Spray-dried treprostinil preparation

Abstract

This disclosure provides aerosol properties of powder compositions administered via a dry powder inhaler, and a spray-drying process. Also provided is a method for treating pulmonary hypertension (PH) in a patient, comprising administering an effective amount of the powder composition to the patient's lungs once daily via inhalation using a dry powder inhaler. A system for treating PH is further provided using the powder composition and the dry powder inhaler. This disclosure addresses the need for novel therapeutic options for pulmonary hypertension (PH) (including pulmonary arterial hypertension (PAH) and PH associated with interstitial lung disease), portal pulmonary hypertension (PPH), and pulmonary fibrosis by providing improved powder compositions of treprostinil prodrugs administered via a dry powder inhaler, and methods for administering them to patients in need of treatment.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority from U.S. Provisional Application No. 63 / 452,985, filed on 17 March 2023, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Pulmonary hypertension is characterized by abnormally high blood pressure in the pulmonary vascular system. It is a progressive, fatal disease that can lead to heart failure and can occur in the pulmonary arteries, pulmonary veins, or pulmonary capillaries. Symptomatic patients experience shortness of breath, dizziness, fainting, and other symptoms, all of which worsen with exercise. There are multiple causes, the origin is unknown, it can be idiopathic, and other systems can contribute to the hypertension, such as portal pulmonary hypertension in patients who have both portal and pulmonary hypertension.

[0003] Pulmonary hypertension (PH) is classified into five groups by the World Health Organization (WHO). Group 1 PH, also called pulmonary arterial hypertension (PAH), includes PAH of unknown cause (idiopathic), hereditary PAH (i.e., familial PAH or FPAH), PAH caused by drugs or toxins, and PAH caused by conditions such as connective tissue disease, HIV infection, liver disease, and congenital heart disease. Group 2 PH is characterized as pulmonary hypertension associated with left heart disease. Group 3 PH is characterized as PH associated with lung diseases such as chronic obstructive pulmonary disease and interstitial lung disease, as well as PH associated with sleep-related breathing disorders (e.g., sleep apnea). Group 4 PH is PH resulting from chronic thrombotic and / or embolic diseases, such as PH caused by thrombi or blood coagulation disorders in the lungs. Group 5 PH includes PH caused by other disorders or conditions, such as hematological disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis), and metabolic disorders (e.g., thyroid disorders, glycogen storage disorders).

[0004] Pulmonary arterial hypertension (PAH) affects approximately 200,000 people worldwide, with around 30,000 to 40,000 patients in the United States. PAH patients experience constriction of the pulmonary arteries, leading to increased pulmonary pressure and difficulty for the heart to pump blood to the lungs. Patients often suffer from shortness of breath and fatigue, which significantly limits their ability to perform physical activities.

[0005] The New York Heart Association (NYHA) classifies patients with PAH into four functional classes to assess the severity of the disease. Class I PAH patients, as classified by the NYHA, have no limitations on physical activity, as normal physical activity does not cause excessive dyspnea or fatigue, chest pain, or near-fainting. Class II PAH patients, as classified by the NYHA, have slight limitations on physical activity. These patients are comfortable at rest, but normal physical activity causes excessive dyspnea or fatigue, chest pain, or near-fainting. Class III PAH patients, as classified by the NYHA, have significant limitations on physical activity. Class III PAH patients are comfortable at rest, but experience excessive dyspnea or fatigue, chest pain, or near-fainting as a result of less-than-normal physical activity. Class IV PAH patients, as classified by the NYHA, are unable to perform physical activity without symptoms. Class IV PAH patients may experience dyspnea and / or fatigue at rest, and physical activity increases their discomfort. Signs of right heart failure often appear in Class IV PAH patients.

[0006] Patients with PAH are treated with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE-5) inhibitors, guanylate cyclase stimulants, prostanoids (e.g., prostacyclin), or combinations thereof. Examples of ERAs include ambrisentan (Letairis®), cytaxentan, bosentan (Tracleer®), and macitentan (Opsumit®). Examples of PDE-5 inhibitors indicated for the treatment of PAH include sildenafil (Revatio®) and tadalafil (Adcirca®). Examples of prostanoids indicated for the treatment of PAH include iloprost (Ventavis®), epoprocentrol (Flolan®, Veletri®), and treprostinil (Remodulin®, Tyvaso®). One approved guanylate cyclase stimulant is riociguat (Adempas®). Furthermore, patients are often treated with combinations of the aforementioned compounds.

[0007] Drugs can be administered to patients via inhalation using a dry powder inhaler (DPI). Typically, powder formulations are prepared using a blending process to reduce aggregation, provide sufficient fluidity, and thus achieve therapeutic benefits. Unfortunately, the particulate fraction (FPF), i.e., the amount of drug-containing particles small enough (<5 μm) to enter the lungs and produce a clinical effect, is typically low, often less than 50%.

[0008] There is a need to develop powder compositions with improved formulation properties (e.g., treprostinyl palmityl inhalation powder) that are administered via a dry powder inhaler for the treatment of patients with PH and PAH. [Overview of the project] [Means for solving the problem]

[0009] This disclosure addresses the need for novel therapeutic options for pulmonary hypertension (PH) (including pulmonary arterial hypertension (PAH) and PH associated with interstitial lung disease), portal pulmonary hypertension (PPH), and pulmonary fibrosis by providing improved powder compositions of treprostinil prodrugs administered via a dry powder inhaler, and methods for administering them to patients in need of treatment.

[0010] In one embodiment, the present disclosure provides (a) a compound of formula (I) in an amount of about 0.5% to about 5% by weight, [ka] In the formula, R 1 The present invention relates to a powder composition comprising (a) a compound, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl; (b) leucine in an amount of about 10% to about 61% by weight, with the remainder being (c) a sugar selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100% by weight. When the powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The present invention provides an aerosol containing approximately 68% or more particulate matter fraction (FPF) when measured using a next-generation impactor (NGI) with a certain inhalation acceleration. In one embodiment, the powder composition is a spray-dried powder composition.

[0011] In some embodiments, the composition contains about 29% to about 61% by weight of leucine. In even further embodiments, the composition contains 0.5% to about 4% by weight of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the FPF is in the range of approximately 68% to approximately 73%. In some embodiments, the FPF is in the range of approximately 68% to approximately 80%. In some embodiments, the FPF is in the range of approximately 78% to approximately 80%.

[0013] In some embodiments, the aerosol contains a particulate matter dose (FPD) of 50% or more of the loaded dose of the powder composition. In some embodiments, the FPD is in the range of about 53% to about 77% or about 60% to about 65%.

[0014] In some embodiments, the aerosol contains an ED of 72% or more. In some embodiments, the ED is in the range of about 79% to about 89%.

[0015] In some embodiments, the aerosol contains an aerodynamic mass median (MMAD) of less than 5 μm. In some embodiments, the MMAD is in the range of about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm.

[0016] In some embodiments, the powder composition comprises particles, at least a portion of which comprises (i) a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, (ii) leucine, and (iii) trehalose, mannitol, or a combination thereof, and the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have a D10 of about 0.3 μm. In some embodiments, the particles have a D50 of about 1.7 μm. In some embodiments, the particles have a D90 of about 3.8 μm. In one embodiment, the powder composition is a spray-dried powder composition.

[0017] In one embodiment, the stereoisomer is a diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, the stereoisomer is a diastereomer of the compound of formula (I). In another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of the compound of formula (I).

[0018] In one embodiment, R 1 is tetradecyl. In further embodiments, R 1 It is a straight-chain tetradecyl.

[0019] In one embodiment, R 1 is pentadecyl. In a further embodiment, R 1 is linear pentadecyl.

[0020] In one embodiment, R 1 is heptadecyl. In a further embodiment, R 1 is linear heptadecyl.

[0021] In one embodiment, R 1 is octadecyl. In a further embodiment, R 1 is linear octadecyl.

[0022] In one embodiment, R 1 is hexadecyl. In a further embodiment, R 1 is linear hexadecyl.

[0023] In one embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts are present at about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, R 1 is hexadecyl. In an even further embodiment, R 1 is linear hexadecyl. In an even further embodiment, the compound of formula (I), or its pharmaceutically acceptable salts are present at about 2 wt% to about 4 wt% of the total weight of the powder composition. In one embodiment, the powder composition is a spray-dried powder composition.

[0024] In one embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts are present at about 1 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, R 1 is hexadecyl. In an even further embodiment, R 1 is linear hexadecyl.

[0025] In one embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts are present at about 1 wt% to about 3.5 wt% of the total weight of the powder composition. In a further embodiment, R1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0026] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 3% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0027] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5% to about 4% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0028] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.8% to about 4% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0029] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.8% to about 3.3% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0030] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 2% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0031] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 1.5% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0032] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in about 1% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0033] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in about 2% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0034] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in about 3% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0035] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in about 4% by weight of the total weight of the powder composition. In further embodiments, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0036] In one embodiment, leucine is present in an amount of about 20% to about 40% by weight of the total weight of the powder composition. In further embodiments, R 1is hexadecyl. In a further embodiment, R 1 This is a linear hexadecyl. In further embodiments, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 4% by weight of the total weight of the powder composition.

[0037] In another embodiment, leucine is present in an amount of about 29% to about 61% by weight of the total weight of the powder composition. In yet another embodiment, R 1 is hexadecyl. In a further embodiment, R 1 This is a linear hexadecyl. In further embodiments, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 4% by weight of the total weight of the powder composition.

[0038] In another embodiment, leucine is present in an amount of about 25% to about 35% by weight of the total weight of the powder composition. In yet another embodiment, R 1 is hexadecyl. In a further embodiment, R 1 This is a linear hexadecyl. In further embodiments, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 4% by weight of the total weight of the powder composition.

[0039] In another embodiment, leucine is present in an amount of about 40% to 61% by weight of the total weight of the powder composition. In yet another embodiment, R 1 is hexadecyl. In a further embodiment, R 1 This is a linear hexadecyl. In further embodiments, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 4% by weight of the total weight of the powder composition. In further embodiments, leucine is present in an amount of about 45% to 61% by weight of the total weight of the powder composition. In even further embodiments, leucine is present in an amount of about 55% to 61% by weight of the total weight of the powder composition.

[0040] In another embodiment, leucine is present in an amount of about 28% to about 33% by weight of the total weight of the powder composition. In yet another embodiment, R 1 is hexadecyl. In a further embodiment, R 1 This is a linear hexadecyl. In further embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.5% to about 4% by weight of the total weight of the powder composition.

[0041] In another embodiment, leucine is present in an amount of about 25% to about 33% by weight of the total weight of the powder composition, for example, about 27% to about 33% by weight, about 27% to about 31% by weight, about 27% to about 30% by weight, about 28% to about 30% by weight, or about 30% by weight of the total weight of the powder composition. In a further embodiment, R 1 is hexadecyl. In a further embodiment, R 1 It is a linear hexadecyl.

[0042] In one embodiment, the powder composition provided herein has a leucine:mannitol weight ratio of about 0.40:1 (leucine:mannitol) to about 0.50:1 (leucine:mannitol). In another embodiment, the powder composition provided herein has a leucine:mannitol weight ratio of about 0.75:1 (leucine:mannitol) to about 0.90:1 (leucine:mannitol). In yet another embodiment, the powder composition provided herein has a leucine:mannitol weight ratio of about 0, about 1.5:1 (leucine:mannitol) to about 1.7:1 (leucine:mannitol).

[0043] In one embodiment, the sugar is mannitol. In further embodiments, R 1 is hexadecyl. In further embodiments, R 1 It is a linear hexadecyl.

[0044] In one embodiment, the powder composition comprises (a) about 1% by weight of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, (b) about 29.3% by weight or about 29.6% by weight of leucine, and the remainder being (c) mannitol. In further embodiments, R 1 is hexadecyl. In further embodiments, R 1 It is a linear hexadecyl.

[0045] In one embodiment, the powder composition comprises (a) about 3 wt% of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, (b) about 29.3 wt% or about 29.6 wt% of leucine, with the remainder being (c) mannitol. In further embodiments, R 1 is hexadecyl. In further embodiments, R 1 It is a linear hexadecyl.

[0046] This disclosure specifies that the powder composition comprises about 160 μg to about 320 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing about 68% or more particulate fraction (FPF) as measured using a next-generation impactor (NGI). In some embodiments, the dry powder inhaler provides an aerosol containing an FPF in the range of 78% to about 80%. In some embodiments, the dry powder inhaler provides an aerosol containing an FPF in the range of 68% to about 73%. In some embodiments, the dry powder inhaler provides an aerosol containing a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition. In some embodiments, the dry powder inhaler provides an aerosol containing an FPD in the range of 60% to about 65%. In some embodiments, the dry powder inhaler provides an aerosol containing an FPF in the range of 53% to about 65%. In some embodiments, the dry powder inhaler provides an aerosol containing a release dose (ED) of 79% or more. In some embodiments, the dry powder inhaler provides an aerosol containing an ED in the range of about 79% to about 89%. In some embodiments, the dry powder inhaler provides an aerosol containing an aerodynamic median mass (MMAD) of less than 5 μm. In some embodiments, the dry powder inhaler provides an aerosol containing an MMAD in the range of about 1.0 μm to about 1.3 μm. In some embodiments, the dry powder inhaler provides an aerosol containing an MMAD in the range of about 1.3 μm to about 1.7 μm.

[0047] In further embodiments, the composition comprises a dose selected from the group consisting of compounds of formula (I) in amounts of 80 μg, 160 μg, 240 μg, 320 μg, 400 μg, 480 μg, 560 μg, 640 μg, 675 μg, 720 μg, 800 μg, 880 μg, 960 μg, 1040 μg, 1120 μg, 1200 μg, and 1280 μg. In yet another embodiment, the composition comprises a dose selected from the group consisting of compounds of formula (I) in amounts of 80 μg, 160 μg, 240 μg, 320 μg, 400 μg, 480 μg, and 640 μg. The dose may be present, for example, in one dry powder capsule or in multiple capsules.

[0048] Another aspect of this disclosure provides a method for treating a patient requiring treatment for pulmonary hypertension (PH). The method involves administering an effective amount of the powder composition disclosed herein to the patient's lungs by inhalation via a dry powder inhaler. In embodiments, the effective amount comprises 80 μg to 1280 μg of the compound of formula (I). In embodiments, the effective amount comprises 80 μg, 160 μg, 240 μg, 320 μg, 400 μg, 480 μg, 640 μg, 675 μg, 720 μg, 800 μg, 880 μg, 960 μg, 1040 μg, 1120 μg, and 1200 μg of the compound of formula (I) out of 1280 μg.

[0049] In one embodiment, PH is a first-group PH as characterized by the World Health Organization (WHO).

[0050] In one embodiment, pulmonary hypertension is pulmonary arterial hypertension (PAH). In one embodiment, PAH is class I PAH as characterized by the New York Heart Association (NYHA). In another embodiment, PAH is class II PAH as characterized by the NYHA. In another embodiment, PAH is class III PAH as characterized by the NYHA. In yet another embodiment, PAH is class IV PAH as characterized by the NYHA.

[0051] In another embodiment, PH is a group 2 PH as characterized by the WHO. In another embodiment, PH is a group 3 PH as characterized by the WHO. In yet another embodiment, group 3 PH is PH associated with interstitial lung disease (ILD). In another embodiment, PH is a group 4 PH as characterized by the WHO. In another embodiment, PH is a group 5 PH as characterized by the WHO.

[0052] In one embodiment of the treatment method described herein, administration is performed once or twice a day.

[0053] In another embodiment, the disclosure relates to a system for treating PH. The system comprises one of the powder compositions disclosed herein and a dry powder inhaler (DPI), which may be a single-dose or multi-dose inhaler. In another embodiment, the DPI is pre-weighed or device-weighed.

[0054] In some embodiments, the powder composition used in the manner described herein comprises about 1% to about 5% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the remainder being one or more pharmaceutically acceptable excipients suitable for use in a dry powder inhaler. [Brief explanation of the drawing]

[0055] [Figure 1] This is a schematic diagram showing the setup of the system, which includes a respiratory simulator and a next-generation impactor (NGI), before the simulation begins. [Figure 2A] This graph shows various simulated inhalation profiles at different accelerations with a target inspiratory flow rate of 60 LPM (1030 mL / s) and a total inhalation volume of 4 liters. [Figure 2B] This graph shows various simulated inhalation profiles at two accelerations (50 ms vs. 2000 ms) with a target inspiratory flow rate of 60 LPM (1030 mL / s) and total inhalation volumes of 1 L, 2 L, or 4 L. [Figure 2C] This graph shows various simulated inhalation profiles at two accelerations (25 ms vs. 1000 ms) with a target inspiratory flow rate of 30 LPM (510 mL / s) and total inhalation volumes of 1 L, 2 L, or 4 L. [Figure 3A] This graph shows the TP aerosol deposition profile in NGI as a function of acceleration. The profile shows the percentage (mean ± SD) of TP recovered from each component of NGI at each inhalation acceleration to reach a peak inspiratory flow rate of 60 LPM at a 4 L inhalation volume. 16 mg TPIP capsule. [Figure 3B] This graph shows the TP aerosol deposition profile in NGI as a function of acceleration. The profile shows the percentage (mean ± SD) of TP recovered from each component of NGI at each inhalation acceleration to reach a peak inspiratory flow rate of 60 LPM at a 4 L inhalation volume. 32 mg TPIP capsule. Accelerations are 20 L / s² (blue), 5.88 L / s² (orange), 2 L / s² (gray), 1 L / s² (yellow), and 0.5 L / s² (light blue). [Figure 4] This graph shows the TP particulate dose (FPD) as a function of inhalation acceleration to reach a peak inspiratory flow rate of 60 LPM for a 4 L inhalation volume. The dotted line shows the change in FPD values ​​for 16 mg TPIP (blue) and 32 mg TPIP (orange) capsules as acceleration increases from 0.5 L / sec² (2000 ms ramp) to 20 L / sec² (50 ms ramp). *p value > 0.05 (comparison of total inhalation acceleration for 16 mg TPIP capsules), #p value < 0.05 (comparison of total inhalation acceleration for 32 mg capsules related to data in Tables 1 and 2). [Figure 5A]This graph shows the TP aerosol deposition profile in NGI as a function of inhalation volume. The profile shows the percentage (mean ± SD) of TP recovered from each component of NGI for each inhalation volume to reach peak inspiratory flow rates of 60 and 30 LPM, at accelerations of 20 and 0.5 L / s². For volumes of 1 L (blue), 2 L (orange), and 4 L (gray), this represents a 16 mg TPIP capsule with a ramp time of 50 ms, and for volumes of 1 L (yellow), 2 L (light blue), and 4 L (green), this represents a 16 mg TPIP capsule with a ramp time of 2000 ms to reach a peak flow rate of 60 LPM. [Figure 5B] This graph shows the TP aerosol deposition profile in NGI as a function of inhalation volume. The profile shows the percentage (mean ± SD) of TP recovered from each component of NGI for each inhalation volume to reach peak inspiratory flow rates of 60 and 30 LPM, at accelerations of 20 and 0.5 L / s². For volumes of 1 L (blue), 2 L (orange), and 4 L (gray), a 32 mg TPIP capsule was administered with a ramp time of 50 ms, and for volumes of 1 L (yellow), 2 L (light blue), and 4 L (green), a 32 mg TPIP capsule was administered with a ramp time of 2000 ms to reach a peak flow rate of 60 LPM. [Figure 5C] This graph shows the TP aerosol deposition profile in NGI as a function of inhalation volume. The profile shows the percentage (mean ± SD) of TP recovered from each component of NGI for each inhalation volume to reach peak inspiratory flow rates of 60 and 30 LPM, at accelerations of 20 and 0.5 L / s². 16 mg TPIP capsules with a ramp time of 25 ms for volumes of 1 L (blue), 2 L (orange), and 4 L (gray), and 16 mg TPIP capsules with a ramp time of 1000 ms for volumes of 1 L (yellow), 2 L (light blue), and 4 L (green) to reach peak flow rates of 30 LPM. [Figure 6A]This graph shows the trend line of TP particulate dose (FPD) as a function of total inhalation volume. The dotted line shows the change in FPD value as inhalation volume increases for 20 L / s² (blue) and 0.5 L / s² (orange) accelerations at peak inspiratory flow rates of 30 and 60 LPM. 16 mg TPIP capsule at a flow rate of 60 LPM. *p values ​​> 0.05 for 1 and 2 L inhalations compared to 4 L inhalation volume, #p value < 0.05 for 1 L inhalation volume compared to 4 L inhalation volume, †p value > 0.05 for the overall comparison of inhalations for 20 L / s² acceleration (16 mg and 32 mg) and 0.5 L / s² acceleration (16 mg), and \p value < 0.05 for the overall comparison of inhalations for 0.5 L / s² acceleration (32 mg) associated with data from Tables 3 and 4. [Figure 6B] This graph shows the trend line of TP particulate dose (FPD) as a function of total inhalation volume. The dotted line shows the change in FPD value as inhalation volume increases for 20 L / s² (blue) and 0.5 L / s² (orange) accelerations at peak inspiratory flow rates of 30 and 60 LPM. 32 mg TPIP capsule at a flow rate of 60 LPM. *p values ​​> 0.05 for 1 and 2 L inhalations compared to 4 L inhalation volume, #p value < 0.05 for 1 L inhalation volume compared to 4 L inhalation volume, †p value > 0.05 for the overall comparison of inhalations for 20 L / s² acceleration (16 mg and 32 mg) and 0.5 L / s² acceleration (16 mg), and \p value < 0.05 for the overall comparison of inhalations for 0.5 L / s² acceleration (32 mg) associated with data from Tables 3 and 4. [Figure 6C]This graph shows the trend line of TP particulate dose (FPD) as a function of total inhalation volume. The dotted line shows the change in FPD value as inhalation volume increases for 20 L / s² (blue) and 0.5 L / s² (orange) accelerations at peak inspiratory flow rates of 30 and 60 LPM. 16 mg TPIP capsule at 30 LPM flow rate. *p values ​​> 0.05 for 1 and 2 L inhalations compared to 4 L inhalation volume, #p value < 0.05 for 1 L inhalation volume compared to 4 L inhalation volume, †p value > 0.05 for the overall comparison of inhalations for 20 L / s² acceleration (16 mg and 32 mg) and 0.5 L / s² acceleration (16 mg), and \p value < 0.05 for the overall comparison of inhalations for 0.5 L / s² acceleration (32 mg) associated with data from Tables 3 and 4. [Figure 7A] This graph shows the TP aerosol particle size distribution profile from a next-generation impactor (NGI). The profile shows the recovery of TP (mean ± SD) from each stage of the NGI with respect to the stage cutoff diameter of ultra-high resistance (UHR, blue), high resistance (HR, orange), medium resistance (MR, gray), and low resistance (LR, yellow) devices. 8 mg TPIP capsule. [Figure 7B] This graph shows the TP aerosol particle size distribution profile from a next-generation impactor (NGI). The profile shows the recovery of TP (mean ± SD) from each stage of the NGI with respect to the stage cutoff diameter of ultra-high resistance (UHR, blue), high resistance (HR, orange), medium resistance (MR, gray), and low resistance (LR, yellow) devices. 16 mg TPIP capsule. [Figure 7C] This graph shows the TP aerosol particle size distribution profile from a next-generation impactor (NGI). The profile shows the recovery of TP (mean ± SD) from each stage of the NGI with respect to the stage cutoff diameter of ultra-high resistance (UHR, blue), high resistance (HR, orange), medium resistance (MR, gray), and low resistance (LR, yellow) devices. 32 mg TPIP capsule. [Figure 8A]This graph shows the TP particulate fraction (FPF). Ultra-high resistance (UHR), high resistance (HR), medium resistance (MR), and low resistance (LR) devices were tested at 40, 60, 85, and 100 LPM, respectively. [Figure 8B] This graph shows the particulate dose (FPD) as a function of device resistance for capsule doses of 8 mg (blue), 16 mg (orange), and 32 mg (gray). Ultra-high resistance (UHR), high resistance (HR), medium resistance (MR), and low resistance (LR) devices were tested at 40, 60, 85, and 100 LPM, respectively. [Figure 8C] This graph shows the TP FPD as a function of capsule dose for each device. Trend lines are shown only for UHR and HR DPI in Figure 8C. Ultra-high resistance (UHR), high resistance (HR), medium resistance (MR), and low resistance (LR) devices were tested at 40, 60, 85, and 100 LPM, respectively. [Figure 9A] This graph shows the TP aerosol particle size distribution profile from a next-generation impactor (NGI). The profile shows the recovery of TP (mean ± SD) from each stage of the NGI with respect to the stage cutoff diameter of a high-resistance (HR) device operating at 40 LPM (blue), 60 LPM (orange), and 80 LPM (gray). 8 mg TPIP capsule. [Figure 9B] This graph shows the TP aerosol particle size distribution profile from a next-generation impactor (NGI). The profile shows the recovery of TP (mean ± SD) from each stage of the NGI with respect to the stage cutoff diameter of a high-resistance (HR) device operating at 40 LPM (blue), 60 LPM (orange), and 80 LPM (gray). 16 mg TPIP capsule. [Figure 9C] This graph shows the TP aerosol particle size distribution profile from a next-generation impactor (NGI). The profile shows the recovery of TP (mean ± SD) from each stage of the NGI with respect to the stage cutoff diameter of a high-resistance (HR) device operating at 40 LPM (blue), 60 LPM (orange), and 80 LPM (gray). 32 mg TPIP capsule. [Modes for carrying out the invention]

[0056] definition Throughout this disclosure, the term “approximately” may be used in conjunction with numerical values ​​and / or ranges. The term “approximately” is understood to mean a value close to the listed values. For example, “approximately 40 [units]” could mean any other value or range of values ​​within ±25% of 40 (e.g., 30 to 50), ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, or any other value in or below that range.

[0057] The term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. The properties of the salt are not important as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Representative pharmaceutically acceptable salts are disclosed in Stahl, PH, Wermuth, CG, Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica Acta / Wiley-VCH: Zurich, 2002, the contents of which are incorporated herein by reference in their entirety. Certain non-limiting examples of inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids include, but are not limited to, carboxylic acids and sulfonic acids containing aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl compounds, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvate, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, emvonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, argonic acid, 3-hydroxybutyric acid, galactaric acid, or galacturonic acid. Suitable pharmaceutically acceptable salts of the free acid-containing compounds disclosed herein include, but are not limited to, metal salts and organic salts. Exemplary metal salts include, but are not limited to, suitable alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.Exemplary organic salts can be prepared from primary amines, secondary amines, tertiary amines, and quaternary ammonium salts, such as tromethamine, diethylamine, tetra-N-methylammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0058] As used herein, the term “stereoisomer” refers to two molecules having the same molecular formula and arrangement of bonded atoms, but differing in the three-dimensional spatial orientation of their atoms. One preferred stereoisomer according to this disclosure is a diastereomer. In one embodiment, the stereoisomer is a diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, the stereoisomer is a diastereomer of the compound of formula (I). In another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of the compound of formula (I). In yet another embodiment, the stereoisomer is a diastereomer of the compound of formula (II). In yet another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of the compound of formula (II).

[0059] Throughout this specification, numerical ranges are provided for specific quantities. It should be understood that these ranges include all subranges within them. Therefore, the range "50-80" includes all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range may be endpoints of the range they encompass (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0060] Throughout this specification, numerical ranges are described as encompassing "approximately 80% to approximately 125%" or "approximately 80% to 125%" of the range of values. It should be understood that these include 80% of the lowest endpoint of the range up to 125% of the highest endpoint of the range, and all values ​​within that range.

[0061] "C max The term "maximum (or peak) treprostinil serum concentration measured after administering a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof to the lungs of a subject via the powder composition described herein. In addition, C max This can be measured after a single dose of a compound of formula (I) or (II) as described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof, or treprostinil C max This can be measured in a steady state. Unless otherwise stated, C max This refers to the mean treprostinil C2 measured after a single dose in the target population (e.g., a population of PH patients). max It refers to.

[0062] The term "AUC" refers to the area under the plasma concentration-time curve of treprostinil, measured from time 0 to a specific time after administration to the target lung, and calculated using a combination of linear and logarithmic trapezoidal methods (linear up / log down). In some embodiments, AUC is the time from 0 to 24 hours after administration ("AUC"). 0-24 AUC may be measured from time 0 to infinity ("AUC"), or AUC may be measured from time 0 to infinity ("AUC") 0-inf It may also be measured in a form up to ''. In addition, treprostinil AUC may be measured after a single dose or at steady state. Unless otherwise stated, AUC refers to the mean AUC measured after a single dose in the target population (e.g., a population of PH patients).

[0063] The term "plasma trough concentration" refers to the plasma concentration of treprostinil prior to administration of the next dose of the compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. For example, the treprostinil plasma trough concentration may be measured within 2 hours, 1 hour, or 30 minutes after administration of the next dose. The plasma trough concentration may be measured after a single dose or at a steady state. Unless otherwise stated, the plasma trough level refers to the mean treprostinil trough level measured among the population of interest (e.g., a population of PH patients).

[0064] The term "adult" refers to a human subject, for example, a human patient who is at least 18 years of age or older. In some embodiments, an adult is between 18 and 100 years of age, for example, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 5 The ages are 8, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100 years old (including all values ​​and ranges in between).

[0065] The term "cascade impact" refers to a method for measuring the performance characteristics of a dry powder inhaler. Next-generation impactors (NGIs) are used for the cascade impact measurements described herein. In some embodiments, the NGI has an inhalation (also interchangeably called gas) flow rate of 30–60 liters per minute (L / min) (e.g., 30, 40, 50, or 60), an inhalation volume of 1–4 L (e.g., 1, 2, 3, or 4 L), and an intake rate of 0.5–20 L / sec 2 It has an intake acceleration of 60 L / min, an intake volume of 4 L, and 0.5-20 L / sec. In certain embodiments, the NGI has an intake airflow of 60 L / min, an intake volume of 4 L, and an intake acceleration of 0.5-20 L / sec. 2 It has an inhalation acceleration. In the embodiment, the inhalation flow rate corresponds to a 4 kPa air pressure drop in the dry powder inhaler.

[0066] Any reference to the compound of formula I in this specification includes its pharmaceutically acceptable salts.

[0067] The term "geometric standard deviation" or "GSD" is a measure of the extent of the aerodynamic particle size distribution.

[0068] A dry powder inhaler (DPI) is a device that can be used to deliver medication to the airways. When inhaled, the medication is transported to the lungs. For medication to be inhaled via a DPI, the compressed drug powder must be broken down in a process called deagglutination.

[0069] The compositions described herein are referred to as “powder.” Such powders administered using DPI are generally referred to as dry powders. Therefore, all references to powders, powder compositions, or powder formulations used herein encompass dry powders, dry powder compositions, or dry powder formulations.

[0070] The powders used in DPIs are typically formulated by blending activators and excipients to prevent aggregation. That is, DPIs typically use micronized drugs blended with carrier particles, such as lactose, to avoid aggregation and provide sufficient fluidity. To enhance the aerosolization of the drug particles, fine lactose particles are often added to the carrier lactose to saturate the high-energy binding sites on the carrier lactose, forming aggregates that are easily separable from the drug particles.

[0071] When the powder is released from the inhaler, drug particles separate from the carrier particles and are delivered to the lungs, while larger carrier particles reach the upper respiratory tract. In this disclosure, it is surprisingly discovered that spray-dried treprostinyl palmityl (e.g., compounds of formulas (I) and (II)) with specific excipients generates free-flowing drug particles of appropriate size and particle size distribution, resulting in improved therapeutic efficacy (e.g., higher FPF) compared to blended formulations, allowing more drug particles to be delivered to the lungs. More specifically, while the FPF of blended formulations was typically less than 45% (e.g., about 11% to about 43%), the spray-dried powder compositions of this disclosure were found at an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5–20 L / sec 2 Measured with intake acceleration, it has an FPF of approximately 68% or more.

[0072] The treprostinyl palmityl inhalation powder (TPIP) provided herein is produced by a spray-drying process using mannitol and leucine as excipients and is administered via a high-resistance (HR) DPI, such as a dry powder inhaler (DPI) like the RS01 Berry Global (formerly Plastiape) device. In one embodiment, TPIP is administered to patients requiring treatment for pulmonary arterial hypertension (PAH) or pulmonary hypertension due to interstitial lung disease (PH-ILD).

[0073] One aspect of the present disclosure provides a powder composition of a treprostinil prodrug. The powder composition is (a) A compound of formula (I) or a pharmaceutically acceptable salt thereof, present in an amount of about 0.5% to about 5% by weight of the total weight of the powder composition, [ka] In the formula, R 1 However, the compound or a pharmaceutically acceptable salt thereof is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. (b) Contains approximately 10% to 61% by weight of leucine, and the remainder is (c) A sugar selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100% by weight. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2When measured using a next-generation impactor (NGI) with an inhalation acceleration, it provides one or more of the following: (i) an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), (ii) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (iii) an aerosol containing an emanating dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iv) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0074] In a further embodiment, the powder composition contains about 25% to about 61% by weight of leucine. In yet another embodiment, the powder composition contains about 25% to about 45% by weight of leucine. In yet another embodiment, the powder composition contains about 45% to about 61% by weight of leucine.

[0075] In some embodiments, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in amounts of about 0.4% by weight, about 0.5% by weight, about 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.5% by weight, about 1.7% by weight, about 2.0% by weight, about 2.3% by weight, about 2.5% by weight, about 2.6% by weight, about 2.7% by weight, about 2.8% by weight, about 2.9% by weight, about 3% by weight, about 3.1% by weight, about 3.2% by weight, about 3.3% by weight, about 3.4% by weight, about 3.5% by weight, about 4% by weight, about 3.5% by weight, or about 5% by weight of the total weight of the powder composition. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0076] Compounds of formula (I) and their pharmaceutically acceptable salts are treprostinyl prodrugs disclosed in International Patent Application Publication No. WO2015 / 061720, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, leucine is present in an amount of about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 58% by weight, or about 60% by weight of the total weight of the powder composition. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0077] In some embodiments, leucine is present in amounts of about 25% to about 30% by weight, about 28% to about 30% by weight, about 25% to about 33% by weight, about 27% to about 33% by weight, about 27% to about 31% by weight, about 27% to about 30% by weight, or about 28% to about 30% by weight of the total weight of the powder composition. In some embodiments, leucine is present in amounts of about 40% to about 45% by weight, about 44% to about 51% by weight, or about 43% to about 48% by weight of the total weight of the powder composition.

[0078] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R 1 is tetradecyl. In further embodiments, R 1 It is a straight-chain tetradecyl.

[0079] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 1 is pentadecyl. In further embodiments, R 1 It is a straight-chain pentadecyl.

[0080] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 1 is heptadecyl. In further embodiments, R 1 It is a linear heptadecyl.

[0081] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 1 is octadecyl. In further embodiments, R 1 It is a linear octadecyl.

[0082] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 1 is hexadecyl. In further embodiments, R 1 It is a linear hexadecyl, that is, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is the compound of formula (II): [ka] The stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In further embodiments, the compound of formula (I) is the compound of formula (II). 1 Compounds of formula (I) in which R is a linear hexadecyl are also referred herein to as C16TR or its internationally non-proprietary name, treprostinylpalmytil. In this application, C16TR and treprostinylpalmytil are used interchangeably. Similarly, compounds of formula (II) are equivalent to compounds of formula (I), where R 1 However, it is a linear hexadecyl.

[0083] In preferred embodiments of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the compound of formula (I) is treprostinyl palmityl (i.e., R 1 (However, it is a linear hexadecyl). In further embodiments, treprostinyl palmityl is in crystalline form. The crystalline form of treprostinyl palmityl is described in U.S. Patent No. 10,781,160, which is incorporated in whole by reference herein.

[0084] In one embodiment, treprostinyl palmityl is crystalline morphology I, having an X-ray powder diffraction (XRPD) pattern showing peaks at two, three, four, five, or all of the following 2θ reflection angles: 3.3±0.2°, 6.6±0.2°, 14.2±0.2°, 18.9±0.2°, 21.3±0.2°, and 22.5±0.2°. In another embodiment, the XRPD pattern of treprostinyl palmityl crystal morphology I further includes peaks at one, two, three, four, five, six, seven, eight, or all of the following 2θ reflection angles: 13.8±0.2°, 15.3±0.2°, 16.9±0.2°, 17.8±0.2°, 19.8±0.2°, 20.6±0.2°, 20.9±0.2°, 24.4±0.2°, and 24.8±0.2°. In one embodiment, treprostinyl palmityl is crystal morphology I having an XRPD pattern showing peaks at the 2θ reflection angles provided in Table A. [Table A]

[0085] In one embodiment, treprostinyl palmityl crystal form I has a differential scanning calorimetry (DSC) thermogram pattern that includes an endothermic peak with a peak onset temperature of approximately 52.2 ± 1°C and a peak maximum value of approximately 54.5 ± 1°C.

[0086] In another embodiment, treprostinyl palmityl is crystalline form II having an XRPD pattern showing peaks at two, three, four, five, or all of the following 2θ reflection angles: 3.4±0.2°, 6.1±0.2°, 9.4±0.2°, 20.3±0.2°, 21.6±0.2°, and 23.4±0.2°. In another embodiment, the XRPD pattern of treprostinyl palmityl crystalline form II further includes peaks at one, two, three, four, five, six, seven, eight, or all of the following 2θ reflection angles: 7.0±0.2°, 9.0±0.2°, 12.2±0.2°, 12.7±0.2°, 17.5±0.2°, 18.0±0.2°, 18.5±0.2°, 19.1±0.2°, and 19.4±0.2°. In one embodiment, treprostinyl palmityl is crystalline form II, having an XRPD pattern showing a peak at the 2θ reflection angle, as provided in Table B. [Table B]

[0087] In one embodiment, treprostinyl palmityl crystalline form II has a DSC thermogram pattern that includes an endothermic peak with a peak onset temperature of approximately 54.6 ± 1°C and a peak maximum value of approximately 56.9 ± 1°C.

[0088] In one embodiment, (a) is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, (a) is a compound of formula (II) or a pharmaceutically acceptable salt thereof. In a further embodiment, (a) is a compound of formula (II).

[0089] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1% to about 5% by weight of the total weight of the powder composition. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1% to about 4.5% by weight of the total weight of the powder composition. In some embodiments, the compound of formula (I) or (II) is present in an amount of about 1% to about 4% by weight of the total weight of the powder composition.

[0090] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1% to about 3.5% by weight of the total weight of the powder composition. In another embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1% to about 3% by weight of the total weight of the powder composition.

[0091] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in amounts of about 1% to about 5% by weight, about 1% to about 4.5% by weight, about 1% to about 4% by weight, about 2% by weight, about 3% by weight, about 4% by weight, or about 5% by weight of the total weight of the powder composition. In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in amounts of about 1% to about 5% by weight, about 1% to about 4.5% by weight, about 1% to about 4% by weight, about 1% to about 2% by weight, about 2% by weight, or about 4% by weight of the total weight of the powder composition.

[0092] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.8% to about 3.3% by weight, or about 1% to about 3% by weight, or about 1% to about 2% by weight, or about 1% to about 1.5% by weight of the total weight of the powder composition.

[0093] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in about 1% by weight of the total weight of the powder composition. In another embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in about 1.5% by weight of the total weight of the powder composition.

[0094] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.8% to about 1.5% by weight of the total weight of the powder composition. In another embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 2.7% to about 4% by weight of the total weight of the powder composition. In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 2.7% to about 3.5% by weight of the total weight of the powder composition, for example, about 2.8% to about 3.2% by weight, or about 2.9% to about 3.1% by weight.

[0095] In one embodiment, leucine is present in an amount of about 25% to about 61% by weight of the total weight of the powder composition. In a further embodiment, leucine is present in an amount of about 25% to about 50% by weight of the total weight of the powder composition. In a further embodiment, leucine is present in an amount of about 25% to about 40% by weight of the total weight of the powder composition. In a further embodiment, leucine is present in an amount of about 20% to about 33% by weight of the total weight of the powder composition, for example, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, or about 33% by weight of the total weight of the powder composition. In a further embodiment, leucine is present in an amount of about 25% to about 33% by weight of the total weight of the powder composition. In a further embodiment, leucine is present in an amount of about 27% to about 33% by weight of the total weight of the powder composition. In further embodiments, leucine is present in an amount of about 27% to about 31% by weight of the total weight of the powder composition. In further embodiments, leucine is present in an amount of about 27% to about 30% by weight of the total weight of the powder composition. In further embodiments, leucine is present in an amount of about 28% to about 30% by weight of the total weight of the powder composition.

[0096] In another embodiment, leucine is present in an amount of about 30% by weight of the total weight of the powder composition.

[0097] In another embodiment, leucine is present in an amount of about 45% to about 61% by weight of the total weight of the powder composition, for example, about 45% to about 55% by weight, or about 50% to about 55% by weight. In a further embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 3% to about 4% by weight of the total weight of the powder composition. In yet another embodiment, R 1 This is a hexadecyl, for example, a linear hexadecyl.

[0098] In some embodiments, the sugar in the powder composition is trehalose. In other embodiments, the sugar in the powder composition is mannitol.

[0099] In one embodiment, the composition has the weight proportions shown in Table C below. In another embodiment, the composition has a weight proportion of ±5% of each component shown in Table C below. In yet another embodiment, the composition has the leucine:mannitol weight ratio ("leucine:mannitol" or "leucine-to-mannitol") shown in Table C. [Table C]

[0100] In one embodiment, the powder composition has the components and weight proportions shown in Table D. [Table D]

[0101] In one embodiment, the leucine:sugar (i.e., mannitol or trehalose) weight ratio in the compositions provided herein is about 0.4:1 (leucine:mannitol or trehalose) to about 1.7:1 (leucine:mannitol or trehalose). In further embodiments, the composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in about 0.5% to about 4% by weight of the total weight of the powder composition. In further embodiments, the leucine:sugar weight ratio is about 0.4:1 (leucine:mannitol or trehalose) to 0.9:1 (leucine:mannitol or trehalose). In yet another embodiment, the leucine:sugar weight ratio is about 0.4:1 (leucine:mannitol or trehalose) to 0.5:1 (leucine:mannitol or trehalose). In further embodiments, the sugar is mannitol. In one embodiment, the leucine is L-leucine.

[0102] In another embodiment, the sugar is mannitol, and the leucine:mannitol weight ratio is about 0.75:1 (leucine:mannitol) to 0.9:1 (leucine:mannitol). In a further embodiment, the composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in about 0.5% to about 4% by weight of the total weight of the powder composition. In a further embodiment, the leucine:mannitol weight ratio is about 0.8:1 (leucine:mannitol) to 0.9:1 (leucine:mannitol). In another embodiment, the sugar is trehalose, and the leucine:trehalose weight ratio is about 0.75:1 (leucine:trehalose) to 0.9:1 (leucine:trehalose). In a further embodiment, the composition contains a compound of formula (I), (II) or a pharmaceutically acceptable salt thereof in about 1% to about 4% by weight of the total weight of the powder composition. In further embodiments, the leucine:trehalose weight ratio is approximately 0.8:1 (leucine:trehalose) to 0.9:1 (leucine:trehalose). In one embodiment, leucine is L-leucine.

[0103] In another embodiment, the sugar is mannitol, and the leucine:mannitol weight ratio is about 1.5:1 (leucine:mannitol) to 1.7:1 (leucine:mannitol). In yet another embodiment, the composition contains a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, in about 0.5% to about 4% by weight of the total weight of the powder composition. In yet another embodiment, the leucine:mannitol weight ratio is about 1.6:1 (leucine:mannitol) to 1.7:1 (leucine:mannitol). In yet another embodiment, the sugar is trehalose, and the leucine:trehalose weight ratio is about 1.5:1 (leucine:trehalose) to 1.7:1 (leucine:trehalose). In yet another embodiment, the composition contains a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, in about 0.5% to about 4% by weight of the total weight of the powder composition. In further embodiments, the composition contains a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, in about 0.5% to about 3% by weight of the total weight of the powder composition. In further embodiments, the composition contains a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, in about 0.5% to about 2% by weight of the total weight of the powder composition. In further embodiments, the composition contains a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, in about 0.5% to about 1.5% by weight of the total weight of the powder composition. In further embodiments, the leucine:mannitol weight ratio is about 1.6:1 (leucine:trehalose) to 1.7:1 (leucine:trehalose).

[0104] In another embodiment, the powder composition comprises (a) about 1-2% by weight of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, (b) about 29% by weight of leucine, with the remainder being (c) mannitol. In a further embodiment, (a) in the powder composition is about 1% by weight of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0105] In another embodiment, (a) in the powder composition is about 1% to about 1.5% by weight of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In another embodiment, (a) in the powder composition is about 2% to about 4% by weight of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In another embodiment, (a) in the powder composition is about 3% to about 4% by weight of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In another embodiment, (a) in the powder composition is about 2% by weight of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0106] In another embodiment, the powder composition comprises (a) about 1% by weight of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, (b) about 29.6% by weight of leucine, with the remainder being (c) mannitol. In a further embodiment, R 1 is the linear hexadecyl in the compound of formula (I).

[0107] In another embodiment, the powder composition comprises (a) about 1.5% by weight of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, (b) about 29.6% by weight of leucine, and the remainder being (c) mannitol. In further embodiments, R 1 is the linear hexadecyl in the compound of formula (I).

[0108] In another embodiment, the powder composition comprises (a) about 1% by weight of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, (b) about 29% to about 30% by weight of leucine, and the remainder being (c) mannitol. In a further embodiment, R 1 is the linear hexadecyl in the compound of formula (I).

[0109] In another embodiment, the powder composition comprises (a) about 1.5% by weight of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, (b) about 29% to about 30% by weight of leucine, and the remainder being (c) mannitol. In a further embodiment, R1 is the straight-chain hexadecyl in the compound of formula (I).

[0110] In another embodiment, the powder composition comprises (a) about 2% by weight of a compound of formula (I) or (II), its stereoisomers, or its pharmaceutically acceptable salts, (b) about 29% to about 30% by weight of leucine, and the remainder is (c) mannitol. In a further embodiment, R 1 is the straight-chain hexadecyl in the compound of formula (I).

[0111] In another embodiment, the powder composition comprises (a) about 3% by weight of a compound of formula (I) or (II), its stereoisomers, or its pharmaceutically acceptable salts, (b) about 29% to about 30% by weight of leucine, and the remainder is (c) mannitol. In a further embodiment, R 1 is the straight-chain hexadecyl in the compound of formula (I).

[0112] In another embodiment, the powder composition comprises (a) about 4% by weight of a compound of formula (I) or (II), its stereoisomers, or its pharmaceutically acceptable salts, (b) about 29% to about 30% by weight of leucine, and the remainder is (c) mannitol. In a further embodiment, R 1 is the straight-chain hexadecyl in the compound of formula (I).

[0113] In one embodiment, the powder composition contains (a) about 0.5% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 60% to about 61% by weight of leucine, and the remainder being (c) mannitol. In another embodiment, the powder composition contains (a) about 1% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 60% to about 61% by weight of leucine, and the remainder being (c) mannitol. In yet another embodiment, the powder composition contains (a) about 1.5% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 60% to about 61% by weight of leucine, and the remainder being (c) mannitol. In one embodiment, the powder composition contains (a) about 2% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 60% to about 61% by weight of leucine, and the remainder being (c) mannitol. In one embodiment, the powder composition contains (a) about 3% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 60% to about 61% by weight of leucine, and the remainder being (c) mannitol. In one embodiment, the powder composition contains (a) about 4% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 60% to about 61% by weight of leucine, and the remainder being (c) mannitol.

[0114] In another embodiment, the powder composition comprises (a) about 0.5% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol. In another embodiment, the powder composition comprises (a) about 1% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol. In another embodiment, the powder composition comprises (a) about 1.5% by weight of a compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol. In another embodiment, the powder composition comprises (a) about 2% by weight of the compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 43% to about 45% by weight of leucine, and the remainder being (c) mannitol. In another embodiment, the powder composition comprises (a) about 3% by weight of the compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 43% to about 45% by weight of leucine, and the remainder being (c) mannitol. In another embodiment, the powder composition comprises (a) about 4% by weight of the compound of formula (I) or (II), where R1 is linear hexadecyl, (b) about 43% to about 45% by weight of leucine, and the remainder being (c) mannitol.

[0115] In some embodiments, the powder composition does not contain distearoyl phosphoethanoamine-polyethylene glycol 2000 (DPSE-PEG2000).

[0116] In one embodiment, the powder composition contains approximately 80 μg to approximately 700 μg of a compound of formula (I) or (II), for example, approximately 80 μg, approximately 100 μg, approximately 110 μg, approximately 112.5 μg, approximately 120 μg, approximately 130 μg, approximately 140 μg, approximately 150 μg, approximately 160 μg, approximately 170 μg, approximately 180 μg, approximately 190 μg, approximately 200 μg, approximately 210μg, about 220μg, about 225μg, about 230μg, about 240μg, about 250μg, about 260μg, about 270μg, about 280μg, about 290μg, about 3 00μg, about 310μg, about 320μg, about 330μg, about 340μg, about 350μg, about 360μg, about 370μg, about 380μg, about 390μg, about 40 0μg, about 410μg, about 420μg, about 430μg, about 440μg, about 450μg, about 460μg, about 470μg, about 480μg, about 490μg, about 500 μg, approximately 510 μg, approximately 520 μg, approximately 530 μg, approximately 540 μg, approximately 550 μg, approximately 560 μg, approximately 570 μg, approximately 580 μg, approximately 590 μg, approximately 600 μg This includes compounds of formula (I), (II) in amounts of approximately 610 μg, 620 μg, 630 μg, 640 μg, 650 μg, 660 μg, 670 μg, 675 μg, 680 μg, 690 μg, or 700 μg, their stereoisomers, or pharmaceutically acceptable salts thereof (including all values ​​and ranges within them).In one embodiment, the powder composition is approximately 80 μg to approximately 1280 μg of a compound of formula (I) or (II), for example, approximately 80 μg, approximately 100 μg, approximately 110 μg, approximately 112.5 μg, approximately 120 μg, approximately 130 μg, approximately 140 μg, approximately 150 μg, approximately 160 μg, approximately 170 μg, approximately 180 μg, approximately 190 μg, approximately 200 μg, approximately 210 μg, approximately 220 μg, approximately 225 μg, approximately 230 μg, approximately 240 μg, approximately 250 μg, approximately 260 μg, approximately 270 μg μg, approximately 280 μg, approximately 290 μg, approximately 300 μg, approximately 310 μg, approximately 320 μg, approximately 330 μg, approximately 340 μg, approximately 350 μg, approximately 360 μg, approximately 370 μg, approximately 380 μg, approximately 390 μg, approximately 400 μg, approximately 41 0μg, about 420μg, about 430μg, about 440μg, about 450μg, about 460μg, about 470μg, about 480μg, about 490μg, about 500μg, about 510μg, about 520μg, about 530μg, about 540μg, about 55 0μg, about 560μg, about 570μg, about 580μg, about 590μg, about 600μg, about 610μg, about 620μg, about 630μg, about 640μg, about 650μg, about 660μg, about 670μg, about 675μg, about 6 80μg, about 690μg, about 700μg, about 720μg, about 740μg, about 760μg, about 780μg, about 800μg, about 820μg, about 840μg, about 860μg, about, about 880μg, about 900μg, about 920μg, The powder composition contains approximately 940 μg, approximately 960 μg, approximately 980 μg, approximately 1000 μg, approximately 1020 μg, approximately 1040 μg, approximately 1060 μg, approximately 1080 μg, approximately 1100 μg, approximately 1120 μg, approximately 1140 μg, approximately 1160 μg, approximately 1180 μg, approximately 1200 μg, approximately 1240 μg, approximately 1260 μg, or approximately 1280 μg of the compound of formula (I) or (II), its stereoisomers, or pharmaceutically acceptable salts thereof (including all values ​​and ranges therein). In one embodiment, the powder composition contains approximately 80 μg to approximately 700 μg of the compound of formula (I) or (II). In another embodiment, the powder composition contains approximately 80 μg to approximately 1280 μg of the compound of formula (I) or (II). In one embodiment, the powder composition contains about 80 μg to about 640 μg of the compound of formula (I) or (II). In another embodiment, the powder composition contains about 80 μg to about 320 μg of the compound of formula (I) or (II).In one embodiment, the composition contains about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of the compound of formula (I) or (II). In one embodiment, the composition contains about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, 560 μg, 640 μg, 675 μg, 720 μg, 800 μg, 880 μg, 960 μg, 1040 μg, 1120 μg, 1200 μg, and 1280 μg of the compound of formula (I) or (II). In one embodiment, the composition may be present in one powder capsule or in multiple (two or more) powder capsules. If present in multiple capsules, one of the aforementioned doses of the compound of formula (I) or (II) is divided within the capsule. In one embodiment, the capsule is a size #3 HPMC capsule.

[0117] Examples of TPIP compositions at different unit strengths are provided in Table E below. It should be understood that the unit strengths of the components provided herein can be calculated based on the weight percentage of the components and the desired dose. For example, in the case of an 80 μg dose of TP, the unit strength of each component is obtained by multiplying each component by 80. [Table E]

[0118] In one embodiment, the powder composition contains about 80 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 When measured using a next-generation impactor (NGI) with an inhalation acceleration, it provides one or more of the following: (i) an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), (ii) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (iii) an aerosol containing an emanating dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iv) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0119] In one embodiment, the powder composition contains about 160 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1is n-hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have a D10 of about 0.3 μm, a D50 of about 1.7 μm, and / or a D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5 to 20 L / sec 2 When measured using a Next Generation Impactor (NGI) having an inhalation acceleration of 2 , an aerosol comprising a fine particle fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about ⑧0%), and (i) a fine particle dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77% or about 60% to about 65%), (ii) an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic mass median diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm or about 0.8 μm to about 2.0 μm).

[0120] In another embodiment, the powder composition comprises about 240 μg of a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a still further embodiment of the compound of formula (I), R 1 is n-hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have a D10 of about 0.3 μm, a D50 of about 1.7 μm, and / or a D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5 to 20 L / sec2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0121] In one embodiment, the powder composition contains about 320 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0122] In another embodiment, the powder composition comprises about 400 μg of the compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0123] In another embodiment, the powder composition comprises about 480 μg of the compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0124] In one embodiment, the powder composition contains about 640 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0125] In one embodiment, the powder composition contains about 720 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0126] In one embodiment, the powder composition contains about 800 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0127] In one embodiment, the powder composition contains about 880 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0128] In one embodiment, the powder composition contains about 960 μg of a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0129] In one embodiment, the powder composition contains about 1040 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0130] In one embodiment, the powder composition contains about 1120 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0131] In one embodiment, the powder composition contains about 1200 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0132] In one embodiment, the powder composition contains about 1280 μg of the compounds of formula (I), (II), or pharmaceutically acceptable salts thereof. In a further embodiment of the compound of formula (I), R 1 is hexadecyl. In a further embodiment of the compound of formula (I), R 1 It is a linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0133] In preferred embodiments of the powder compositions provided herein, leucine is L-leucine. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition includes particles. In some embodiments, the spray-dried powder composition includes particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0134] In another aspect, the disclosure provides a powder composition comprising a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, that provides a specific pharmacokinetic profile after once-daily administration. Advantageously, the pharmacokinetic profile is C max It has a low half-life and a long half-life.

[0135] In one embodiment, a powder composition exhibiting one of the pharmacokinetic profiles described herein is a composition described in U.S. Patent Application Publication No. 2020 / 0338005 and International Publication No. WO2022 / 094100, which are incorporated herein by reference in whole for all purposes.

[0136] In another embodiment, a powder composition exhibiting one of the pharmacokinetic profiles described herein comprises (a) a compound of formula (I) or (II) in about 1% to about 5% by weight of the total weight of the powder composition, (b) about 25% to about 61% by weight of leucine, and the remainder being (c) a sugar selected from trehalose and mannitol. The total of (a), (b), and (c) is 100% by weight. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0137] Example 5 of WO2022 / 094100 presents that the pharmacokinetic (PK) profile measured for a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof was linear over the dose range of 112.5 μg to 675 μg. Based on this data, those skilled in the art can determine the pharmacokinetic parameters for doses outside or within this range that were not specifically tested in Example 5 of WO2022 / 094100. For example, to find the pharmacokinetic parameters at doses, C associated with a specific dose (112.5 μg, 225 μg, 450 μg, and / or 675 μg) is used. max The AUC may also be plotted. The scatter plot may be fitted to a line, y = mx + b, where m is the slope of the line and b is the y-intercept, and the value of the unknown pharmacokinetic parameter (y) may be calculated by plugging in the dose of x. Furthermore, the dose range of 112.5 μg to 675 μg is R 1 Based on the molecular weight of the compound of formula (I) when is hexadecyl (i.e., the compound of formula (II)). Equivalent dose (R) of other treprostinyl prodrugs 1 (If R is tetradecyl, pentadecyl, heptadecyl, or octadecyl) can be calculated using the molecular weight of the treprostinyl prodrug of interest. For example, the compound of formula II (R 1 (This corresponds to 112.5 μg of hexadecyl) 1The dose of the compound of formula (I) when is tetradecyl is R 1 The ratio of the molecular weight of the compound in formula (II) (614.95 μg / mol) to the molecular weight of the compound in formula (I) (586.9 μg / mol) when tetradecyl can be calculated by multiplying this ratio by 112.5 μg.

[0138] In embodiments, the powder compositions of the present disclosure are formulated to administer a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, in a dose ranging from about 80 μg to about 1280 μg, to the target lung once daily by inhalation, and provide at least one of the following features: (a) Maximum plasma concentration of treprostinil in the range of approximately 14 pg / mL to approximately 3000 pg / mL (C max ),or (b) Treprostinil area under the plasma concentration curve (AUC) in the range of approximately 500 pg*h / mL to approximately 20000 pg*h / mL.

[0139] In further embodiments, the powder composition contains about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 μg, about 480 μg, about 640 μg, about 675 μg, about 720 μg, about 800 μg, about 960 μg, about 1040 μg, about 1120 μg, about 1200 μg, or about 1280 μg of the compound of formula (I). In further embodiments, R 1This is hexadecyl, for example, linear hexadecyl. In one embodiment, the powder composition may be present in one powder capsule or in multiple (two or more) powder capsules. If present in multiple capsules, one of the compounds of formula (I) in the aforementioned doses is divided within the capsule. Using these multiple capsules, a composition containing one of the aforementioned doses (e.g., about 480 μg, about 560 μg, about 640 μg, about 675 μg, about 720 μg, about 800 μg, about 960 μg, about 1040 μg, about 1120 μg, about 1200 μg, or about 1280 μg) can be administered. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0140] In embodiments, the powder compositions of the present disclosure are formulated to administer a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, in a dose ranging from about 80 μg to about 675 μg, to the target lungs once daily by inhalation, and provide at least one of the following features: (a) Maximum plasma concentration of treprostinil in the range of approximately 14 pg / mL to approximately 1430 pg / mL (C max ),or (b) Treprostinil area under the plasma concentration curve (AUC) in the range of approximately 500 pg*h / mL to approximately 10000 pg*h / mL.

[0141] In further embodiments, the powder composition comprises about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 μg, about 480 μg, about 640 μg, or about 675 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. In further embodiments, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. In further embodiments of the compound of formula (I), R 1 This is hexadecyl, for example, linear hexadecyl. In one embodiment, the powder composition may be present in one powder capsule or in multiple (two or more) powder capsules. If present in multiple capsules, one of the compounds of formula (I) or (II) in the aforementioned doses, its stereoisomer, or a pharmaceutically acceptable salt thereof is divided within the capsule. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, if the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2When measured using a next-generation impactor (NGI) having an inhalation acceleration of, there is provided an aerosol comprising a fine particle fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and (i) a fine particle dose (FPD) of 50% or more (e.g., about 53% to about 77% or about 60% to about 65%) of the loading dose of the powder composition, (ii) an aerosol comprising an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic mass median diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm or about 0.8 μm to about 2.0 μm), or one or more of them.

[0142] In embodiments, the powder composition of the present disclosure is formulated to administer a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in a dose ranging from about 80 μg to about 1280 μg to the lungs of a subject (e.g., a patient) once a day by inhalation, and provides at least one of the following characteristics: (a) A maximum plasma concentration (C max ) of treprostinil in the range of about 14 pg / mL to about 3000 pg / mL, or (b) The area under the plasma concentration curve (AUC) of treprostinil in the range of about 380 pg*h / mL to about 20000 pg*h / mL.

[0143] In a further embodiment, the powder composition comprises about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 μg, about 480 μg, about 640 μg, about 675 μg, about 720 μg, about 800 μg, about 960 μg, about 1040 μg, about 1120 μg, about 1200 μg, or about 1280 μg of a compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the composition may be present in one powder capsule or a plurality (two or more) of powder capsules. When present in a plurality of capsules, one of the aforementioned dosages of the compound of formula (I) or (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, is divided within the capsule. Thus, a plurality of capsules may be administered to achieve one of the aforementioned dosages.

[0144] In an embodiment, the powder composition of the present disclosure is formulated to administer, by inhalation, to the lungs of a subject (e.g., a patient) once a day, a dosage of a compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the range of about 80 μg to about 640 μg, and provides at least one of the following characteristics: (a) A maximum plasma concentration (C max ) of treprostinil in the range of about 14 pg / mL to about 1430 pg / mL, or (b) An area under the plasma concentration curve (AUC) of treprostinil in the range of about 380 pg*h / mL to about 10000 pg*h / mL.

[0145] In a further embodiment, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of a compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the composition may be present in one powder capsule or a plurality (two or more) of powder capsules. When present in a plurality of capsules, one of the aforementioned dosages of the compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is divided within the capsule.

[0146] In one embodiment, the powder composition is formulated to administer a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, in a dose ranging from about 112.5 μg to about 675 μg, to the lungs of a subject (e.g., a patient) once daily by inhalation, and provides at least one of the following features: (a) Maximum plasma concentration of treprostinil in the range of approximately 17 pg / mL to approximately 1370 pg / mL (C max ),or (b) Treprostinil area under the plasma concentration curve (AUC) in the range of approximately 700 pg*h / mL to approximately 7800 pg*h / mL.

[0147] In further embodiments, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the composition may be present in one powder capsule or in multiple (two or more) powder capsules. If present in multiple capsules, one of the aforementioned doses of compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is divided within the capsule.

[0148] In embodiments, the powder composition is formulated to be administered once daily to the lungs of a subject (e.g., a patient) by inhalation of about 80 μg to about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, for example, about 80 μg to about 1200 μg or about 320 μg to about 1280 μg, providing the pharmacokinetic profile described herein. In one embodiment, a powder composition having one of the pK profiles described herein is approximately 80 μg, approximately 100 μg, approximately 110 μg, approximately 112.5 μg, approximately 120 μg, approximately 130 μg, approximately 140 μg, approximately 150 μg, approximately 160 μg, approximately 170 μg, approximately 180 μg, approximately 190 μg, approximately 200 μg, approximately 210 μg, approximately 220 μg, approximately 225 μg, approximately 230 μg, approximately 240 μg, approximately 250 μg, approximately 260 μg, approximately 270 μg, approximately 280 μg μg, approximately 290 μg, approximately 300 μg, approximately 310 μg, approximately 320 μg, approximately 330 μg, approximately 340 μg, approximately 350 μg, approximately 360 μg, approximately 370 μg, approximately 380 μg, approximately 390 μg, approximately 400 μg, approximately 410 μg, approximately 42 0μg, about 430μg, about 440μg, about 450μg, about 460μg, about 470μg, about 480μg, about 490μg, about 500μg, about 510μg, about 520μg, about 530μg, about 540μg, about 550μg, about 5 60μg, about 570μg, about 580μg, about 590μg, about 600μg, about 610μg, about 620μg, about 630μg, about 640μg, about 650μg, about 660μg, about 670μg, about 675μg, about 680μg, about 690μg, about 700μg, about 720μg, about 740μg, about 760μg, about 780μg, about 800μg, about 820μg, about 840μg, about 860μg, about, about 880μg, about 900μg, about 920μg, about 940μg g, approximately 960 μg, approximately 980 μg, approximately 1000 μg, approximately 1020 μg, approximately 1040 μg, approximately 1060 μg, approximately 1080 μg, approximately 1100 μg, approximately 1120 μg, approximately 1140 μg, approximately 1160 μg, approximately 1180 μg, approximately 1200 μg, approximately 1240 μg, approximately 1260 μg, or approximately 1280 μg of the compound of formula (I) or (II), its stereoisomers, or pharmaceutically acceptable salts thereof (including all values ​​and ranges therein). In further embodiments, R 1This is hexadecyl, for example, linear hexadecyl. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0149] In one embodiment, the powder composition is formulated to be administered once daily to the lungs of a subject (e.g., a patient) by inhalation of about 80 μg to about 675 μg of a compound of formula (I) or (II), or its stereoisomer or pharmaceutically acceptable salt, for example, about 80 μg to about 640 μg or about 112.5 μg to about 675 μg, to provide the pharmacokinetic profile described herein. In one embodiment, the powder composition having one of the pK profiles described herein is available in doses of about 80 μg, about 100 μg, about 110 μg, about 112.5 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, and about 21 μg. 0μg, about 220μg, about 225μg, about 230μg, about 240μg, about 250μg, about 260μg, about 270μg, about 280μg, about 290μg, about 300μg, about 310μg, about 320μg, about 330μg, about 340μg, about 350μg, about 360μg, about 370μg, about 380μg, about 390μg, Approximately 400μg, approximately 410μg, approximately 420μg, approximately 430μg, approximately 440μg, approximately 450μg, approximately 460μg, approximately 470μg, approximately 480μg, approximately 490μg g, about 500μg, about 510μg, about 520μg, about 530μg, about 540μg, about 550μg, about 560μg, about 570μg, about 580μg, about 590 The compound of formula (I) or a pharmaceutically acceptable salt thereof (including all values ​​and ranges thereof) in amounts of approximately μg, about 600 μg, about 610 μg, about 620 μg, about 630 μg, about 640 μg, about 650 μg, about 660 μg, about 670 μg, about 675 μg, about 680 μg, about 690 μg, or about 700 μg. In further embodiments, R 1 This is a hexadecyl, for example, a linear hexadecyl.

[0150] In some embodiments, a dry powder composition containing about 80 μg to about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, followed by the administration of the powder composition or method of use in a range of about 10 pg / mL to about 3000 pg / mL, for example, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 7 5pg / mL, approximately 80pg / mL, approximately 85pg / mL, approximately 90pg / mL, approximately 95pg / mL, approximately 100pg / mL, approximately 110pg / mL, approximately 120pg / mL, approximately 130pg / mL, approximately 140pg / mL, approximately 150pg / mL, approximately 160pg / mL, approximately 170pg / mL, approximately 180pg / mL, approximately 190pg / mL, approximately 200pg / mL, approximately 210pg / mL, approximately 220pg / mL, approximately 230pg / mL, approximately 240pg / mL, approximately 250pg / mL, approximately 260pg / mL, approximately 270pg / mL, approximately 280pg / mL, approximately 290pg / mL, approximately 300pg / mL, approximately 310pg / mL, approximately 320pg / mL, approximately 330pg / mL, approximately 340pg / mL, approximately 350pg / mL, approximately 360pg / mL, approximately 370pg / mL, approximately 380pg / mL, approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, Approximately 430pg / mL, approximately 440pg / mL, approximately 450pg / mL, approximately 460pg / mL, approximately 470pg / mL, approximately 480pg / mL, approximately 490pg / mL, approximately 500pg / mL, approximately 510pg / mL, approximately 520pg / mL, approximately 530pg / mL, approximately 540pg / mL, approximately 550p g / mL, approximately 560pg / mL, approximately 570pg / mL, approximately 580pg / mL, approximately 590pg / mL, approximately 600pg / mL, approximately 610pg / mL, approximately 620pg / mL, approximately 630pg / mL, approximately 640pg / mL, approximately 650pg / mL, approximately 660pg / mL, approximately 670pg / mL , about 680pg / mL, about 690pg / mL, about 700pg / mL, about 750pg / mL, about 800pg / mL, about 850pg / mL, about 900pg / mL, about 950pg / mL, about 1000pg / mL, about 1050pg / mL, about 1100pg / mL, about 1150pg / mL,About 1200pg / mL, about 1250pg / mL, about 1300pg / mL, about 1350pg / mL, about 1400pg / mL, about 1450pg / mL, about 1500pg / mL, about 1550pg / mL, about 1600pg / mL, about 1650p g / mL, approximately 1700pg / mL, approximately 1750pg / mL, approximately 1800pg / mL, approximately 1850pg / mL, approximately 1900pg / mL, approximately 2000pg / mL, approximately 2050pg / mL, approximately 2100pg / mL, approximately 2150pg / mL, approximately 2 Maximum plasma concentration of treprostinil (C) at 200 pg / mL, approximately 2250 pg / mL, approximately 2300 pg / mL, approximately 2350 pg / mL, approximately 2400 pg / mL, approximately 2450 pg / mL, approximately 2500 pg / mL, approximately 2550 pg / mL, approximately 2600 pg / mL, approximately 2650 pg / mL, approximately 2700 pg / mL, approximately 2750 pg / mL, approximately 2800 pg / mL, approximately 2850 pg / mL, approximately 2900 pg / mL, or approximately 3000 pg / mL (including all values ​​and ranges within that range). max ) provides. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0151] In some embodiments, a powder composition containing a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in an amount of about 80 μg to about 675 μg (e.g., about 80 μg to about 640 μg, or about 112.5 μg to about 675 μg) is administered once daily, followed by administration of the powder composition or method of use in a range of about 10 pg / mL to about 2000 pg / mL, for example, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL. Approximately 30pg / mL, approximately 35pg / mL, approximately 40pg / mL, approximately 45pg / mL, approximately 50pg / mL, approximately 55pg / mL, approximately 60pg / mL, approximately 65pg / mL, approximately 70pg / mL, approximately 75pg / mL, approximately 80pg / mL, Approximately 85pg / mL, approximately 90pg / mL, approximately 95pg / mL, approximately 100pg / mL, approximately 110pg / mL, approximately 120pg / mL, approximately 130pg / mL, approximately 140pg / mL, approximately 150pg / mL, approximately 160pg / mL, approximately 17 0pg / mL, approximately 180pg / mL, approximately 190pg / mL, approximately 200pg / mL, approximately 210pg / mL, approximately 220pg / mL, approximately 230pg / mL, approximately 240pg / mL, approximately 250pg / mL, approximately 260pg / mL, approximately 2 70pg / mL, approximately 280pg / mL, approximately 290pg / mL, approximately 300pg / mL, approximately 310pg / mL, approximately 320pg / mL, approximately 330pg / mL, approximately 340pg / mL, approximately 350pg / mL, approximately 360pg / mL, approximately 3 70pg / mL, approximately 380pg / mL, approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, approximately 430pg / mL, approximately 440pg / mL, approximately 450pg / mL, approximately 460pg / mL, approximately 470pg / mL, approximately 480pg / mL, approximately 490pg / mL, approximately 500pg / mL, approximately 510pg / mL, approximately 520pg / mL, approximately 530pg / mL, approximately 540pg / mL, approximately 550pg / mL, approximately 560pg / mL, approximately 570pg / mL, approximately 580pg / mL, approximately 590pg / mL, approximately 600pg / mL, approximately 610pg / mL, approximately 620pg / mL, approximately 630pg / mL, approximately 640pg / mL, approximately 650pg / mL, approximately 660pg / mL, approximately 670pg / mL, approximately 680pg / mL, approximately 690pg / mL, approximately 700pg / mL, approximately 750pg / mL, approximately 800pg / mL, approximately 850pg / mL, approximately 900pg / mL, approximately 950pg / mL, approximately 1000pg / mL,Maximum plasma concentrations of treprostinil (C) of approximately 1050 pg / mL, 1100 pg / mL, 1150 pg / mL, 1200 pg / mL, 1250 pg / mL, 1300 pg / mL, 1350 pg / mL, 1400 pg / mL, 1450 pg / mL, 1500 pg / mL, 1550 pg / mL, 1600 pg / mL, 1650 pg / mL, 1700 pg / mL, 1750 pg / mL, 1800 pg / mL, 1850 pg / mL, 1900 pg / mL, or 2000 pg / mL (including all values ​​and ranges within that range). max ) provides. In one embodiment, the powder composition is a spray-dried powder composition.

[0152] In some embodiments, a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in an amount of about 80 μg to about 1280 μg (e.g., about 80 μg to about 640 μg, or about 360 μg to about 1280 μg) is administered once daily, followed by the use of the powder composition or method of use in the range of about 300 pg*h / mL to about 20000 pg*h / mL, for example, about 300 pg*h / mL, about 400 pg*h / mL, about 500 pg*h / mL, about 600 pg*h / mL, about 700 pg*h / mL, about 800 pg*h / mL, about 900 pg*h / mL, about 1000 pg*h / mL. Approximately 1100pg*h / mL, approximately 1200pg*h / mL, approximately 1300pg*h / mL, approximately 1400pg*h / mL, approximately 1500pg*h / mL, approximately 1600pg*h / mL, approximately 1700pg*h / mL, approximately 1800pg*h / mL, approximately 1900pg*h / mL, approximately 20 00pg*h / mL, approximately 2100pg*h / mL, approximately 2200pg*h / mL, approximately 2300pg*h / mL, approximately 2400pg*h / mL, approximately 2500pg*h / mL, approximately 2600pg*h / mL, approximately 2700ng*h / mL, approximately 2800ng*h / mL, approximately 2900p g*h / mL, approximately 3000pg*h / mL, approximately 3100pg*h / mL, approximately 3200pg*h / mL, approximately 3300pg*h / mL, approximately 3400pg*h / mL, approximately 3500pg*h / mL, approximately 3600pg*h / mL, approximately 3700pg*h / mL, approximately 3800pg*h / mL, approximately 3900pg*h / mL, approximately 4000pg*h / mL, approximately 4100pg*h / mL, approximately 4200pg*h / mL, approximately 4300pg*h / mL, approximately 4400pg*h / mL, approximately 4500pg*h / mL, approximately 4600pg*h / mL, approximately 4700pg*h / mL , about 4800pg*h / mL, about 4900pg*h / mL, about 5000pg*h / mL, about 5100pg*hr / mL, about 5200pg*hr / mL, about 5300pg*hr / mL, about 5400pg*hr / mL, about 5500pg*hr / mL, about 5600pg*hr / mL, approximately 5700pg*hr / mL, approximately 5800pg*hr / mL, approximately 5900pg*hr / mL, approximately 6000pg*hr / mL, approximately 6100pg*hr / mL, approximately 6200pg*hr / mL, approximately 6300pg*h / mL*hr / mL, approximately 6400pg*h / mL,Approximately 6500 pg*h / mL*hr / mL, approximately 6600 pg*hr / mL, approximately 6700 pg*hr / mL, approximately 6800 pg*hr / mL, approximately 6900 pg*hr / mL, approximately 7000 pg*hr / mL, approximately 7100 pg*hr / mL, approximately 7200 pg*hr / mL, approximately 7300 pg*hr / mL, approximately 7400 pg*hr / mL, approximately 7500 pg*hr / mL, approximately 7600 pg*hr / mL, approximately 7700 pg*hr / mL, approximately 7800 pg*hr / mL, approximately 7900 pg*hr / mL, approximately 8000 pg*hr / mL, approximately 8100 pg*hr / mL, approximately 820 0 pg*hr / mL, approximately 8300 pg*hr / mL, approximately 8400 pg*hr / mL, approximately 8500 pg*hr / mL, approximately 8600 pg*hr / mL, approximately 8700 pg*hr / mL, approximately 8800 pg*hr / mL, approximately 8900 pg*hr / mL, approximately 9000 pg*hr / mL, approximately 9100 pg*hr / mL, approximately 9200 pg*hr / mL, approximately 9300 pg*hr / mL, approximately 9400 pg*hr / mL, approximately 9500 pg*hr / mL, approximately 9600 pg*hr / mL, approximately 9700 pg*hr / mL, approximately 9800 pg*hr / mL, approximately 9900 pg*hr / mL Approximately 10000 pg*hr / mL, approximately 10100 pg*hr / mL, approximately 10200 pg*hr / mL, approximately 10300 pg*hr / mL, approximately 10400 pg*hr / mL, approximately 10500 pg*hr / mL, approximately 10600 pg*hr / mL, approximately 10700 pg*hr / mL, approximately 10800 pg*hr / mL, approximately 10900 pg*hr / mL, approximately 11000 pg*hr / mL, approximately 11100 pg*hr / mL, approximately 11200 pg*hr / mL, approximately 11300 pg*hr / mL, approximately 11400 pg*hr / mL, approximately 11500 pg*hr / mL, approximately 11600 pg*hr / mL g*hr / mL, approximately 11700 pg*hr / mL, approximately 11800 pg*hr / mL, approximately 11900 pg*hr / mL, approximately 12000 pg*hr / mL, approximately 12100 pg*hr / mL, approximately 12200 pg*hr / mL, approximately 12300 pg*hr / mL, approximately 12400 pg*hr / mL, approximately 12500 pg*hr / mL, approximately 12600 pg*hr / mL, approximately 12700 pg*hr / mL, approximately 12800 pg*hr / mL, approximately 12900 pg*hr / mL, approximately 13000 pg*hr / mL, approximately 13100 pg*hr / mL, approximately 13200 pg*hr / mLApproximately 13300 pg*hr / mL, approximately 13400 pg*hr / mL, approximately 13500 pg*hr / mL, approximately 13600 pg*hr / mL, approximately 13700 pg*hr / mL, approximately 13800 pg*hr / mL, approximately 13900 pg*hr / mL, approximately 14000 pg*hr / mL, approximately 14100 pg*hr / mL, approximately 14200 pg*hr / mL, approximately 14300 pg*hr / mL, approximately 14400 pg*hr / mL, approximately 14500 pg*hr / mL, approximately 14600 pg*hr / mL, approximately 14700 pg*hr / mL, approximately 14800 pg*hr / mL, approximately 14900 pg*hr / mL g*hr / mL, approximately 15000 pg*hr / mL, approximately 15100 pg*hr / mL, approximately 15200 pg*hr / mL, approximately 15300 pg*hr / mL, approximately 15400 pg*hr / mL, approximately 15500 pg*hr / mL, approximately 15600 pg*hr / mL, approximately 15700 pg*hr / mL, approximately 15800 pg*hr / mL, approximately 15900 pg*hr / mL, approximately 16000 pg*hr / mL, approximately 16100 pg*hr / mL, approximately 16200 pg*hr / mL, approximately 16300 pg*hr / mL, approximately 16400 pg*hr / mL, approximately 16500 pg*hr / mL Approximately 16600 pg*hr / mL, approximately 16700 pg*hr / mL, approximately 16800 pg*hr / mL, approximately 16900 pg*hr / mL, approximately 17000 pg*hr / mL, approximately 17100 pg*hr / mL, approximately 17200 pg*hr / mL, approximately 17300 pg*hr / mL, approximately 17400 pg*hr / mL, approximately 17500 pg*hr / mL, approximately 17600 pg*hr / mL, approximately 17700 pg*hr / mL, approximately 17800 pg*hr / mL, approximately 17900 pg*hr / mL, approximately 18000 pg*hr / mL, approximately 18100 pg*hr / mL, approximately 18200 pg*hr / mL g*hr / mL, approximately 18300 pg*hr / mL, approximately 18400 pg*hr / mL, approximately 18500 pg*hr / mL, approximately 18600 pg*hr / mL, approximately 18700 pg*hr / mL, approximately 18800 pg*hr / mL, approximately 18900 pg*hr / mL, approximately 19000 pg*hr / mL, approximately 19100 pg*hr / mL, approximately 19200 pg*hr / mL, approximately 19300 pg*hr / mL, approximately 19400 pg*hr / mL, approximately 19500 pg*hr / mL, approximately 19600 pg*hr / mL, approximately 19700 pg*hr / mL, approximately 19800 pg*hr / mLThe area under the plasma concentration curve (AUC) provides an area of ​​approximately 19900 pg*hr / mL or approximately 20000 pg*hr / mL (including all values ​​and ranges within that range). In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of approximately 1.0 μm to approximately 2.0 μm. In some embodiments, the particles have D10 of approximately 0.3 μm, D50 of approximately 1.7 μm, and / or D90 of approximately 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec. 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0153] In some embodiments, approximately 80 μg to approximately 675 μg (e.g., approximately 80 μg to approximately 640 μg, or approximately 112.5 μg to approximately 675 μg) of a compound of formula (I) or (II), or its stereoisomer or a pharmaceutically acceptable salt thereof, is administered once daily. The powder composition or method of use is administered in a range of approximately 300 pg*h / mL to approximately 11000 pg*h / mL, for example, approximately 300 pg*h / mL, approximately 400 pg*h / mL, approximately 500 pg*h / mL, approximately 600 pg*h / mL, approximately 700 pg*h / mL, approximately 800 pg*h / mL, approximately 900 pg*h / mL, approximately 1000pg*h / mL, approximately 1100pg*h / mL, approximately 1200pg*h / mL, approximately 1300pg*h / mL, approximately 1400pg*h / mL, approximately 1500pg*h / mL, approximately 1600pg*h / mL, approximately 1700pg*h / mL, approximately 1800pg*h / mL, approximately 1 900pg*h / mL, approximately 2000pg*h / mL, approximately 2100pg*h / mL, approximately 2200pg*h / mL, approximately 2300pg*h / mL, approximately 2400pg*h / mL, approximately 2500pg*h / mL, approximately 2600pg*h / mL, approximately 2700ng*h / mL, approximately 2800ng* h / mL, approximately 2900pg*h / mL, approximately 3000pg*h / mL, approximately 3100pg*h / mL, approximately 3200pg*h / mL, approximately 3300pg*h / mL, approximately 3400pg*h / mL, approximately 3500pg*h / mL, approximately 3600pg*h / mL, approximately 3700pg*h / mL, approximately 3800pg*h / mL, approximately 3900pg*h / mL, approximately 4000pg*h / mL, approximately 4100pg*h / mL, approximately 4200pg*h / mL, approximately 4300pg*h / mL, approximately 4400pg*h / mL, approximately 4500pg*h / mL, approximately 4600pg*h / mL, approximately 4700pg *h / mL, approximately 4800pg*h / mL, approximately 4900pg*h / mL, approximately 5000pg*h / mL, approximately 5100pg*hr / mL, approximately 5200pg*hr / mL, approximately 5300pg*hr / mL, approximately 5400pg*hr / mL, approximately 5500pg*hr / mL, approximately 5600pg* hr / mL, approximately 5700pg*hr / mL, approximately 5800pg*hr / mL, approximately 5900pg*hr / mL, approximately 6000pg*hr / mL, approximately 6100pg*hr / mL, approximately 6200pg*hr / mL, approximately 6300pg*h / mLg*hr / mL, approximately 6400pg*h / mL,Approx. 6500pg*h / mLg*hr / mL, approx. 6600pg*hr / mL, approx. 6700pg*hr / mL, approx. 6800pg*hr / mL, approx. 6900pg*hr / mL, approx. 7000pg*hr / m L, approx. 7100pg*hr / mL, approx. 7200pg*hr / mL, approx. 7300pg*hr / mL, approx. 7400pg*hr / mL, approx. 7500pg*hr / mL, approx. 7600pg*hr / mL, approx. 7 700pg*hr / mL, approx. 7800pg*hr / mL, approx. 7900pg*hr / mL, approx. 8000pg*hr / mL, approx. 8100pg*hr / mL, approx. 8200pg*hr / mL, approx. 8300p g*hr / mL, approximately 8400pg*hr / mL, approximately 8500pg*hr / mL, approximately 8600pg*hr / mL, approximately 8700pg*hr / mL, approximately 8800pg*hr / mL, approximately 8900pg*hr / mL, approximately 9000pg*hr / mL, approximately 9100pg*hr / mL, approximately 9200pg*hr / mL, approximately 9300pg*hr / mL, approximately 9400pg*hr / mL, approximately 9500pg*hr / mL, Approx. 9600pg*hr / mL, approx. 9700pg*hr / mL, approx. 9800pg*hr / mL, approx. 9900pg*hr / mL, approx. 10000pg*hr / mL, approx. 10100pg*hr / mL, approx. 1 It provides the area under the plasma concentration curve (AUC) for approximately 0.200 pg*hr / mL, approximately 10.300 pg*hr / mL, approximately 10.400 pg*hr / mL, approximately 10.500 pg*hr / mL, approximately 10.600 pg*hr / mL, approximately 10.700 pg*hr / mL, approximately 10.800 pg*hr / mL, approximately 10.900 pg*hr / mL, or approximately 11.000 pg*hr / mL (including all values ​​and ranges within these). In one embodiment, the powder composition is a spray-dried powder composition.

[0154] In some embodiments, the powder composition or method of use achieves a treprostinil plasma trough concentration during the administration period of the powder composition. In some embodiments, the plasma trough level is sufficient to produce a sustained therapeutic response during the administration period.

[0155] In some embodiments, the powder composition or method of use comprises about 80 μg to about 1280 μg of a compound of formula (I) or (II), or its stereoisomer or a pharmaceutically acceptable salt thereof, and after once-daily administration, the treprostinil plasma trough concentration is in the range of about 3 pg / mL to about 250 mg / mL, for example, about 4 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL. Approximately 30pg / mL, approximately 35pg / mL, approximately 40pg / mL, approximately 45pg / mL, approximately 50pg / mL, approximately 55pg / mL, approximately 60pg / mL, approximately 65pg / mL, approximately 70pg / mL, approximately 75pg / mL, approximately 80pg / m L, approximately 85pg / mL, approximately 90pg / mL, approximately 95pg / mL, approximately 100pg / mL, approximately 100pg / mL, approximately 105pg / mL, approximately 110pg / mL, approximately 115pg / mL, approximately 120pg / mL, approximately 125pg / mL These values ​​are approximately 130 pg / mL, 135 pg / mL, 140 pg / mL, 145 pg / mL, 150 pg / mL, 155 pg / mL, 160 pg / mL, 165 pg / mL, 170 pg / mL, 175 pg / mL, 180 pg / mL, 185 pg / mL, 190 pg / mL, 195 pg / mL, 200 pg / mL, 200 pg / mL, 205 pg / mL, 210 pg / mL, 215 pg / mL, 220 pg / mL, 225 pg / mL, 230 pg / mL, 235 pg / mL, 240 pg / mL, 245 pg / mL, or 250 pg / mL (including all values ​​and ranges within these ranges). In some embodiments, the powder composition is a spray-dried powder. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0156] In some embodiments, the powder composition or method of use includes about 80 μg to about 675 μg of the compound of formula (I) or its stereoisomer (e.g., R 1 The powder composition contains hexadecyl (for example, linear hexadecyl), and after administration once daily, the amount of hexadecyl is at least about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, about 100 pg / mL, about 110 pg / mL Provides treprostinil plasma trough concentrations of approximately 120 pg / mL, approximately 130 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, and approximately 200 pg / mL (including all values ​​and ranges within these), or the subject (e.g., patient) has them.

[0157] In some embodiments, the powder composition or method of use comprises about 80 μg to about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and after once-daily administration, the treprostinil plasma trough concentration is in the range of about 3 pg / mL to about 125 pg / mL, for example, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL. The concentrations are approximately 30 pg / mL, 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, 75 pg / mL, 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, 100 pg / mL, 100 pg / mL, 110 pg / mL, and 120 pg / mL (including all values ​​and ranges within these). In some embodiments, the powder composition contains approximately 80 μg to approximately 640 μg of the compound of formula (II), and the treprostinil plasma trough concentration is in the range of approximately 10 pg / mL to approximately 100 pg / mL.

[0158] In some embodiments, after once-daily administration of a powder composition containing approximately 80 μg to approximately 675 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, the powder composition or method of use provides the following, or the subject (e.g., patient) has at least one of the following characteristics: (a) A range of approximately 17 pg / mL to approximately 1150 pg / mL, for example, approximately 13 pg / mL, approximately 14 pg / mL, approximately 15 pg / mL, approximately 20 pg / mL, approximately 25 pg / mL, approximately 30 pg / mL, approximately 35 pg / mL, approximately 40 pg / mL, approximately 45 pg / mL, approximately 50 pg / mL, approximately 55 pg / mL, approximately 60 pg / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL , about 140pg / mL, about 150pg / mL, about 160pg / mL, about 170pg / mL, about 180pg / mL, about 190pg / mL, about 200pg / mL, about 210pg / mL, about 220pg / mL, about 230pg / mL, about 240pg / mL, about 250pg / mL , about 260pg / mL, about 270pg / mL, about 280pg / mL, about 290pg / mL, about 300pg / mL, about 310pg / mL, about 320pg / mL, about 330pg / mL, about 340pg / mL, about 350pg / mL, about 360pg / mL, about 370pg / mL , about 380pg / mL, about 390pg / mL, about 400pg / mL, about 410pg / mL, about 420pg / mL, about 430pg / mL, about 440pg / mL, about 450pg / mL, about 460pg / mL, about 470pg / mL, about 480pg / mL, about 490pg / mL , about 500pg / mL, about 510pg / mL, about 520pg / mL, about 530pg / mL, about 540pg / mL, about 550pg / mL, about 560pg / mL, about 570pg / mL, about 580pg / mL, about 590pg / mL, about 600pg / mL, about 610pg / mL , about 620pg / mL, about 630pg / mL, about 640pg / mL, about 650pg / mL, about 660pg / mL, about 670pg / mL, about 680pg / mL, about 690pg / mL, about 700pg / mL, about 750pg / mL, about 800pg / mL, about 850pg / mL , about 900pg / mL, about 950pg / mL, about 1000pg / mL, about 1050pg / mL, about 1100pg / mL, about 1150pg / mL, about 1200pg / mL, about 1250pg / mL, about 1300pg / mL, about 1350pg / mL, about 1400pg / mL,Alternatively, the maximum plasma concentration of treprostinil (C) is within the range of approximately 80% to approximately 125% of approximately 1430 pg / mL (including all values ​​and ranges within that range). max ),or (b) A range of approximately 475 pg*h / mL to approximately 8000 pg*h / mL, for example, approximately 370 pg*h / mL, approximately 400 pg*h / mL, approximately 450 pg*h / mL, approximately 500 pg*h / mL, approximately 550 pg*h / mL, approximately 600 pg*h / mL, approximately 650 pg*h / mL, approximately 700 pg*h / mL, approximately 800 pg*h / mL, approximately 900 pg*h / mL, approximately 1000 pg*h / mL, approximately 1100 pg*h / mL, approximately 1200 pg*h / mL, approximately 1300 pg*h / mL, approximately 1400 pg*h / mL, approximately 1500 pg*h / mL, approximately 1600 pg*h / mL, approximately 1 700pg*h / mL, approximately 1800pg*h / mL, approximately 1900pg*h / mL, approximately 2000pg*h / mL, approximately 2100pg*h / mL, approximately 2200pg*h / mL, approximately 2300pg*h / mL, approximately 2400pg*h / mL, approximately 2500pg*h / mL, approximately 2600pg*h / mL, approximately 2700ng*h / mL, approximately 2800ng*h / mL, approximately 2900pg*h / mL, approximately 3000pg*h / mL, approximately 3100pg*h / mL, approximately 3200pg*h / mL, approximately 3300pg*h / mL, approximately 3400pg*h / mL, approximately 3500pg*h / mL, approximately 36 00pg*h / mL, approximately 3700pg*h / mL, approximately 3800pg*h / mL, approximately 3900pg*h / mL, approximately 4000pg*h / mL, approximately 4100pg*h / mL, approximately 4200pg*h / mL, approximately 4300pg*h / mL, approximately 4400pg*h / mL, approximately 4500pg*h / mL, approximately 4600pg*h / mL, approximately 4700pg*h / mL, approximately 4800pg*h / mL, approximately 4900pg*h / mL, approximately 5000pg*h / mL, approximately 5100pg*hr / mL, approximately 5200pg*hr / mL, approximately 5300pg*hr / mL, approximately 5400pg*hr / mL, Approx. 5500pg*hr / mL, approx. 5600pg*hr / mL, approx. 5700pg*hr / mL, approx. 5800pg*hr / mL, approx. 5900pg*hr / mL, approx. 6000pg*hr / mL, approx. 6100pg*hr / mL, approx. 6200pg*hr / mL, approx. 6300pg*hr / mL , about 6400pg*h / mL, about 6500pg*h / mL, about 6600pg*hr / mL, about 6700pg*hr / mL, about 6800pg*hr / mL, about 6900pg*hr / mL, about 7000pg*hr / mL, about 7100pg*hr / mL, about 7200pg*hr / mL,Approx. 7300pg*hr / mL, approx. 7400pg*hr / mL, approx. 7500pg*hr / mL, approx. 7600pg*hr / mL, approx. 7700pg*hr / mL, approx. 7800pg*hr / mL, approx. 7900pg*hr / mL, approx. 8000pg*hr / mL, approximately 8100pg*hr / mL, approximately 8200pg*hr / mL, approximately 8300pg*h / mL, approximately 8400pg*h / mL, approximately 8500pg*h / mL, approximately 8600pg*hr / mL, approximately 8700pg*hr / mL, approximately 8800pg*hr / m Plasma concentration curves (AUC) within the range of approximately 80% to 125% of L, approximately 8900 pg*hr / mL, approximately 9000 pg*hr / mL, approximately 9100 pg*hr / mL, approximately 9200 pg*hr / mL, approximately 9300 pg*hr / mL, approximately 9400 pg*hr / mL, approximately 9500 pg*hr / mL, approximately 9600 pg*hr / mL, approximately 9700 pg*hr / mL, approximately 9800 pg*hr / mL, approximately 9900 pg*hr / mL, or approximately 10000 pg*hr / mL (including all values ​​and ranges within that range). 0-inf ) Treprostinyl area below.

[0159] In some embodiments, the powder composition comprises about 80 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt, administered once daily in a dose range of about 14 pg / mL to about 155 pg / mL, for example, about 14 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, about 105 pg / mL. Treprostinil C at approximately 110 pg / mL, 115 pg / mL, 120 pg / mL, 125 pg / mL, 130 pg / mL, 135 pg / mL, 140 pg / mL, 145 pg / mL, 150 pg / mL, and 155 pg / mL (including all values ​​and ranges within these). maxIn some embodiments, approximately 80 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 17 pg / mL to approximately 125 pg / mL. max In some embodiments, approximately 80 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 35 pg / mL to approximately 105 pg / mL. max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0160] In some embodiments, the powder composition comprises about 112.5 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and about 80% to about 125% of treprostinyl C at about 78.4 (72.9) pg / mL. maxProvides (CV%). In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0161] In some embodiments, the powder composition comprises about 160 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a dose range of about 30 pg / mL to about 335 pg / mL, for example, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, about 105 pg / mL. Approx. 110pg / mL, approx. 115pg / mL, approx. 120pg / mL, approx. 125pg / mL, approx. 130pg / mL, approx. 135pg / mL, approx. 140p g / mL, approximately 145pg / mL, approximately 150pg / mL, approximately 155pg / mL, approximately 160pg / mL, approximately 165pg / mL, approximately 170pg / mL, Approx. 175pg / mL, approx. 180pg / mL, approx. 1850pg / mL, approx. 190pg / mL, approx. 195pg / mL, approx. 200pg / mL, approx. 205 pg / mL, approx. 210 pg / mL, approx. 215 pg / mL, approx. 220 pg / mL, approx. 225 pg / mL, approx. 230 pg / mL, approx. 235 pg / mL Treprostinil C at approximately 240 pg / mL, 245 pg / mL, 250 pg / mL, 255 pg / mL, 260 pg / mL, 265 pg / mL, 270 pg / mL, 275 pg / mL, 280 pg / mL, 285 pg / mL, 290 pg / mL, 295 pg / mL, 300 pg / mL, 305 pg / mL, 310 pg / mL, 315 pg / mL, 320 pg / mL, 325 pg / mL, 330 pg / mL, 335 pg / mL, 340 pg / mL, 345 pg / mL, or 350 pg / mL (including all values ​​and ranges within that range). max In some embodiments, approximately 160 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 35 pg / mL to approximately 270 pg / mL. maxIn some embodiments, approximately 160 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 76 pg / mL to approximately 230 pg / mL. max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0162] In some embodiments, the powder composition comprises about 225 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily to a dose of about 287 (46.6) pg / mL of treprostinil C in the range of about 80% to about 125%. max The present invention provides: In some embodiments, the powder composition comprises about 225 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and steady-state treprostinyl C in a range of about 80% to about 125% at about 193 (32.9) pg / mL. maxThe present invention provides: In some embodiments, the powder composition comprises about 225 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily to a steady-state treprostinil C at a concentration of about 228 (46.4) pg / mL, ranging from about 80% to about 125%. max Provides (CV%). In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0163] In some embodiments, the powder composition comprises about 240 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a dose range of about 45 pg / mL to about 520 pg / mL, for example, about 45 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL. / mL, approx. 100pg / mL, approx. 110pg / mL, approx. 120pg / mL, approx. 130pg / mL, approx. 140pg / mL, approx. 150pg / mL, approx. 160pg / mL, approx. 17 0pg / mL, approx. 180pg / mL, approx. 190pg / mL, approx. 200pg / mL, approx. 210pg / mL, approx. 220pg / mL, approx. 230pg / mL, approx. 240pg / mL, approx. 250pg / mL, approx. 260pg / mL, approx. 270pg / mL, approx. 280pg / mL, approx. 290pg / mL, approx. 300pg / mL, approx. 310pg / mL, approx. 320pg / m L, approx. 330pg / mL, approx. 340pg / mL, approx. 350pg / mL, approx. 360pg / mL, approx. 370pg / mL, approx. 380pg / mL, approx. 390pg / mL, approx. 400p Treprostinil C in g / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, or approximately 520 pg / mL (including all values ​​and ranges within these ranges). max In some embodiments, approximately 240 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 55 pg / mL to approximately 415 pg / mL. max The present invention provides: In some embodiments, approximately 240 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 115 pg / mL to approximately 355 pg / mL. maxTo provide. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have a D10 of about 0.3 μm, a D50 of about 1.7 μm, and / or a D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5 to 20 L / sec 2 When measured using a Next Generation Impactor (NGI) having an inhalation acceleration of 2 , an aerosol containing a fine particle fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and (i) a fine particle dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77% or about 60% to about 65%), (ii) an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic mass median diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm or about 0.8 μm to about 2.0 μm) is provided.

[0164] In some embodiments, the powder composition comprises about 320 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a dose range of about 60 pg / mL to about 700 pg / mL, for example, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL. Approximately 140pg / mL, approximately 150pg / mL, approximately 160pg / mL, approximately 170pg / mL, approximately 180pg / mL, approximately 190pg / mL, approximately 200pg / mL, approximately 210pg / mL, approximately 220pg / mL, approximately 230pg / mL, Approximately 240pg / mL, approximately 250pg / mL, approximately 260pg / mL, approximately 270pg / mL, approximately 280pg / mL, approximately 290pg / mL, approximately 300pg / mL, approximately 310pg / mL, approximately 320pg / mL, approximately 330pg / mL, Approximately 340pg / mL, approximately 350pg / mL, approximately 360pg / mL, approximately 370pg / mL, approximately 380pg / mL, approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, approximately 430pg / mL, Approx. 440pg / mL, approx. 450pg / mL, approx. 460pg / mL, approx. 470pg / mL, approx. 480pg / mL, approx. 490pg / mL, approx. 500pg / mL, approx. 510pg / mL, approx. 520pg / mL, approx. 530pg / mL, Treprostinil C at approximately 540 pg / mL, 550 pg / mL, 560 pg / mL, 570 pg / mL, 580 pg / mL, 590 pg / mL, 600 pg / mL, 610 pg / mL, 620 pg / mL, 630 pg / mL, 640 pg / mL, 650 pg / mL, 660 pg / mL, 670 pg / mL, 680 pg / mL, 690 pg / mL, or 700 pg / mL (including all values ​​and ranges within these). max The present invention provides: In some embodiments, approximately 320 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 80 pg / mL to approximately 560 pg / mL. maxIn some embodiments, approximately 320 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 160 pg / mL to approximately 480 pg / mL. max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0165] In some embodiments, the powder composition comprises about 400 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a dose range of about 80 pg / mL to about 885 pg / mL, for example, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL. , about 200pg / mL, about 210pg / mL, about 220pg / mL, about 230pg / mL, about 240pg / mL, about 250pg / mL, about 260pg / mL, about 270pg / mL, about 280pg / mL, about 290pg / mL, about 300pg / mL, about 310pg / mL , about 320pg / mL, about 330pg / mL, about 340pg / mL, about 350pg / mL, about 360pg / mL, about 370pg / mL, about 380pg / mL, about 390pg / mL, about 400pg / mL, about 410pg / mL, about 420pg / mL, about 430pg / mL, Approximately 440pg / mL, approximately 450pg / mL, approximately 460pg / mL, approximately 470pg / mL, approximately 480pg / mL, approximately 490pg / mL, approximately 500pg / mL, approximately 510pg / mL, approximately 520pg / mL, approximately 530pg / mL, approximately 540pg / mL, approximately 550pg / mL, Approximately 560pg / mL, approximately 570pg / mL, approximately 580pg / mL, approximately 590pg / mL, approximately 600pg / mL, approximately 610pg / mL, approximately 620pg / mL, approximately 630pg / mL, approximately 640pg / mL, approximately 650pg / mL, approximately 660pg / mL, approximately 670pg / mL, approximately Treprostinil C at 680 pg / mL, approximately 690 pg / mL, and approximately 700 pg / mL, approximately 710 pg / mL, approximately 720 pg / mL, approximately 730 pg / mL, approximately 740 pg / mL, approximately 750 pg / mL, approximately 760 pg / mL, approximately 770 pg / mL, approximately 780 pg / mL, approximately 790 pg / mL, approximately 800 pg / mL, approximately 810 pg / mL, approximately 820 pg / mL, approximately 830 pg / mL, approximately 840 pg / mL, approximately 850 pg / mL, approximately 860 pg / mL, approximately 870 pg / mL, or approximately 880 pg / mL (including all values ​​and ranges within that range). maxIn some embodiments, approximately 400 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 100 pg / mL to approximately 705 pg / mL. max In some embodiments, approximately 400 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 200 pg / mL to approximately 605 pg / mL. max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0166] In some embodiments, the powder composition comprises about 450 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily to a dose of about 80% to 125% of treprostinil C at a concentration of about 387 (38.6) pg / mL. maxThe present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0167] In some embodiments, the powder composition comprises about 480 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a range of about 95 pg / mL to about 1065 pg / mL, for example, about 95 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL. g / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL , about 340pg / mL, about 350pg / mL, about 360pg / mL, about 370pg / mL, about 380pg / mL, about 390pg / mL, about 400pg / mL, about 410pg / mL, about 420pg / mL, about 430pg / mL, about 440pg / mL, about 450pg / mL, about 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL, approximately 580 pg / m L, about 590pg / mL, about 600pg / mL, about 610pg / mL, about 620pg / mL, about 630pg / mL, about 640pg / mL, about 650pg / mL, about 660pg / mL, about 670pg / mL, about 680pg / mL, about 690pg / mL, and about 700pg / mL, Approximately 710pg / mL, approximately 720pg / mL, approximately 730pg / mL, approximately 740pg / mL, approximately 750pg / mL, approximately 760pg / mL, approximately 770pg / mL, approximately 780pg / mL, approximately 790pg / mL, approximately 800pg / mL, approximately 810pg / mL, approximately 820pg / mL, approximately 830p g / mL, approximately 840pg / mL, approximately 850pg / mL, approximately 860pg / mL, approximately 870pg / mL, approximately 880pg / mL, approximately 890pg / mL, approximately 900pg / mL, approximately 910pg / mL, approximately 920pg / mL, approximately 930pg / mL, approximately 940pg / mL, approximately 950pg / mL,Treprostinil C at approximately 960 pg / mL, approximately 970 pg / mL, approximately 980 pg / mL, approximately 1000 pg / mL, approximately 1010 pg / mL, approximately 1020 pg / mL, approximately 1030 pg / mL, approximately 1040 pg / mL, approximately 1050 pg / mL, approximately 1060 pg / mL, or approximately 1065 pg / mL (including all values ​​and ranges within these), max In some embodiments, approximately 480 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C at a concentration of approximately 120 pg / mL to approximately 855 pg / mL. max The present invention provides: In some embodiments, approximately 480 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 240 pg / mL to approximately 730 pg / mL. max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0168] In some embodiments, the powder composition comprises about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a dose range of about 130 pg / mL to about 1430 pg / mL, for example, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL. pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL , about 380pg / mL, about 390pg / mL, about 400pg / mL, about 410pg / mL, about 420pg / mL, about 430pg / mL, about 440pg / mL, about 450pg / mL, about 460pg / mL, about 470pg / mL, about 480pg / mL, about 490pg / mL, about 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL, approximately 580 pg / mL, approximately 590 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL , about 630pg / mL, about 640pg / mL, about 650pg / mL, about 660pg / mL, about 670pg / mL, about 680pg / mL, about 690pg / mL, and about 700pg / mL, about 710pg / mL, about 720pg / mL, about 730pg / mL, about 740pg / mL, about 750pg / mL, approximately 760pg / mL, approximately 770pg / mL, approximately 780pg / mL, approximately 790pg / mL, approximately 800pg / mL, approximately 810pg / mL, approximately 820pg / mL, approximately 830pg / mL, approximately 840pg / mL, approximately 850pg / mL, approximately 860pg / mL, approximately 870pg / mL, approximately 880pg / mL, approximately 890pg / mL, approximately 900pg / mL, approximately 910pg / mL, approximately 920pg / mL, approximately 930pg / mL, approximately 940pg / mL, approximately 950pg / mL, approximately 960pg / mL, approximately 970pg / mL, approximately 980pg / mL, approximately 1000pg / mL,About 1010pg / mL, about 1020pg / mL, about 1030pg / mL, about 1040pg / mL, about 1050pg / mL, about 1060pg / mL, about 1070pg / mL, about 1080pg / mL, about 1090pg / mL, about 1100pg / mL, about 1110pg / mL, about 1120 pg / mL, approximately 1130pg / mL, approximately 1140pg / mL, approximately 1150pg / mL, approximately 1160pg / mL, approximately 1170pg / mL, approximately 1180pg / mL, approximately 1190pg / mL, approximately 1200pg / mL, approximately 1210pg / mL, approximately 1220pg / mL, approximately 1230pg / mL Treprostinil C at approximately 1240 pg / mL, approximately 1250 pg / mL, approximately 1260 pg / mL, approximately 1270 pg / mL, approximately 1280 pg / mL, approximately 1290 pg / mL, approximately 1300 pg / mL, approximately 1310 pg / mL, approximately 1320 pg / mL, approximately 1330 pg / mL, approximately 1340 pg / mL, approximately 1350 pg / mL, approximately 1360 pg / mL, approximately 1370 pg / mL, approximately 1380 pg / mL, approximately 1390 pg / mL, approximately 1400 pg / mL, approximately 1410 pg / mL, approximately 1420 pg / mL, or approximately 1430 pg / mL (including all values ​​and ranges within that range), max In some embodiments, approximately 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% treprostinil C in the range of approximately 160 pg / mL to approximately 1140 pg / mL. max In some embodiments, approximately 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, along with approximately 80% to 125% of treprostinil C in the range of approximately 325 pg / mL to approximately 980 pg / mL. maxThe present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0169] In some embodiments, the powder composition comprises about 675 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily to a dose of about 717 (52.8) pg / mL of treprostinil C in the range of about 80% to about 125%. max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0170] In some embodiments, the powder composition comprises about 720 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a concentration of about 80% to about 125% of treprostinil C in the range of about 185 pg / mL to about 1300 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In some embodiments, the powder composition comprises about 720 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, containing about 80% to about 125% of treprostinil C in the range of about 368 pg / mL to about 1105 pg / mL (including all values ​​and ranges therewith). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0171] In some embodiments, the powder composition comprises about 800 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, in a dose of about 80% to about 125% of treprostinil C in the range of about 200 pg / mL to about 1430 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In some embodiments, the powder composition comprises about 800 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a concentration of about 80% to about 125% of treprostinil C in the range of about 400 pg / mL to about 1230 pg / mL (including all values ​​and ranges therewith). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0172] In some embodiments, the powder composition comprises about 880 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, in a concentration of about 80% to about 125% of treprostinil C in the range of about 225 pg / mL to about 1580 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In some embodiments, the powder composition comprises about 880 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a dose of about 80% to about 125% of treprostinil C in the range of about 450 pg / mL to about 1360 pg / mL (including all values ​​and ranges therewith). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0173] In some embodiments, the powder composition comprises about 960 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a dose of about 80% to about 125% of treprostinil C in the range of about 240 pg / mL to about 1720 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In some embodiments, the powder composition comprises about 960 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a dose of about 80% to about 125% of treprostinil C in the range of about 490 pg / mL to about 1480 pg / mL (including all values ​​and ranges therewith). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0174] In some embodiments, the powder composition comprises about 1040 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, in a concentration of about 80% to about 125% of treprostinil C in the range of about 530 pg / mL to about 1605 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0175] In some embodiments, the powder composition comprises about 1120 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a dose of about 80% to about 125% of treprostinil C in the range of about 280 pg / mL to about 2020 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In some embodiments, the powder composition comprises about 1120 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a concentration of about 80% to about 125% of treprostinil C in the range of about 575 pg / mL to about 1730 pg / mL (including all values ​​and ranges therewith). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0176] In some embodiments, the powder composition comprises about 1200 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, in a concentration of about 80% to about 125% of treprostinil C in the range of about 300 pg / mL to about 2165 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In some embodiments, the powder composition comprises about 1200 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, containing about 80% to about 125% of treprostinil C in the range of about 615 pg / mL to about 1855 pg / mL (including all values ​​and ranges therewith). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0177] In some embodiments, the powder composition comprises about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, with a concentration of treprostinil C in the range of about 80% to about 125% of about 325 pg / mL to about 2310 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In some embodiments, the powder composition comprises about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a dose of about 80% to about 125% of treprostinil C in the range of about 660 pg / mL to about 1980 pg / mL (including all values ​​and ranges within that range). max The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0178] In some embodiments, the powder composition comprises about 80 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a range of about 375 pg*h / mL to about 1800 pg*h / mL, for example, 375 pg*h / mL, 400 pg*h / mL, 500 pg*h / mL, 600 pg*h / mL, about 700 pg*h / mL, about 800 Treprostinil AUC in pg*h / mL, approximately 900pg*h / mL, approximately 1000pg*h / mL, approximately 1100pg*h / mL, approximately 1200pg*h / mL, approximately 1300pg*h / mL, approximately 1400pg*h / mL, approximately 1500pg*h / mL, approximately 1600pg*h / mL, approximately 1700pg*h / mL, or approximately 1800pg*h / mL (including all values ​​and ranges within this range). 0-inf In some embodiments, approximately 80 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, resulting in approximately 80% to 125% of treprostinil AUC in the range of approximately 475 pg*h / mL to approximately 1430 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 80 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and upon administration, the powder composition or method of use provides about 80% to 125% of treprostinil AUC at a concentration of about 660 pg*h / mL to about 1240 pg*h / mL. 0-infThe present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0179] In some embodiments, the powder composition comprises about 112.5 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a treprostinil AUC in the range of about 80% to about 125% of about 1090 (91.8) pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0180] In some embodiments, the powder composition comprises about 160 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a dose range of about 630 pg*h / mL to about 3000 pg*h / mL, for example, 630 pg*h / mL, about 700 pg*h / mL, about 800 pg*h / mL, about 900 pg*h / mL, about 1000 pg*h / mL, about 1100 pg*h / mL, about 1200 pg*h / mL, about 1300 pg*h / mL, about 1400 pg*h / mL, about 1500 pg*h / mL. Treprostinil AUC in the range of 3000 pg*h / mL, approximately 1600 pg*h / mL, approximately 1700 pg*h / mL, approximately 1800 pg*h / mL, approximately 1900 pg*h / mL, approximately 2000 pg*h / mL, approximately 2100 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 pg*h / mL, approximately 2800 pg*h / mL, approximately 2900 pg*h / mL, or approximately 3000 pg*h / mL (including all values ​​and ranges within that range). 0-inf The present invention provides: In some embodiments, the powder composition comprises about 160 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 785 pg*h / mL to about 2370 pg*h / mL. 0-infThe present invention provides: In some embodiments, the powder composition comprises about 160 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 1100 pg*h / mL to about 2050 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0181] In some embodiments, the powder composition comprises about 225 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, with an AUC in the range of about 80% to about 125% of about 2130 (30.0) ng*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 225 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a steady-state treprostinil AUC in the range of about 80% to about 125% of about 1680 (28.7) ng*h / mL.0-24 (CV%) is provided. In some embodiments, the powder composition comprises about 225 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to provide a steady-state treprostinil AUC in the range of about 80% to about 125% of about 1790 (39.6) ng*h / mL. 0-24 Provides (CV%). In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0182] In some embodiments, the powder composition comprises about 450 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a treprostinil AUC in the range of about 80% to about 125% of about 4040 (27.4) pg*h / mL. 0-infThe present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0183] In some embodiments, the powder composition comprises about 240 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a dose range of about 880 pg*h / mL to about 4130 pg*h / mL, for example, about 800 pg*h / mL, about 900 pg*h / mL, about 950 pg*h / mL, about 1000 pg*h / mL, about 1050 pg*h / mL, about 1100 pg*h / mL, about 1150 pg*h / mL, about 1200 pg*h / mL, about 1250 pg*h / mL, about 1300 pg*h / mL, about 1350 pg*h / mL, approximately 1400pg*h / mL, approximately 1450pg*h / mL, approximately 1500pg*h / mL, approximately 1550pg*h / mL, approximately 1600pg*h / mL, approximately 1650pg*h / mL, approximately 1700pg*h / mL, approximately 1750pg*h / mL, approximately 1800pg*h / mL, approximately 1850pg*h / mL, approximately 1950pg*h / mL, approximately 2000pg*h / mL, approximately 2050pg*h / mL, approximately 2100pg*h / mL, approximately 2150pg*h / mL, approximately 2200pg*h / mL, approximately 2250pg*h / mL, approximately 2300pg*h / mL, 2350pg*h / mL, 2400pg*h / mL, 2450pg*h / mL, 2500pg*h / mL, 2550pg*h / mL, 2600pg*h / mL, 2650pg*h / mL, 2700pg*h / mL, 2750pg*h / mL, 280 0pg*h / mL, approximately 2850pg*h / mL, approximately 2950pg*h / mL, approximately 3000pg*h / mL, approximately 3050pg*h / mL, approximately 3100pg*h / mL, approximately 3150pg*h / mL, approximately 3200pg*h / mL, approximately 3250pg*h / mL, approximately 3300pg* Treprostinil AUC in h / mL, approximately 3350 pg*h / mL, approximately 3400 pg*h / mL, approximately 3450 pg*h / mL, approximately 3500 pg*h / mL, approximately 3550 pg*h / mL, approximately 3600 pg*h / mL, approximately 3650 pg*h / mL, approximately 3700 pg*h / mL, approximately 3750 pg*h / mL, approximately 3800 pg*h / mL, approximately 3850 pg*h / mL, approximately 3950 pg*h / mL, approximately 4000 pg*h / mL, approximately 4050 pg*h / mL, approximately 4100 pg*h / mL, and approximately 4130 pg*h / mL (including all values ​​and ranges within this range). 0-infThe present invention provides: In some embodiments, the powder composition comprises about 240 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 1100 pg*h / mL to about 3305 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 240 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and yielding about 80% to 125% of treprostinil AUC in the range of about 1540 pg*h / mL to about 2865 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0184] In some embodiments, the powder composition comprises about 320 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a range of about 1130 pg*h / mL to about 5310 pg*h / mL, for example, about 1130 pg*h / mL, about 1200 pg*h / mL, about 1300 pg*h / mL, about 1400 pg*h / mL, about 1450 pg*h / mL, and about 1500 pg*h / mL. , about 1550pg*h / mL, about 1600pg*h / mL, about 1700pg*h / mL, about 1800pg*h / mL, about 1900pg*h / mL, about 2000pg*h / mL, about 2100pg*h / mL, about 2 200pg*h / mL, approx. 2300pg*h / mL, approx. 2400pg*h / mL, approx. 2500pg*h / mL, approx. 2600pg*h / mL, approx. 2700pg*h / mL, approx. 2800pg*h / mL, approx. 2900p g*h / mL, approx. 3000pg*h / mL, approx. 3100pg*h / mL, approx. 3200pg*h / mL, approx. 3300pg*h / mL, approx. 3400pg*h / mL, approx. 3500pg*h / mL, approx. 3600pg*h / mL, approximately 3700pg*h / mL, approximately 3800pg*h / mL, approximately 3900pg*h / mL, approximately 4000pg*h / mL, approximately 4100pg*h / mL, approximately 4200pg*h / mL, approximately 4300pg*h / mL Treprostinil AUC of approximately 4400 pg*h / mL, approximately 4500 pg*h / mL, approximately 4600 pg*h / mL, approximately 4700 pg*h / mL, approximately 4800 pg*h / mL, approximately 4900 pg*h / mL, approximately 5000 pg*h / mL, approximately 5100 pg*h / mL, approximately 5200 pg*h / mL, approximately 5300 pg*h / mL, approximately 5300 pg*h / mL, or approximately 5310 pg*h / mL (including all values ​​and ranges within that range). 0-inf The present invention provides: In some embodiments, the powder composition comprises about 320 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, with a treprostinil AUC of about 80% to 125% in the range of about 1400 pg*h / mL to about 4250 pg*h / mL. 0-infIn some embodiments, approximately 320 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, resulting in approximately 80% to 125% of treprostinil AUC in the range of approximately 1975 pg*h / mL to approximately 3680 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0185] In some embodiments, the powder composition comprises about 400 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a range of about 1380 pg*h / mL to about 6480 pg*h / mL, for example, about 1380 pg*h / mL, about 1400 pg*h / mL, about 1450 pg*h / mL, about 1500 pg*h / mL, about 1550 pg*h / mL, about 1600 pg*h / mL, about 1700 pg*h / mL, and about 1800 pg*h / mL. , about 1900pg*h / mL, about 2000pg*h / mL, about 2100pg*h / mL, about 2200pg*h / mL, about 2300pg*h / mL, about 2400pg*h / mL, about 2500pg*h / mL, about 2600pg*h / mL, about 2 700pg*h / mL, approximately 2800pg*h / mL, approximately 2900pg*h / mL, approximately 3000pg*h / mL, approximately 3100pg*h / mL, approximately 3200pg*h / mL, approximately 3300pg*h / mL, approximately 3400pg*h / mL, approximately 3500p g*h / mL, approximately 3600pg*h / mL, approximately 3700pg*h / mL, approximately 3800pg*h / mL, approximately 3900pg*h / mL, approximately 4000pg*h / mL, approximately 4100pg*h / mL, approximately 4200pg*h / mL, approximately 4300pg*h / mL, approximately 4400pg*h / mL, approximately 4500pg*h / mL, approximately 4600pg*h / mL, approximately 4700pg*h / mL, approximately 4800pg*h / mL, approximately 4900pg*h / mL, approximately 5000pg*h / mL, approximately 5100pg*h / mL Treprostinil AUC of approximately 5200 pg*h / mL, approximately 5300 pg*h / mL, approximately 5400 pg*h / mL, approximately 5500 pg*h / mL, approximately 5600 pg*h / mL, approximately 5700 pg*h / mL, approximately 5800 pg*h / mL, approximately 5900 pg*h / mL, approximately 6000 pg*h / mL, approximately 6100 pg*h / mL, approximately 6200 pg*h / mL, approximately 6300 pg*h / mL, approximately 6400 pg*h / mL, or approximately 6480 pg*h / mL (including all values ​​and ranges within that range). 0-infThe present invention provides: In some embodiments, the powder composition comprises about 400 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 1725 pg*h / mL to about 5180 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 400 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 2415 pg*h / mL to about 4490 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0186] In some embodiments, the powder composition comprises about 480 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a range of about 1630 pg*h / mL to about 7650 pg*h / mL, for example, about 1630 pg*h / mL, about 1700 pg*h / mL, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL. g*h / mL, approximately 2600pg*h / mL, approximately 2700pg*h / mL, approximately 2800pg*h / mL, approximately 2900pg*h / mL, approximately 3000pg*h / mL, approximately 3100pg*h / mL, approximately 3200pg*h / mL, approximately 3300pg*h / mL, approximately 3400p g*h / mL, approximately 3500pg*h / mL, approximately 3600pg*h / mL, approximately 3700pg*h / mL, approximately 3800pg*h / mL, approximately 3900pg*h / mL, approximately 4000pg*h / mL, approximately 4100pg*h / mL, approximately 4200pg*h / mL, approximately 4300p g*h / mL, approximately 4400pg*h / mL, approximately 4500pg*h / mL, approximately 4600pg*h / mL, approximately 4700pg*h / mL, approximately 4800pg*h / mL, approximately 4900pg*h / mL, approximately 5000pg*h / mL, approximately 5100pg*h / mL, approximately 5200p g*h / mL, approximately 5300pg*h / mL, approximately 5400pg*h / mL, approximately 5500pg*h / mL, approximately 5600pg*h / mL, approximately 5700pg*h / mL, approximately 5800pg*h / mL, approximately 5900pg*h / mL, approximately 6000pg*h / mL, approximately 6100p Treprostinil AUC in g*h / mL, approximately 6200 pg*h / mL, approximately 6300 pg*h / mL, approximately 6400 pg*h / mL, approximately 6500 pg*h / mL, approximately 6600 pg*h / mL, approximately 6700 pg*h / mL, approximately 6800 pg*h / mL, approximately 6900 pg*h / mL, approximately 7000 pg*h / mL, approximately 7100 pg*h / mL, approximately 7200 pg*h / mL, approximately 7300 pg*h / mL, approximately 7400 pg*h / mL, approximately 7500 pg*h / mL, or approximately 7650 pg*h / mL (including all values ​​and ranges within these ranges). 0-infThe present invention provides: In some embodiments, the powder composition comprises about 480 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 2040 pg*h / mL to about 6120 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 480 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and yielding about 80% to 125% of treprostinil AUC in the range of about 2855 pg*h / mL to about 5310 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2 The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0187] In some embodiments, the powder composition comprises about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily in a range of about 2130 pg*h / mL to about 10000 pg*h / mL, for example, about 2130 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 pg*h / mL, about 2700 pg*h / mL, about 2800 pg*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, and about 3100 pg *h / mL, approximately 3200pg*h / mL, approximately 3300pg*h / mL, approximately 3400pg*h / mL, approximately 3500pg*h / mL, approximately 3600pg*h / mL, approximately 3700pg*h / mL, approximately 3800pg*h / mL, approximately 3900pg*h / mL, approximately 4000pg*h / mL, approximately 4100pg*h / mL, approx. 4200pg*h / mL, approx. 4300pg*h / mL, approx. 4400pg*h / mL, approx. 4500pg*h / m L, approx. 4600pg*h / mL, approx. 4700pg*h / mL, approx. 4800pg*h / mL, approx. 4900pg*h / mL, approx. 5000pg*h / mL, approximately 5100pg*h / mL, approximately 5200pg*h / mL, approximately 5300pg*h / mL, approximately 5400pg*h / mL, approximately 5500pg*h / mL, approximately 5600pg*h / mL, approximately 5700pg*h / mL, approximately 5800pg*h / mL, approximately 5900pg*h / mL, approximately 60 00pg*h / mL, approximately 6100pg*h / mL, approximately 6200pg*h / mL, approximately 6300pg*h / mL, approximately 6400pg*h / mL, Approx. 6500pg*h / mL, approx. 6600pg*h / mL, approx. 6700pg*h / mL, approx. 6800pg*h / mL, approx. 6900pg*h / m L, about 7000pg*h / mL, about 7100pg*h / mL, about 7200pg*h / mL, about 7300pg*h / mL, about 7400pg*h / mL, about 7500pg*h / mL, about 7600pg*h / mL, about 7700pg*h / mL, about 7800pg*h / mL, about 8000 pg*h / mL, approximately 8100pg*h / mL, approximately 8200pg*h / mL, approximately 8300pg*h / mL, approximately 8400pg*h / mL, approximately 8500pg*h / mL, approximately 8600pg*h / mL, approximately 8700pg*h / mL, approximately 8800pg*h / mL, approximately 8900pg*h / mL,Treprostinil AUC of approximately 9000 pg*h / mL, approximately 9100 pg*h / mL, approximately 9200 pg*h / mL, approximately 9300 pg*h / mL, approximately 9350 pg*h / mL, approximately 9400 pg*h / mL, approximately 9450 pg*h / mL, approximately 9500 pg*h / mL, approximately 9600 pg*h / mL, approximately 9700 pg*h / mL, approximately 9800 pg*h / mL, approximately 9900 pg*h / mL, or approximately 10000 pg*h / mL (including all values ​​and ranges within that range), 0-inf The present invention provides: In some embodiments, the powder composition comprises about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to provide about 80% to 125% of treprostinil AUC in the range of about 2650 pg*h / mL to about 8000 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 3730 to about 6935 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0188] In some embodiments, the powder composition comprises about 675 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a treprostinil AUC in the range of about 80% to about 125% of about 5480 (13.8) pg*h / mL. 0-24 The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0189] In some embodiments, the powder composition comprises about 720 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a concentration of about 80% to 125% of treprostinil AUC in the range of about 2975 pg*h / mL to about 8940 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 720 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 4170 pg*h / mL to about 7750 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0190] In some embodiments, the powder composition comprises about 800 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to deliver about 80% to 125% of treprostinil AUC in the range of about 3290 pg*h / mL to about 9900 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 800 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 4600 pg*h / mL to about 8560 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0191] In some embodiments, the powder composition comprises about 880 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to yield about 80% to 125% of treprostinil AUC in the range of about 3605 pg*h / mL to about 10815 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 880 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 5045 pg*h / mL to about 9380 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0192] In some embodiments, the powder composition comprises about 960 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and upon administration, the powder composition or method of use contains about 80% to 125% of treprostinil AUC in the range of about 3900 pg*h / mL to about 11800 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 960 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 5485 pg*h / mL to about 10190 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0193] In some embodiments, the powder composition comprises about 1040 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to a concentration of about 80% to 125% of treprostinil AUC in the range of about 4230 pg*h / mL to about 12700 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 1040 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 5920 pg*h / mL to about 11000 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0194] In some embodiments, the powder composition comprises about 1120 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, with a treprostinil AUC of about 80% to 125% in the range of about 4500 pg*h / mL to about 13650 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 1120 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 6360 pg*h / mL to about 11815 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0195] In some embodiments, the powder composition comprises about 1200 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to deliver about 80% to 125% of treprostinil AUC in the range of about 4850 pg*h / mL to about 14600 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 1200 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 6795 pg*h / mL to about 12630 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0196] In some embodiments, the powder composition comprises about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, to yield about 80% to 125% of treprostinil AUC in the range of about 5150 pg*h / mL to about 15550 pg*h / mL. 0-inf The present invention provides: In some embodiments, the powder composition comprises about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, administered once daily, and containing about 80% to 125% of treprostinil AUC in the range of about 7235 pg*h / mL to about 13445 pg*h / mL. 0-inf The present invention provides: In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0197] In some embodiments, the powder composition comprises about 80 μg to about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition is in the range of about 3 pg / mL to about 250 mg / mL, for example, about 4 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL. Approximately 30pg / mL, approximately 35pg / mL, approximately 40pg / mL, approximately 45pg / mL, approximately 50pg / mL, approximately 55pg / mL, approximately 60pg / mL, approximately 65pg / mL, approximately 70pg / mL, approximately 75pg / mL, approximately 80pg / m L, approximately 85pg / mL, approximately 90pg / mL, approximately 95pg / mL, approximately 100pg / mL, approximately 100pg / mL, approximately 105pg / mL, approximately 110pg / mL, approximately 115pg / mL, approximately 120pg / mL, approximately 125pg / mL Approximately 130pg / mL, approximately 135pg / mL, approximately 140pg / mL, approximately 145pg / mL, approximately 150pg / mL, approximately 155pg / mL, approximately 160pg / mL, approximately 165pg / mL, approximately 170pg / mL, approximately 175pg / mL, approximately 180 pg / mL, approximately 185pg / mL, approximately 190pg / mL, approximately 195pg / mL, approximately 200pg / mL, approximately 200pg / mL, approximately 205pg / mL, approximately 210pg / mL, approximately 215pg / mL, approximately 220pg / mL, approximately 225pg / mL The treprostinil plasma trough concentration is provided at approximately 230 pg / mL, approximately 235 pg / mL, approximately 240 pg / mL, approximately 245 pg / mL, or approximately 250 pg / mL (including all values ​​and ranges therewith), or after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of approximately 1.0 μm to approximately 2.0 μm. In some embodiments, the particles have D10 at approximately 0.3 μm, D50 at approximately 1.7 μm, and / or D90 at approximately 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0198] In some embodiments, the powder composition comprises about 80 μg to about 675 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition is in the range of about 3 pg / mL to about 150 mg / mL, for example, about 4 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL. Approximately 30pg / mL, approximately 35pg / mL, approximately 40pg / mL, approximately 45pg / mL, approximately 50pg / mL, approximately 55pg / mL, approximately 60pg / mL, approximately 65pg / mL, approximately 70pg / mL, approximately 75pg / mL, approximately 80pg / m L, approximately 85pg / mL, approximately 90pg / mL, approximately 95pg / mL, approximately 100pg / mL, approximately 100pg / mL, approximately 105pg / mL, approximately 110pg / mL, approximately 115pg / mL, approximately 120pg / mL, approximately 125pg / mL The treprostinil plasma trough concentration is provided at approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 145 pg / mL, or approximately 150 pg / mL (including all values ​​and ranges within these), or after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of approximately 1.0 μm to approximately 2.0 μm. In some embodiments, the particles have D10 at approximately 0.3 μm, D50 at approximately 1.7 μm, and / or D90 at approximately 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0199] In some embodiments, the powder composition comprises about 80 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 3 pg / mL to about 25 mg / mL, for example, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, or about 25 pg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In further embodiments, the treprostinil plasma trough concentration is in the range of about 6 pg / mL to about 18 mg / mL. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0200] In some embodiments, the powder composition comprises about 112.5 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 4 pg / mL to about 30 mg / mL, for example, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, or about 30 pg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0201] In some embodiments, the powder composition comprises about 160 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 5 pg / mL to about 35 mg / mL, for example, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, or about 35 pg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In further embodiments, the treprostinil plasma trough concentration is in the range of about 10 pg / mL to about 30 mg / mL, or 15 pg / mL to about 25 pg / mL. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0202] In some embodiments, the powder composition comprises about 225 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 15 pg / mL to about 45 mg / mL, for example, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, or about 45 pg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0203] In some embodiments, the powder composition comprises about 240 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 7 pg / mL to about 50 mg / mL, for example, about 7 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, or about 50 pg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In some embodiments, the treprostinil plasma trough concentration is in the range of about 15 pg / mL to about 50 mg / mL, or 20 pg / mL to about 45 pg / mL. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition includes particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0204] In some embodiments, the powder composition comprises about 320 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 9 pg / mL to about 65 mg / mL, for example, about 9 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, or about 65 pg / mL (including all values ​​and ranges therein), or after once-daily administration, the subject (e.g., patient) has them. In some embodiments, the treprostinil plasma trough concentration is in the range of about 15 pg / mL to about 50 mg / mL, or 20 pg / mL to about 45 pg / mL. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0205] In some embodiments, the powder composition comprises about 400 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 10 pg / mL to about 80 mg / mL, for example, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, or about 80 pg / mL (including all values ​​and ranges therein), or after once-daily administration, the subject (e.g., patient) has them. In some embodiments, the treprostinil plasma trough concentration is in the range of about 35 pg / mL to about 70 mg / mL, or 40 pg / mL to about 65 pg / mL. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0206] In some embodiments, the powder composition comprises about 450 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 30 pg / mL to about 75 mg / mL, for example, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, and about 75 pg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0207] In some embodiments, the powder composition comprises about 480 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 13 pg / mL to about 95 mg / mL, for example, about 13 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL (including all values ​​and ranges therein), or after once-daily administration, the subject (e.g., patient) has them. In some embodiments, the treprostinil plasma trough concentration is in the range of about 25 pg / mL to about 75 mg / mL, or 30 pg / mL to about 70 pg / mL. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0208] In some embodiments, the powder composition comprises about 640 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition is in the range of about 15 pg / mL to about 125 mg / mL, for example, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 The treprostinil plasma trough concentration is provided at pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 105 pg / mL, approximately 110 pg / mL, approximately 115 pg / mL, approximately 120 pg / mL, or approximately 125 pg / mL (including all values ​​and ranges within these ranges), or after once-daily administration, the subject (e.g., patient) has them. In some embodiments, the treprostinil plasma trough concentration is in the range of approximately 35 pg / mL to approximately 100 mg / mL, or 50 pg / mL to approximately 90 pg / mL. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition contains particles. In some embodiments, the particles have an average diameter in the range of approximately 1.0 μm to approximately 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0209] In some embodiments, the powder composition comprises about 675 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides treprostinil plasma trough concentrations in the range of about 50 pg / mL to about 100 mg / mL, for example, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, and about 100 pg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0210] In some embodiments, the powder composition comprises about 720 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides a treprostinil plasma trough concentration in the range of about 20 pg / mL to about 135 mg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0211] In some embodiments, the powder composition comprises about 800 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides a treprostinil plasma trough concentration in the range of about 21 pg / mL to about 150 mg / mL (including all values ​​and ranges within that range), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0212] In some embodiments, the powder composition comprises about 960 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides a treprostinil plasma trough concentration in the range of about 25 pg / mL to about 180 mg / mL (including all values ​​and ranges within that range), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0213] In some embodiments, the powder composition comprises about 1040 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides a treprostinil plasma trough concentration in the range of about 28 pg / mL to about 195 mg / mL (including all values ​​and ranges within that range), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0214] In some embodiments, the powder composition comprises about 1120 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides a treprostinil plasma trough concentration in the range of about 30 pg / mL to about 209 mg / mL (including all values ​​and ranges therein), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0215] In some embodiments, the powder composition comprises about 1200 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides a treprostinil plasma trough concentration in the range of about 32 pg / mL to about 224 mg / mL (including all values ​​and ranges within that range), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0216] In some embodiments, the powder composition comprises about 1280 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and the powder composition provides a treprostinil plasma trough concentration in the range of about 34 pg / mL to about 238 mg / mL (including all values ​​and ranges within that range), or, after once-daily administration, the subject (e.g., patient) has them. In one embodiment, the powder composition is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm. In some embodiments, the particles have D10 of about 0.3 μm, D50 of about 1.7 μm, and / or D90 of about 3.8 μm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec 2The product provides an aerosol containing a particulate fraction (FPF) of about 68% or more (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%) when measured using a next-generation impactor (NGI) having an inhalation acceleration, and one or more of the following: (i) a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol containing an emitted dose (ED) of 72% or more, e.g., about 79% to about 89%, or (iii) an aerodynamic median mass diameter (MMAD) of less than 5 μm (e.g., about 0.75 μm to about 3.0 μm, or about 0.8 μm to about 2.0 μm).

[0217] In some embodiments, one or more pharmaceutically acceptable excipients suitable for use in a dry powder inhaler include sugars, amino acids, and optionally distearoylphosphoethanolamine-polyethylene glycol 2000 (DPSE-PEG2000). In some embodiments of the powder compositions or methods described herein, the powder composition contains about 25% to about 61% by weight of leucine, with the remainder being one or more sugars. In some embodiments, the one or more sugars are selected from trehalose and mannitol. In some embodiments of the powder compositions or methods described herein, the powder composition does not contain distearoylphosphoethanolamine-polyethylene glycol 2000 (DPSE-PEG2000).

[0218] Aerosolized composition The powder compositions described herein are, in some embodiments, aerosolized via DPI, providing aerosolized compositions. In one embodiment, the powder composition is a spray-dried powder composition.

[0219] Aerosolized compositions are administered to patients requiring treatment for pulmonary fibrosis (PH), such as PAH or PH associated with interstitial lung disease (PH-ILD). In one embodiment, the aerosolized composition is administered to patients requiring treatment for pulmonary fibrosis (e.g., PH-ILD where ILD is pulmonary fibrosis). The aerosolized composition can be characterized by certain parameters known to those skilled in the art, such as particulate fraction (FPF), particulate dose (FPD), discharged dose (ED), median mass aerodynamic diameter (MMAD), and / or particle size and distribution. In embodiments, these parameters are measured by NGI. In embodiments, the NGI uses a flow rate corresponding to an air pressure drop of 3 kPa to 4.5 kPa over the resistance of the DPI. In embodiments, the pressure drop is 4 kPa. For example, the performance of ultra-high resistance (UHR), high resistance (HR), and medium resistance (MR) devices may also be evaluated by drawing 4 L of air through the DPI at flow rates of 40, 60, and 85 LPM, respectively, corresponding to an air pressure drop of 4 kPa. The aerosol characterization data for the above parameters can be compared across different DPI devices (with different resistances). In embodiments, the average inhaler resistance of the high-resistance DPI used to achieve the parameters described herein is 0.025–0.040 kPA 1 / 2 (L / min -1 ) -1 The range is as follows. In embodiments, the average inhaler resistance of the high-resistance DPI used to achieve the parameters described herein is 0.030 to 0.040 kPA. 1 / 2 (L / min -1 ) -1 The range is as follows. In embodiments, the average inhaler resistance of the high-resistance DPI used to achieve the parameters described herein is approximately 0.034 to 0.036 kPA 1 / 2 (L / min -1 ) -1 It is within the range.

[0220] (i) Fine particle fraction (FPF) "Particulate Fraction" or "FPF" refers to the fraction of aerosols with a particle size of less than 5 μm in diameter, as measured by cascade impact such as NGI. FPF is usually expressed as a percentage. FPF has been shown to correlate with the fraction of powder deposited in the lungs of a subject (e.g., a patient).

[0221] In some embodiments, the powder composition is in the form of an aerosol containing particles having at least 50%, at least 55%, at least 60%, at least 65%, at least 68%, at least 70%, at least 74%, at least 75%, at least 80%, at least 85%, or at least 90% FPF. In some embodiments, the powder composition is in the form of an aerosol containing particles having an FPF of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, or any value or range therein. In one embodiment, the aerosolized powder composition contains particles having an FPF of about 50% to about 100%, about 60% to about 90%, about 65% to about 85%, about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%, as measured by NGI.

[0222] In some embodiments, the aerosolized powder composition is subjected to an intake flow rate of 30-60 liters per minute (L / min), an intake volume of 1-4 L, and an intake rate of 0.5-20 L / sec. 2When measured using a next-generation impactor (NGI) having an inhalation acceleration, it has an FPF of at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 77%, at least 76%, at least 79%, at least 78%, at least 81%, at least 80%, at least 83%, at least 82%, at least 85%, at least 84%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90%, or any range within that range.

[0223] In one embodiment, the powder composition exhibiting one of the FPF profiles provided above comprises mannitol. In another embodiment, the powder composition exhibiting the FPF profile provided above comprises trehalose.

[0224] In some embodiments, the powder composition comprises (a) about 0.5% to about 5% by weight of a compound of formula (I), where R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; (b) about 10% to about 61% by weight of leucine; and (c) trehalose, mannitol, or a combination thereof, where the sum of (a), (b), and (c) is 100%. When the powder composition is administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an airflow rate of 0.5 to 20 L / sec. 2 This provides an aerosol containing approximately 68% or more particulate matter (FPF) when measured using a next-generation impactor (NGI) with a certain inhalation acceleration.

[0225] In some embodiments, the aerosolized powder composition has an FPF in the range of 78% to about 80% in a 16 mg TPIP capsule (containing 160 μg of TP) at an inhalation volume of 4 L and an inhalation flow rate of 60 LPM. In some embodiments, the powder composition has an FPF in the range of 76% to about 80% in a 16 mg TPIP capsule (containing 160 μg of TP) at an inhalation volume of 1 L or 2 L and an inhalation flow rate of 60 LPM. In some embodiments, the powder composition has an FPF in the range of 74% to about 76% in a 16 mg TPIP capsule (containing 160 μg of TP) at an inhalation volume of 1 L or 2 L and an inhalation flow rate of 30 LPM.

[0226] In some embodiments, the aerosolized powder composition has an FPF in the range of 68% to about 73% in a 32 mg TPIP capsule (containing 320 μg of TP) with an inhalation volume of 4 L and an inhalation flow rate of 60 LPM. In some embodiments, the powder composition has an FPF in the range of 63% to about 68% in a 32 mg TPIP capsule with an inhalation volume of 1 L or 2 L and an inhalation flow rate of 60 LPM.

[0227] (ii) Fine particle dose (FPD) As used herein, the term “particulate dose” or “FPD” refers to the mass of a drug in an aerosol having a particle size less than 5 μm in diameter, as measured by cascade impact. FPD may be expressed as a percentage or mass. In this disclosure, FPD is expressed as a percentage.

[0228] In some embodiments, the FPD of the aerosolized powder composition has an intake flow rate of 30-60 liters per minute (L / min), an intake volume of 1-4 L, and an intake rate of 0.5-20 L / sec. 2When measured using a next-generation impactor (NGI) having an inhalation acceleration of , the amount of powder composition loaded is at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%. In some embodiments, the inhalation flow rate is 30–60 liters per minute (L / min), the inhalation volume is 1–4 L, and the airflow rate is 0.5–20 L / sec 2 When measured using a next-generation impactor (NGI) with an inhalation acceleration of approximately 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, or more, or any range within that range, of the loaded amount of the powder composition in an FPD.

[0229] In some embodiments, the aerosolized powder composition has an FPD ranging from 53% to about 77% in a 16 or 32 mg TPIP capsule at different inhalation flow rates, different accelerations, and inhalation volumes taught herein.

[0230] In some embodiments, the aerosolized powder composition is subjected to an intake flow rate of 30-60 liters per minute (L / min), an intake volume of 1-4 L, and an intake rate of 0.5-20 L / sec. 2When measured using a next-generation impactor (NGI) with a certain inhalation acceleration, the 32 mg TPIP capsule (containing 320 μg of TP) has an FPD in the range of 53% to approximately 65%, and the 16 mg TPIP capsule (containing 160 μg of TP) has an FPD in the range of 60% to approximately 65%.

[0231] (iii) Emitted dose (ED) As used herein, the terms “released dose” or “ED” refer to the proportion of drug recovered by the NGI to the total drug recovery rate. ED is an indicator of drug delivery from a suitable inhaler device after a discharge or dispersion event. For powder compositions, ED is a measure of the proportion of powder drawn from a unit dose package. ED is defined as the ratio of the dose delivered by the inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed in the DPI before discharge).

[0232] In some embodiments, the aerosolized powder composition is subjected to an intake flow rate of 30-60 liters per minute (L / min), an intake volume of 1-4 L, and an intake rate of 0.5-20 L / sec. 2 When measured using a next-generation impactor (NGI) with an inhalation acceleration of , it has an ED of at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90% or more.

[0233] In some embodiments, the aerosolized powder composition is subjected to an intake flow rate of 30-60 liters per minute (L / min), an intake volume of 1-4 L, and an intake rate of 0.5-20 L / sec. 2When measured using a next-generation impactor (NGI) with an inhalation acceleration, it has an ED of approximately 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% or more (including any range within that).

[0234] In some embodiments, the aerosolized powder composition has an ED of approximately 79% or more in 16 or 32 mg TPIP capsules at 60 LPM, and approximately 72% or more in 16 mg TPIP capsules at 30 LPM.

[0235] In some embo...

Claims

1. A powder composition, (a) A compound of formula (I) in an amount of about 0.5% to about 5% by weight, 【Transformation 6】 In the formula, R1 is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. (b) Approximately 10% to 61% by weight of leucine, (c) comprising trehalose, mannitol, or a combination thereof, The sum of (a), (b), and (c) is 100%, When administered via a dry powder inhaler, the dry powder inhaler has an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and 0.5 to 20 L / sec ２ A powder composition that provides an aerosol containing approximately 68% or more particulate matter fraction (FPF) when measured using a next-generation impactor (NGI) with a certain inhalation acceleration.

2. The powder composition according to claim 1, wherein the FPF is in the range of 68% to about 73%.

3. The powder composition according to claim 1, wherein the FPF is in the range of 78% to about 80%.

4. The powder composition according to any one of claims 1 to 3, wherein the aerosol contains a fine particle dose (FPD) of 50% or more of the loaded amount of the powder composition.

5. The powder composition according to any one of claims 1 to 4, wherein the FPD is in the range of about 53% to about 77%.

6. The powder composition according to any one of claims 1 to 4, wherein the FPD is in the range of about 60% to about 65%.

7. The powder composition according to any one of claims 1 to 6, wherein the aerosol contains an ED of 72% or more.

8. The powder composition according to claim 7, wherein the ED is in the range of about 79% to about 89%.

9. The powder composition according to any one of claims 1 to 8, wherein the aerosol contains an aerodynamic median mass (MMAD) of less than 5 μm.

10. The powder composition according to claim 9, wherein the MMAD is in the range of about 0.75 μm to about 3.0 μm.

11. The powder composition according to claim 9, wherein the MMAD is in the range of about 0.8 μm to about 2.0 μm.

12. The particles include, and at least a portion of the particles are (i) A compound or stereoisomer of formula (I) or a pharmaceutically acceptable salt, (ii) Leucine and (iii) containing trehalose, mannitol, or a combination thereof, The powder composition according to any one of claims 1 to 11, wherein the particles have an average diameter in the range of about 1.0 μm to about 2.0 μm.

13. The powder composition according to claim 12, wherein the particles have a D10 of about 0.3 μm.

14. The powder composition according to claim 12, wherein the particles have a D50 of about 1.7 μm.

15. The powder composition according to claim 12, wherein the particles have a D90 of about 3.8 μm.

16. The powder composition according to claim 1, wherein R1 is hexadecyl.

17. The powder composition according to claim 16, wherein R1 is a linear hexadecyl.

18. The powder composition according to claim 1, wherein R1 is tetradecyl.

19. The powder composition according to claim 18, wherein R1 is a linear tetradecyl.

20. The powder composition according to claim 1, wherein R1 is pentadecyl.

21. The powder composition according to claim 20, wherein R1 is linear pentadecyl.

22. The powder composition according to claim 1, wherein R1 is hexadecyl.

23. The powder composition according to claim 22, wherein R1 is a linear hexadecyl.

24. The powder composition according to claim 1, wherein R1 is heptadecyl.

25. The powder composition according to claim 24, wherein R1 is linear heptadecyl.

26. The powder composition according to claim 1, wherein R1 is octadecyl.

27. The powder composition according to claim 26, wherein R1 is a linear octadecyl.

28. The powder composition according to any one of claims 1 to 27, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 4.5% by weight of the total weight of the powder composition.

29. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 4.5% by weight of the total weight of the powder composition.

30. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 4% by weight of the total weight of the powder composition.

31. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 3.5% by weight of the total weight of the powder composition.

32. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 3% by weight of the total weight of the powder composition.

33. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 2.5% by weight of the total weight of the powder composition.

34. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 2% by weight of the total weight of the powder composition.

35. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 1.5% by weight of the total weight of the powder composition.

36. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2% to about 4% by weight of the total weight of the powder composition.

37. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2% to about 3.5% by weight of the total weight of the powder composition.

38. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2% to about 3% by weight of the total weight of the powder composition.

39. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2% to about 2.5% by weight of the total weight of the powder composition.

40. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3% to about 4.5% by weight of the total weight of the powder composition.

41. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3% to about 4% by weight of the total weight of the powder composition.

42. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3% to about 3.5% by weight of the total weight of the powder composition.

43. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 2% by weight of the total weight of the powder composition.

44. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 1.5% by weight of the total weight of the powder composition.

45. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 1% by weight of the total weight of the powder composition.

46. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3.5% to about 4.5% by weight of the total weight of the powder composition.

47. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 4% to about 4.5% by weight of the total weight of the powder composition.

48. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% by weight of the total weight of the powder composition.

49. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1% by weight of the total weight of the powder composition.

50. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5% by weight of the total weight of the powder composition.

51. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2% by weight of the total weight of the powder composition.

52. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2.5% by weight of the total weight of the powder composition.

53. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3% by weight of the total weight of the powder composition.

54. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3.5% by weight of the total weight of the powder composition.

55. The powder composition according to claim 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 4% by weight of the total weight of the powder composition.

56. The powder composition according to any one of claims 1 to 55, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is the compound of formula (II).

57. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 25% to about 61% by weight of the total weight of the powder composition.

58. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 40% to about 61% by weight of the total weight of the powder composition.

59. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 50% to about 61% by weight of the total weight of the powder composition.

60. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 55% to about 61% by weight of the total weight of the powder composition.

61. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 58% to about 61% by weight of the total weight of the powder composition.

62. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 40% to about 45% by weight of the total weight of the powder composition.

63. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 44% to about 51% by weight of the total weight of the powder composition.

64. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 43% to about 48% by weight of the total weight of the powder composition.

65. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 25% to about 30% by weight of the total weight of the powder composition.

66. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 28% to about 30% by weight of the total weight of the powder composition.

67. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 25% to about 33% by weight of the total weight of the powder composition.

68. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 27% to about 33% by weight of the total weight of the powder composition.

69. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 27% to about 31% by weight of the total weight of the powder composition.

70. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 27% to about 30% by weight of the total weight of the powder composition.

71. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 28% to about 30% by weight of the total weight of the powder composition.

72. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 30% by weight of the total weight of the powder composition.

73. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 45% by weight of the total weight of the powder composition.

74. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in an amount of about 60% by weight of the total weight of the powder composition.

75. The powder composition according to any one of claims 1 to 74, wherein the sugar is trehalose.

76. The powder composition according to any one of claims 1 to 74, wherein the sugar is mannitol.

77. The powder composition according to claim 1, selected from one of the following compositions. Table 12

78. The powder composition according to claim 1, having a leucine:mannitol weight ratio of approximately 0.40:1 (leucine:mannitol) to approximately 0.50:1 (leucine:mannitol).

79. The powder composition according to claim 78, having a leucine:mannitol weight ratio of approximately 0.40:1 (leucine:mannitol) to approximately 0.45:1 (leucine:mannitol).

80. The powder composition according to claim 1, having a leucine:mannitol weight ratio of approximately 0.75:1 (leucine:mannitol) to approximately 0.90:1 (leucine:mannitol).

81. The powder composition according to claim 80, having a leucine:mannitol weight ratio of approximately 0.80:1 (leucine:mannitol) to approximately 0.90:1 (leucine:mannitol).

82. The powder composition according to claim 1, having a leucine:mannitol weight ratio of approximately 1.5:1 (leucine:mannitol) to approximately 1.7:1 (leucine:mannitol).

83. The powder composition according to claim 82, having a leucine:mannitol weight ratio of approximately 1.65:1 (leucine:mannitol) to approximately 1.7:1 (leucine:mannitol).

84. The powder composition according to any one of claims 78 to 83, comprising the compound of formula (I) in an amount of about 0.5% to about 4% by weight of the total weight of the powder composition.

85. The powder composition according to any one of claims 78 to 83, comprising the compound of formula (I) in an amount of about 0.5% to about 3% by weight of the total weight of the powder composition.

86. The powder composition according to any one of claims 78 to 83, comprising the compound of formula (I) in an amount of about 0.5% to about 2% by weight of the total weight of the powder composition.

87. The powder composition according to any one of claims 78 to 83, comprising the compound of formula (I) in an amount of about 0.5% to about 1.5% by weight of the total weight of the powder composition.

88. The powder composition according to any one of claims 78 to 87, comprising the compound of formula (I) in an amount of about 1% to about 1.5% by weight of the total weight of the powder composition.

89. The powder composition according to any one of claims 78 to 87, comprising the compound of formula (I) in an amount of about 2% to about 4% by weight of the total weight of the powder composition.

90. The powder composition according to any one of claims 78 to 87, comprising the compound of formula (I) in an amount of about 3% to about 4% by weight of the total weight of the powder composition.

91. The powder composition according to any one of claims 78 to 90, wherein R1 is a linear hexadecyl.

92. The powder composition according to claim 1, comprising (a) about 0.5% by weight of the compound of formula (I), wherein R1 is a linear hexadecyl compound, (b) about 29% to about 30% by weight of leucine, with the remainder being (c) mannitol.

93. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 1% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 29% to about 30% by weight of leucine, with the remainder being (c) mannitol.

94. The powder composition according to claim 1, comprising (a) about 1.5% by weight of the compound of formula (I), wherein R1 is a linear hexadecyl compound, and (b) about 29% to about 30% by weight of leucine, with the remainder being (c) mannitol.

95. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 2% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 29% to about 30% by weight of leucine, with the remainder being (c) mannitol.

96. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 3% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 29% to about 30% by weight of leucine, with the remainder being (c) mannitol.

97. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 4% by weight, wherein R1 is a linear hexadecyl compound, (b) about 29% to about 30% by weight of leucine, with the remainder being (c) mannitol.

98. The powder composition according to claim 1, comprising (a) about 0.5% by weight of the compound of formula (I), wherein R1 is a linear hexadecyl compound, and (b) about 60% to about 61% by weight of leucine, with the remainder being (c) mannitol.

99. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 1% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 60% to about 61% by weight of leucine, with the remainder being (c) mannitol.

100. The powder composition according to claim 1, comprising (a) about 1.5% by weight of the compound of formula (I), wherein R1 is a linear hexadecyl compound, and (b) about 60% to about 61% by weight of leucine, with the remainder being (c) mannitol.

101. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 2% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 60% to about 61% by weight of leucine, with the remainder being (c) mannitol.

102. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 3% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 60% to about 61% by weight of leucine, with the remainder being (c) mannitol.

103. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 4% by weight, wherein R1 is a linear hexadecyl compound, (b) about 60% to about 61% by weight of leucine, with the remainder being (c) mannitol.

104. The powder composition according to claim 1, comprising (a) about 0.5% by weight of the compound of formula (I), wherein R1 is a linear hexadecyl compound, and (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol.

105. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 1% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol.

106. The powder composition according to claim 1, comprising (a) about 1.5% by weight of the compound of formula (I), wherein R1 is a linear hexadecyl compound, and (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol.

107. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 2% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol.

108. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 3% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol.

109. The powder composition according to claim 1, comprising (a) a compound of formula (I) in an amount of about 4% by weight, wherein R1 is a linear hexadecyl compound, and (b) about 43% to about 45% by weight of leucine, with the remainder being (c) mannitol.

110. The powder composition according to any one of claims 1 to 109, wherein the leucine is L-leucine.

111. A powder composition according to any one of claims 1 to 110, comprising approximately 80 μg to approximately 360 μg of the compound of formula (I).

112. The powder composition according to claim 111, comprising approximately 80 μg to approximately 320 μg of the compound of formula (I).

113. The powder composition according to claim 111, comprising approximately 160 μg to approximately 320 μg of the compound of formula (I).

114. The powder composition according to claim 111, comprising approximately 80 μg of the compound of formula (I).

115. The powder composition according to claim 111, comprising approximately 160 μg of the compound of formula (I).

116. The powder composition according to claim 111, comprising approximately 240 μg of the compound of formula (I).

117. The powder composition according to claim 111, comprising approximately 320 μg of the compound of formula (I).

118. The powder composition according to any one of claims 1 to 117, wherein the composition comprises about 160 μg to about 320 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing about 68% or more particulate fraction (FPF) as measured using a next-generation impactor (NGI).

119. The powder composition according to any one of claims 1 to 118, wherein the composition comprises about 160 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing 78% to about 80% of the FPF.

120. The powder composition according to any one of claims 1 to 118, wherein the composition comprises about 320 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing 68% to about 73% of the FPF.

121. The powder composition according to any one of claims 1 to 120, wherein the composition comprises about 160 μg to about 320 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing a particulate dose (FPD) of 50% or more of the loaded dose of the powder composition.

122. The powder composition according to any one of claims 1 to 121, wherein the composition comprises about 160 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing 60% to about 65% of the FPD.

123. The powder composition according to any one of claims 1 to 121, wherein the composition comprises about 320 μg of a compound of formula (I), where R1 is a linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing 53% to about 65% of the FPD.

124. The powder composition according to any one of claims 1 to 123, wherein the composition comprises about 160 μg to about 320 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing 72% or more of the released dose (ED).

125. The powder composition according to any one of claims 1 to 124, wherein the composition comprises about 160 μg to about 320 μg of a compound of formula (I), where R1 is linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing about 79% to about 89% of the ED.

126. The powder composition according to any one of claims 1 to 125, wherein the composition comprises about 160 μg to about 320 μg of a compound of formula (I), where R1 is a linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol having an aerodynamic median mass (MMAD) of less than 5 μm.

127. The powder composition according to any one of claims 1 to 126, wherein the composition comprises about 160 μg of a compound of formula (I), where R1 is a linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing the MMAD in the range of about 1.0 μm to about 1.3 μm.

128. The powder composition according to any one of claims 1 to 126, wherein the composition comprises about 320 μg of a compound of formula (I), where R1 is a linear hexadecyl, and when administered by inhalation once daily via a dry powder inhaler, the dry powder inhaler provides an aerosol containing the MMAD in the range of about 1.3 μm to about 1.7 μm.

129. A method for treating a patient requiring treatment for pulmonary hypertension (PH), comprising administering an effective amount of the powder composition according to any one of claims 1 to 128 to the patient's lungs once daily during the treatment period by inhalation using a dry powder inhaler (DPI).

130. The method according to claim 129, wherein administration comprises (i) aerosolizing the powder composition via the DPI to provide the aerosolized powder composition, and (ii) administering the aerosolized powder composition to the patient's lungs via inhalation using the DPI.

131. The method according to claim 129 or 130, wherein the effective amount of the powder composition comprises about 80 μg to about 1280 μg of the compound of formula (I).

132. The method according to any one of claims 129 to 131, wherein the patient is administered two or more different doses of the compound of formula (I) during the administration period.

133. The method according to claim 132, wherein the patient is administered two different doses of the compound of formula (I) during the administration period.

134. The method according to claim 132, wherein the patient is administered three different doses of the compound of formula (I) during the administration period.

135. The method according to claim 132, wherein the patient is administered four different doses of the compound of formula (I) during the administration period.

136. The method according to claim 132, wherein the patient is administered five different doses of the compound of formula (I) during the administration period.

137. The method according to any one of claims 132 to 136, wherein the patient is administered a lower dose for two or more consecutive days before receiving a higher dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

138. The method according to any one of claims 132 to 136, wherein the patient is administered lower doses for three consecutive days or more before receiving a higher dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

139. The method according to any one of claims 129 to 138, wherein the PH is a Group 1 PH as classified by the World Health Organization (WHO).

140. The method according to any one of claims 129 to 138, wherein the PH is a group 2 PH as classified by the WHO.

141. The method according to any one of claims 129 to 138, wherein the PH is a group 3 PH as classified by the WHO.

142. The method according to any one of claims 129 to 138, wherein the PH is a group 4 PH as classified by the WHO.

143. The method according to any one of claims 129 to 138, wherein the PH is a group 5 PH as classified by the WHO.

144. The method according to any one of claims 129 to 138, wherein the PH is pulmonary arterial hypertension (PAH).

145. The method according to claim 144, wherein the pulmonary arterial hypertension is Class I pulmonary arterial hypertension as characterized by the New York Heart Association (NYHA).

146. The method according to claim 144, wherein the pulmonary arterial hypertension is class II pulmonary arterial hypertension as characterized by the NYHA.

147. The method according to claim 144, wherein the pulmonary arterial hypertension is class III pulmonary arterial hypertension as characterized by the NYHA.

148. The method according to claim 144, wherein the pulmonary arterial hypertension is class IV pulmonary arterial hypertension as characterized by the NYHA.

149. The method according to claim 141, wherein the PH is portal pulmonary hypertension (PPH).

150. The method according to claim 141, wherein the PH is a PH associated with interstitial lung disease (ILD).

151. The method according to claim 150, wherein the ILD includes one or more lung conditions selected from the group consisting of idiopathic pulmonary fibrosis (IPF), idiopathic organizing pneumonia (COP), desquamative interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, acute interstitial pneumonia, interstitial pneumonia, connective tissue disease, sarcoidosis, or asbestososis.

152. The method according to claim 150, wherein the ILD is idiopathic interstitial pneumonia (IIP).

153. The method according to claim 150, wherein the ILD is sarcoidosis.

154. The method according to claim 150, wherein the ILD is connective tissue disease-associated interstitial lung disease (CTD-ILD).

155. The method according to claim 150, wherein the ILD is idiopathic pulmonary fibrosis (IPF).

156. The method according to any one of claims 129 to 155, wherein the treatment comprises reducing the pulmonary vascular index (PVRI) of the patient during the administration period compared to the patient's PVRI before the administration period.

157. The method according to any one of claims 129 to 156, wherein the treatment includes reducing the mean pulmonary artery pressure of the patient during the administration period compared to the mean pulmonary artery pressure of the patient before the administration period.

158. The method according to any one of claims 129 to 157, wherein the treatment includes increasing the patient's hypoxemia score during the period of administration.

159. The method according to any one of claims 129 to 158, wherein the oxygenation index of the patient during the administration period is reduced compared to the oxygenation index of the patient before the administration period.

160. The method according to any one of claims 129 to 159, wherein the treatment includes improving the right ventricular function of the patient during the administration period compared to the right ventricular function of the patient before the administration period.

161. The method according to any one of claims 129 to 160, wherein the treatment includes improving the patient's motor function during the administration period compared to the patient's motor function before the administration period.

162. The method according to claim 161, wherein motor ability is measured by a 6-minute walk test (6MWT).

163. The method according to claim 162, wherein improving athletic ability includes increasing the distance the patient walked at 6 MWT during 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 compared to the distance the patient walked at 6 MWT before the administration period.

164. The method according to claim 162, wherein improving athletic ability includes increasing the distance the patient walked at 6 MWT during the administration period by approximately 5 to 60 meters, approximately 5 to 50 meters, approximately 10 to 50 meters, approximately 15 to 50 meters, or approximately 20 to 40 meters, compared to the distance the patient walked at 6 MWT before the administration period.

165. The method according to any one of claims 129 to 164, wherein the treatment includes improving the quality of life of the patient during the administration period compared to the quality of life of the patient before the administration period.

166. The method according to claim 165, wherein the quality of life of the patient is measured by the Cambridge Pulmonary Hypertension Outcomes Review (CAMPHOR) questionnaire.

167. The method according to claim 166, wherein the treatment includes reducing the patient's Camphor Questionnaire score during the administration period by 1 to about 10, 1 to about 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 compared to the patient's Camphor Questionnaire score before the administration period.

168. The method according to any one of claims 129 to 167, wherein the treatment includes increasing the resting degree of peripheral capillary oxygenation saturation (SpCh) of the patient, as assessed by pulse oximetry during the administration period, compared to the resting SpCh of the patient, as assessed by pulse oximetry prior to the administration period.

169. The method according to any one of claims 129 to 167, wherein the treatment includes improving the patient's lung function during the administration period compared to the patient's lung function before the administration period.

170. The method according to claim 169, wherein improving the lung function of the patient includes increasing the patient's forced vital capacity (FVC) during the administration period compared to the patient's PVC before the administration period.

171. The method according to claim 169, wherein improving the lung function of the patient includes increasing the patient's expected percentage of forced vital capacity (ppFVC) during the administration period compared to the patient's ppFVC before the administration period.

172. Improving the lung function of the patient is the patient's forced expiratory volume in one second (FEV1) during the administration period. １ ) The patient before the administration period FEV １ The method according to claim 169, which includes increasing compared to.

173. During the administration period, the patient's forced expiratory volume in one second (FEV1) １ Increasing the patient's FEVI is equivalent to the patient's FEVI before the administration period. １ The method according to claim 172, comprising increasing by approximately 5% to approximately 50%, approximately 5% to approximately 40%, or approximately 5% to approximately 30% compared to.

174. The FEV １ The method according to claim 172, wherein increasing the amount includes increasing it by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

175. The FEV １ The method according to claim 172, wherein 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%.

176. The FEV １ The method according to claim 172, wherein increasing by approximately 5% to approximately 50%, approximately 5% to approximately 40%, approximately 5% to approximately 30%, approximately 5% to approximately 20%, approximately 10% to approximately 50%, approximately 15% to approximately 50%, approximately 20% to approximately 50%, or approximately 25% to approximately 50%.

177. said FEV １ The method of claim 172, wherein increasing said FEV includes increasing by at least about 5%.

178. The FEV １ The method according to claim 172, wherein increasing the amount comprises increasing it by about 5% to about 50%, or about 10% to about 50%, or about 15% to about 50%.

179. The FEV １ The method according to claim 172, wherein increasing the amount includes increasing it by about 25 mL to about 500 mL.

180. The FEV １ The method according to claim 172, wherein increasing the amount includes increasing it by about 25 mL to about 250 mL.

181. The method according to claim 170, wherein increasing the patient's forced vital capacity (FVC) during the administration period is an increase of approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, or approximately 90%.

182. The method according to claim 170, wherein increasing the patient's forced vital capacity (FVC) during the administration period is to increase the patient's FVC by about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, 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% compared to the patient's FVC before the administration period.

183. The method according to claim 169, wherein improving the lung function of the patient includes increasing the total lung volume (TLC) of the patient during the administration period compared to the patient's TLC before the administration period.

184. The method according to claim 183, wherein increasing the patient's total lung capacity (TLC) is an increase of 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 at least about 50% compared to the patient's TLC before the administration period.

185. The method according to claim 183, comprising increasing the patient's total lung capacity (TLC) by approximately 1% to approximately 50%, approximately 5% to approximately 50%, approximately 5% to approximately 40%, approximately 5% to approximately 30%, approximately 5% to approximately 20%, approximately 10% to approximately 50%, approximately 15% to approximately 50%, approximately 20% to approximately 50%, or approximately 25% to approximately 50% compared to the patient's TLC before the administration period.

186. The method according to any one of claims 129 to 185, wherein the administration period is approximately 1 year to approximately 30 years.

187. The method according to claim 186, wherein the administration period is approximately 1 year to approximately 25 years.

188. The method according to claim 186, wherein the administration period is approximately 5 to 30 years.

189. The method according to claim 186, wherein the administration period is approximately 1 year to approximately 20 years.

190. The method according to claim 186, wherein the administration period is approximately 1 year to approximately 15 years.

191. The method according to claim 186, wherein the administration period is approximately 1 year to approximately 10 years.

192. The method according to claim 186, wherein the administration period is approximately 1 year to approximately 5 years.

193. The method according to any one of claims 129 to 192, wherein the dry powder inhaler (DPI) is a capsule-based DPI, and the composition is present in a single DPI capsule.

194. The method according to any one of claims 129 to 192, wherein the dry powder inhaler (DPI) is a capsule-based DPI, and the composition is divided into two DPI capsules.

195. A system for treating pulmonary hypertension comprising (i) a powder composition and (ii) a dry powder inhaler, The aforementioned powder (a) A compound of formula (I) in an amount of about 0.5% to about 5% by weight, 【Transformation 7】 In the formula, R1 is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. (b) Approximately 10% to 61% by weight of leucine, (c) comprising trehalose, mannitol, or a combination thereof, The sum of (a), (b), and (c) is 100%, The dry powder inhaler has an inhalation flow rate of 60 liters per minute (L / min), an inhalation volume of 4 L, and a flow rate of 0.5 to 20 L / sec. ２ A system that provides an aerosol containing approximately 68% or more particulate fraction (FPF) when measured using a next-generation impactor (NGI) with a certain inhalation acceleration.

196. The system according to claim 195, wherein the dry powder inhaler is a high-resistance dry powder inhaler.

197. The aforementioned dry powder inhaler has an output of approximately 0.030 to approximately 0.040 kPa. １／２ (L / min －１ ) －１ A powder, method, or system according to any one of claims 1 to 196, having resistance in the range of .

198. The dry powder inhaler has an output of approximately 0.034 to approximately 0.036 kPa. １／２ (L / min －１ ) －１ A powder, method, or system according to any one of embodiments 1 to 197, having resistance in the range of .

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