R 1 is linear tetradecyl.
  • R 1 is pentadecyl.
  • R 1 is linear pentadecyl.
  • R 1 is heptadecyl. In a further embodiment, R 1 is linear heptadecyl. [0097] In some embodiments of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R 1 is octadecyl. In a further embodiment, R 1 is 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.
  • CAS Chemical Abstract Services
  • R 1 is hexadecyl.
  • 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]
  • 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).
  • TP treprostinil palmitil
  • the compound of Formula (II) or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of a compound of Formula (II).
  • 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 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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°.
  • the treprostinil palmitil is a crystal Form I having an XRPD pattern exhibiting peaks at the 2 ⁇ 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.
  • d of Formula (I) is treprost p 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.
  • treprostinil palmitil crystal Form II has an XRPD pattern exhibiting peaks at two, three, four, five or all of the following 2 ⁇ 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°.
  • 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 2 ⁇ 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°.
  • the treprostinil palmitil is a crystal Form II having an XRPD pattern exhibiting peaks at the 2 ⁇ 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.
  • 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.
  • the dry powder composition is present in the medicament container.
  • the medicament container is a capsule for use within a dry powder inhaler (DPI).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, R 1 is hexadecyl, e.g., linear hexadecyl.
  • 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.
  • 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 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.
  • 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).
  • the sugar is mannitol.
  • the leucine in some embodiments, is L-leucine.
  • 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.
  • 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.
  • the medicament container e.g., a dry powder capsule
  • the medicament container 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.
  • 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.
  • 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.
  • the pulmonary hypertension is group 3 PH, as characterized by the WHO.
  • the method provided herein is a method for treating PH associated with interstitial lung disease (PH-ILD).
  • 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.
  • 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.
  • CCD-ILD connective tissue disease- associated interstitial lung disease
  • the ILD is sarcoidosis.
  • the ILD is IPF.
  • ILD is an idiopathic interstitial pneumonia (IIP).
  • IIP idiopathic interstitial pneumonia
  • the ILD includes pulmonary fibrosis, e.g., idiopathic pulmonary fibro
  • 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.
  • 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.
  • time 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 ⁇ g to about 200 ⁇ g, for example by about 80 ⁇ g or by about 160 ⁇ g. In a preferred embodiment, the incremental increase is by about 80 ⁇ g. In a preferred embodiment, the incremental increase is by about 160 ⁇ g.
  • 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.
  • 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 ⁇ g.
  • the titration period comprises an upwards dose titration.
  • 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 ⁇ g.
  • 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 ⁇ g increment.
  • 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 ⁇ g increment.
  • the medicament delivery device e.g., DPI
  • medicament container e.g., dry powder capsule
  • the medicament delivery device e.g., DPI
  • medicament container e.g., dry powder capsule
  • 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 ⁇ g of a compound of Formula (I), wherein R 1 is 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 ⁇ g or less, administered once daily in a single dosing session.
  • MTD maximum tolerated dose
  • R 1 is hexadecyl.
  • an administration period can comprise both a titration period and a maintenance period, where a MTD is administered.
  • 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 ⁇ g 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 ⁇ g or less, and wherein during the maintenance period, the MTD is administered once daily in a single dosing session.
  • MTD maximum tolerated dose
  • 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.
  • the compound is administered via a dry powder inhaler (DPI) (medicament delivery device).
  • DPI dry powder inhaler
  • 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).
  • the titration period comprises an upwards dose titration.
  • 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 ⁇ g.
  • 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 ⁇ g increment.
  • 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 ⁇ g increment.
  • the starting dose is titrated to one or more doses selected from about 160 ⁇ g, about 240 ⁇ g, about 320 ⁇ g, about 400 ⁇ g, about 450 ⁇ g, about 480 ⁇ g, about 640 ⁇ g, about 720 ⁇ g, about 800 ⁇ g, about 880 ⁇ g, about 960 ⁇ g, about 1040 ⁇ g, about 1120 ⁇ g, about 1200 ⁇ g, or about 1280 ⁇ g.
  • the starting dose is titrated by increments of about 80 ⁇ g or 160 ⁇ g until achieving a dose of about 700-1300 ⁇ g. In one embodiment, the starting dose is 80 ⁇ g. In another embodiment, the starting dose is 160 ⁇ g. 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 ⁇ g to about 1280 ⁇ g.
  • the MTD is about 720 ⁇ g, about 800 ⁇ g, about 880 ⁇ g, about 960 ⁇ g, about 1040 ⁇ g, about 1120 ⁇ g, about 1200 ⁇ g, or about 1280 ⁇ g.
  • 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.
  • 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.
  • 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.
  • 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).
  • DPI mediumcament delivery device
  • a “dosing session” refers to 1 to 5 inhalations (puffs) from a DPI as required to administer from about 80 ⁇ g to about 1280 ⁇ g 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 ⁇ g dose, two 320 ⁇ g DPI capsules can be used.
  • 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.
  • 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.
  • the fixed dose ranges from about 80 ⁇ g to about 1280 ⁇ g of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, e.g., about 80 ⁇ g, about 112.5 ⁇ g, about 160 ⁇ g, about 225 ⁇ g, about 240 ⁇ g, about 320 ⁇ g, about 400 ⁇ g, about 450 ⁇ g, about 480 ⁇ g, about 640 ⁇ g, 675 ⁇ g, about 720 ⁇ g, about 800 ⁇ g, about 880 ⁇ g, about 960 ⁇ g, about 1040 ⁇ g, about 1120 ⁇ g, about 1200 ⁇ g, or about 1280 ⁇ g of the compound of Formula (II), a stereoisomer thereof, or pharmaceutically acceptable salt thereof.
  • 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.
  • 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 ⁇ g, about 112.5 ⁇ g, about 160 ⁇ g, about 225 ⁇ g, about 240 ⁇ g, about 320 ⁇ g, about 400 ⁇ g, about 450 ⁇ g, about 480 ⁇ g, about 640 ⁇ g, 675 ⁇ g, about 720 ⁇ g, about 800 ⁇ g, about 880 ⁇ g, about 960 ⁇ g, about 1040 ⁇ g, about 1120 ⁇ g, about 1200 ⁇ g, or about 1280 ⁇ g 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.
  • the capsule comprises a dry powder composition including about 320 ⁇ g 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 ⁇ g, even if takes 2 or more puffs from two capsules to administer the 640 ⁇ g.
  • the amount administered is 640 ⁇ g 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).
  • 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.
  • one 80 ⁇ g capsule and one 160 ⁇ g capsule may be used to administer a dosage of 240 ⁇ g of a compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the DPI may be filed with a first 80 ⁇ g capsule, and after emptying the cartridge in 1 or more puffs, a 160 ⁇ g 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 ⁇ g.
  • the effective amount comprises an escalating dose during the administration period.
  • the effective amount is based upon an upwards titration, based on the highest tolerated dose for the patient.
  • the patient is initially administered 80 ⁇ g. 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.
  • each patient’s dose can be uptitrated to the maximum tolerated dose for that patient.
  • a patient starts the method of the invention with a single 80 ⁇ g DPI capsule, once-daily. If this dose is well tolerated, the dose is uptitrated until reaching the patient’s highest tolerable dose.
  • 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 ⁇ g, 160 ⁇ g, or 240 ⁇ g, 3 days at 320 ⁇ g or 4 days at 400 ⁇ g or 480 ⁇ g) prior to starting the next higher dose.
  • 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.
  • 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.
  • 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.
  • the administration period comprises a 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 ⁇ g.
  • a patient tolerates a dose of 1280 ⁇ g then 1280 ⁇ g is considered the maximum tolerated dose.
  • an individual maximum tolerated dose may be less than 1280 ⁇ g.
  • a patient’s maximum tolerated dose is selected from the group consisting of 720 ⁇ g, 800 ⁇ g, 880 ⁇ g, 960 ⁇ g, 1040 ⁇ g, 1120 ⁇ g, 1200 ⁇ g and 1280 ⁇ g.
  • 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.
  • the titration period comprises an upwards dose titration (also referred to as a uptitration).
  • the upwards titration is initiated from a starting dose and the starting dose is incrementally increased until reaching the maximum tolerated dose.
  • 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.
  • a dose X of the compound of Formula (I), or enantiomer, diastereomer or pharmaceutically acceptable salt thereof is increased by about 80 ⁇ g to about 200 ⁇ g to a dose Y (e.g., by about 80 ⁇ g to about 160 ⁇ g or by about 80 ⁇ g), if the patient is shown to tolerate dose X.
  • dose X may be the starting dose or any dose between the starting dose and the maximum tolerated dose
  • dose Y may be the next sequential dose (e.g., a dose that is 80-160 ⁇ g higher than dose X), or dose Y may be the patient’s maximum tolerated dose.
  • 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 ⁇ g 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 ⁇ g, and repeating until reaching the maximum tolerated dose.
  • a period of time e.g., 2-7 days
  • the upwards titration comprises increasing the dose of the compound of Formula (I), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof by increments of about 80-160 ⁇ g.
  • 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 ⁇ g.
  • 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 ⁇ g.
  • 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.
  • 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.
  • the maximum tolerated dose is about 1280 ⁇ g.
  • a patient’s maximum tolerated dose is selected from the group consisting of 720 ⁇ g, 800 ⁇ g, 880 ⁇ g, 960 ⁇ g, 1040 ⁇ g, 1120 ⁇ g, 1200 ⁇ g and 1280 ⁇ g.
  • the maximum tolerated dose is 1280 ⁇ g.
  • the maximum tolerated dose is 1200 ⁇ g.
  • the maximum tolerated dose is 1120 ⁇ g.
  • the maximum tolerated dose is 1040 ⁇ g.
  • the maximum tolerated dose is 960 ⁇ g.
  • the maximum tolerated dose is 880 ⁇ g.
  • the maximum tolerated dose is 800 ⁇ g. In some embodiments, the maximum tolerated dose is 720 ⁇ g. 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.
  • 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).
  • 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.
  • a patient in one embodiment, is initially administered a starting dose of 80 ⁇ g of a compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, once daily during a single dosing session.
  • the compound of Formula (I) is treprostinil palmitil and is present in a dry powder composition.
  • the 80 ⁇ g of the compound of Formula (I), in one embodiment, is present in a dry powder composition, for example, in a single DPI capsule.
  • Uptitration 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 ⁇ g after a patient is shown to tolerate a prior dose for about 2-7 days.
  • a patient in one embodiment, is initially administered a starting dose of 160 ⁇ g of a compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, once daily during a single dosing session.
  • the compound of Formula (I) is treprostinil palmitil and is present in a dry powder composition.
  • the 160 ⁇ g 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.
  • the dose is gradually (in increments) uptitrated until reaching the patient’s maximum tolerated dose.
  • Uptitration comprises incrementally increasing the patient’s dose of the compound of Formula (I) by about 80 or 160 ⁇ g after a patient is shown to tolerate a prior dose for about 2-7 days.
  • 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.
  • a patient During a titration period, a patient’s maximum tolerated dose does not exceed 1280 ⁇ g. In other words, the titration period ends when a patient is shown to tolerate a dose of 1280 ⁇ g.
  • the maximum tolerated dose is 1280 ⁇ g.
  • the maximum tolerated dose is 1200 ⁇ g.
  • the maximum tolerated dose is 1120 ⁇ g.
  • the maximum tolerated dose is 1040 ⁇ g.
  • the maximum tolerated dose is 960 ⁇ g.
  • the maximum tolerated dose is 880 ⁇ g.
  • the maximum tolerated dose is 800 ⁇ g.
  • the maximum tolerated dose is 720 ⁇ g.
  • the patient’s maximum tolerated dose is administered to the patient as a maintenance dose to treat the pulmonary hypertension in the patient.
  • the 1280 ⁇ g dose is administered to the patient as a maintenance dose to treat the pulmonary hypertension in the patient.
  • 1200 ⁇ g, 1120 ⁇ g, 1040 ⁇ g, 960 ⁇ g, 880 ⁇ g, 800 ⁇ g, or 720 ⁇ g 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.
  • the 1280 ⁇ g dose in one embodiment, is present in multiple capsules for use with a capsule-based DPI.
  • the patient continues to administer the maximum tolerated dose (e.g., about 1280 ⁇ g), for a period of time during a maintenance treatment 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the dose is uptitrated in increments of from about 10 ug to about 200 ⁇ g, e.g., about 10 ⁇ g, about 15 ⁇ g, about 20 ⁇ g, about 30 ⁇ g, about 40 ⁇ g, about 50 ⁇ g, about 60 ⁇ g, about 70 ⁇ g, about 80 ⁇ g, about 90 ⁇ g, about 100 ⁇ g, about 110 43 Attorney Docket No.
  • the dose is uptitrated in increments of about 80 ⁇ g or about 160 ⁇ g until the patient’s maximum tolerated dose is achieved or a dose of 1280 ⁇ g is achieved. In yet another embodiment, during the titration period, the dose is uptitrated in increments of 80 ⁇ g until the patient’s maximum tolerated dose is achieved or a dose of 1280 ⁇ g is achieved.
  • the patient receives one or more of a 720 ⁇ g dose, an 800 ⁇ g dose, an 880 ⁇ g dose, a 960 ⁇ g dose, a 1040 ⁇ g dose, a 1120 ⁇ g dose, a 1200 ⁇ g dose, and a 1280 ⁇ g dose.
  • the maximum tolerated dose of a patient undergoing a PH treatment method is 720 ⁇ g, 800 ⁇ g, 880 ⁇ g, 960 ⁇ g, 1040 ⁇ g, 1120 ⁇ g, 1200 ⁇ g, or 1280 ⁇ g. [0167]
  • the patient is shown to tolerate a dose before titrating to a higher dose.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ g is achieved, to 1280 ⁇ g daily.
  • the previously effective dose ranges from 160-640 ⁇ g, 240-640 ⁇ g, 320-640 ⁇ g, 400-640 ⁇ g, 480-640 ⁇ g, or 560-640-640 ⁇ g of a compound of Formula (I) (e.g., treprostinil palmitil).
  • the previously effective dose is 640 ⁇ g 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.
  • the dose of a compound of Formula (I) can be uptitrated to a higher dose, such as a maximum tolerated dose (MTD), e.g., an MTD of 1280 ⁇ g, whichever is less
  • MTD maximum tolerated dose
  • the higher dose is 720 ⁇ g, 800 ⁇ g, 880 ⁇ g, 960 ⁇ g, 1040 ⁇ g, 1120 ⁇ g, 1200 ⁇ g, or 1280 ⁇ g.
  • the dose is increased in 160 ⁇ g increments.
  • the dose is increased in 80 ⁇ g increments.
  • 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).
  • PVRI pulmonary vascular resistance index
  • 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.
  • 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.
  • the same equipment is used to perform the 6MWT.
  • the same person administers the 6MWT.
  • 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.
  • 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%.
  • 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%.
  • 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%.
  • 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 is measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Questionnaire.
  • 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.
  • 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.
  • 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 SpO 2 at rest prior to the administration period.
  • SpO2 peripheral capillary oxygenation
  • 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.
  • 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.
  • 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%.
  • 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.
  • Improving the lung function of the patient 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.
  • FVC forced vital capacity
  • ppFVC percent predicted forced vital capacity
  • FEV1 forced expiratory volume in 1 second
  • ppFEV1 percent predicted forced expiratory volume in one second
  • FVC forced expiratory flow between 25% and 75% of FVC
  • TLC total lung capacity
  • DLCO carbon monoxide
  • the assessment of lung function 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.
  • 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.
  • PFT pulmonary function test
  • spirometry e.g., FEV1, FVC, FEF(25- 75%), and TLC
  • ATS American Thorasic Society
  • ERS European Respiratory Society
  • 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.
  • 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 .
  • the total resistance to airflow of the spirometer at 14 L•s -1 is ⁇ 1.5 cmH2O•L- 1 •s -1 (0.15 kPa•L -1 •s -1 ).
  • 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.
  • 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.
  • BTPS body temperature, ambient pressure, saturated with water vapor
  • 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.
  • 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.
  • FVC forced vital capacity
  • the FVC is expressed in liters at body temperature and ambient pressure 49 Attorney Docket No. INMD-196/01WO saturated with water vapor (BTPS).
  • the improvement in lung function is an improvement in the percent predicted forced vital capacity (ppFVC).
  • FVC Formal vital capacity
  • ppFVC predicted FVC
  • 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%.
  • 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%.
  • 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.
  • 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.
  • the patient’s ppFVC is from 30% to 80%, from 40% to 70%, or from 50% to 60%, prior to the administration period.
  • 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.
  • TLC total lung capacity
  • FEV is the volume of gas exhaled in a specified time (typically 1 second, i.e., FEV 1 ) 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 FEV 1 (i.e., ppFEV 1 ) obtained from a normal population, based on the patient’s gender, height, and age, and sometimes race and weight.
  • 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 FEV 1 or ppFEV 1 prior to the administration period.
  • the increase in FEV 1 or 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%.
  • the increase in FEV 1 or ppFEV 1 is an increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.
  • 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%.
  • increasing FEV 1 or ppFEV 1 is 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%.
  • increasing FEV 1 or ppFEV 1 is increasing in pre-bronchodilator FEV1 or ppFEV1.
  • increasing FEV1 or ppFEV1 is increasing post- bronchodilator FEV 1 or ppFEV 1 . 51 Attorney Docket No. INMD-196/01WO [0189]
  • the patient’s ppFEV1 is 80% or less prior to the administration period.
  • the patient’s ppFEV1 is 70% or less prior to the administration period. In some further embodiments, the patient’s ppFEV 1 is 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.
  • 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.
  • increasing FEV1 is increasing pre-bronchodilator FEV1.
  • increasing FEV 1 is increasing post-bronchodilator FEV 1 .
  • 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.
  • FEF 25-75%
  • the FEF(25- 75%) index is taken from the blow with the largest sum of FEV 1 and FVC.
  • 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%.
  • 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%.
  • Total lung capacity 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 (V T ) 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.
  • 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.
  • 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%.
  • 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%.
  • lung diffusion capacity for carbon monoxide 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).
  • 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].
  • 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.
  • 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.
  • 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.
  • the patient’s DLCO % predicted is adjusted for hemoglobin.
  • 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%.
  • 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%.
  • the patient’s DLCO or DLCO % predicted is adjusted for hemoglobin.
  • the patient’s DLCO % predicted is 80% or less, 70% or less, 60% or less, or 50% or less, prior to the administration period.
  • the patient’s DLCO % predicted is adjusted for hemoglobin.
  • the patient’s DLCO % predicted is from 30% to 80%, from 40% to 70%, or from 50% to 60%, prior to the administration period.
  • the patient’s DLCO % predicted is adjusted for hemoglobin.
  • 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.
  • a respiratory indication e.g., dyspnea, and/or deterioration of lung function indicated by reductions in FVC, 54 Attorney Docket No.
  • 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.
  • 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.
  • a method for treating PH 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).
  • FRC functional residual capacity
  • TLC total lung capacity
  • the lung lobar volume is the volume of the lung lobar structure of the patient’s respiratory system at TLC or FRC
  • the airway volume is the volume of the airway structure of the patient’s respiratory system at TLC or FRC.
  • 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%.
  • 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%.
  • 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.
  • a medicament delivery system such as medicament delivery system 1000 as described herein with reference to FIGS.1-12.
  • aspects of the method 60 may be accomplished via additional embodiments of the medicament delivery system 1000 or components thereof as described herein.
  • the method 60 may be implemented on any suitable device as described herein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, R 1 is hexadecyl.
  • the compound of Formula (I) is treprostinil palmitil.
  • 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.
  • Step 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.
  • 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.
  • 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.
  • the delivery member 1210 can be rotated relative to the body member 1230 to expose a chamber.
  • 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.
  • 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.
  • the actuator 1220 is biased radially outward and in contact with the rib portion 1156.
  • the medicament container assembly 1250 is in an unpunctured or unruptured configuration.
  • a force F applied to the medicament delivery device 1200 e.g., to the delivery member 1210 and/or the body member 1230
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the delivery member of the medicament delivery device 1200 can be placed into the patient’s mouth.
  • this can be done with the cover 1100 disposed about the base of the medicament delivery device 1200, as shown in FIG.14.
  • 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.
  • 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.
  • 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.
  • a medicament delivery system such as medicament delivery system 1000 as described herein with reference to FIGS. 1-12.
  • aspects of the method 80 may be accomplished via additional embodiments of the medicament delivery system 1000 or components thereof as described herein.
  • the method 80 may be implemented on any suitable device as described herein.
  • 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.
  • 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.
  • 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.
  • the method 80 optionally loading a medicament container assembly (e.g., a capsule) into the dry powder inhaler.
  • a medicament container assembly e.g., a capsule
  • 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 R 1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. In a further embodiment, R 1 is hexadecyl. In even a further embodiment, the compound of Formula (I) is treprostinil palmitil.
  • 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.

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Abstract

L'invention concerne un couvercle permettant d'actionner un dispositif d'administration de médicament. Le couvercle comprend une première partie d'extrémité et une seconde partie d'extrémité. La seconde partie d'extrémité est conçue pour entourer un élément d'administration du dispositif d'administration de médicament dans une configuration de stockage. Le couvercle comprend également une paroi qui s'étend entre la première partie d'extrémité et la seconde partie d'extrémité. Une surface interne de la paroi délimite au moins en partie un volume intérieur et est conçue pour déplacer un actionneur du dispositif d'administration de médicament lorsque l'élément d'administration est positionné à l'extérieur du volume intérieur et que le dispositif d'administration de médicament est déplacé à l'intérieur du volume intérieur du couvercle.
PCT/US2024/053536 2023-10-30 2024-10-30 Dispositif d'administration de médicament, couvercle et procédés d'administration de médicament Pending WO2025096521A1 (fr)

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