Spray-dried treprostinil formulations

Abstract

The present disclosure provides aerosol properties of a powder composition applied by a dry powder inhaler and a spray drying method. Also provided is a method for treating pulmonary hypertension (PH) in a patient comprising administering an effective amount of the powder composition once a day to the lung of the patient by inhalation with the dry powder inhaler. Further provided is a system for treating PH using the powder composition and the dry powder inhaler.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 452,985, filed March 17, 2023, the disclosure of which is incorporated by reference herein in its entirety. BACKGROUND

[0003] Pulmonary hypertension is characterized by abnormally high blood pressure in the blood vessels of the lungs. It is a progressive and fatal disease that leads to heart failure and can occur in the pulmonary arteries, pulmonary veins, or pulmonary capillaries. Symptomatic patients experience shortness of breath, dizziness, syncope, and other symptoms, all of which are exacerbated by exertion. The disease can arise from a variety of causes and can be idiopathic in origin and can lead to high pressures in other systems, for example, portal pulmonary hypertension in patients with both portal hypertension and pulmonary hypertension.

[0004] The World Health Organization (WHO) has classified pulmonary hypertension (PH) into five groups. Group 1 PH is referred to as pulmonary arterial hypertension (PAH) and includes PAH of unknown cause (idiopathic), genetic 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 by pulmonary hypertension associated with left heart disease. Group 3 PH is characterized by PH associated with lung disease, such as chronic obstructive pulmonary disease and interstitial lung disease, and PH associated with sleep-related breathing disorders (e.g., sleep apnea). Group 4 PH is PH due to chronic thrombotic and / or embolic disease, for example, PH caused by blood clots or blood clotting disorders in the lungs. Group 5 PH includes PH caused by other disorders or conditions, for example, blood disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis), and metabolic disorders (e.g., thyroid disease, glycogen storage disease).

[0005] Worldwide, approximately 200,000 people are afflicted with pulmonary arterial hypertension (PAH), of which approximately 30,000-40,000 are in the United States. PAH patients experience constriction of the pulmonary arteries leading to pulmonary arterial hypertension, making it difficult for the heart to pump blood to the lungs. Patients suffer from shortness of breath and fatigue, which often severely limits the ability to perform physical activities.

[0006] The New York Heart Association (NYHA) classifies PAH patients into four functional classes to assess the severity of the disease. Class I PAH patients by NYHA classification have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II PAH patients by NYHA classification have slight limitation of physical activity. These patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III PAH patients by NYHA classification have marked limitation of physical activity. Class III PAH patients are comfortable at rest, but less than ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV PAH patients by NYHA classification are unable to carry out any physical activity without symptoms. Class IV PAH patients can be experiencing dyspnea and / or fatigue at rest, and any physical activity increases discomfort. Class IV PAH patients often show signs of right heart failure.

[0007] Patients with PAH are treated with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE-5) inhibitors, guanylate cyclase stimulators, prostacyclins (e.g., prostacyclins), or combinations thereof. ERAs include ambrisentan (Letairis®), sitaxentan, bosentan (Tracleer®), and macitentan (Opsumit®). PDE-5 inhibitors indicated for the treatment of PAH include sildenafil (Revatio®) and tadalafil (Adcirca®). Prostacyclins indicated for the treatment of PAH include iloprost (Ventavis®), epoprostenol (Flolan®, Veletri®), and treprostinil (Remodulin®, Tyvaso®). One approved guanylate cyclase stimulator is riociguat (Adempas®). Additionally, patients are often treated with combinations of the foregoing compounds.

[0008] Dry powder inhalers (DPIs) can be used to administer a drug to a patient by inhalation. Typically, powder formulations are prepared using a blending method to reduce aggregation and provide sufficient flowability, and thus, therapeutic effectiveness. Unfortunately, the fine particle fraction (FPF), i.e., the amount of drug-containing particles that are small enough (< 5 pm) to reach the lungs and provide a clinical effect, is often low, often less than 50%.

[0009] There is a need to develop powder compositions (e.g., treprostinil palmitate inhalation powders) with improved formulation properties for administration by dry powder inhalers to treat patients with PH and PAH. SUMMARY

[0010] This disclosure addresses the need for novel treatment 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 an improved powder composition of treprostacyclin prodrug administered via a dry powder inhaler and a method for administering the powder composition to a patient in need of treatment.

[0011] In one aspect, this disclosure relates to a powder composition comprising: (a) about 0.5 wt% to about 5 wt% of a compound of formula (I):

[0012] (I),

[0013] Its stereoisomer or its pharmaceutically acceptable salt, wherein R 1 (a) tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl; (b) about 10 wt% to about 61 wt% leucine; and the remainder being (c) sugars selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%. When the powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68%, an inspiratory flow rate of 60 L / min, an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec, as measured using a next-generation impactor (NGI). 2 In one embodiment, the powder composition is a spray-dried powder composition.

[0014] In some embodiments, the composition comprises about 29 wt% to about 61 wt% of leucine. In even further embodiments, the composition comprises 0.5 wt% to about 4 wt% of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the FPF ranges from about 68% to about 73%. In some embodiments, the FPF ranges from about 68% to about 80%. In some embodiments, the FPF ranges from about 78% to about 80%.

[0016] In some embodiments, the aerosol comprises a fine particulate matter (FPD) dose greater than or equal to 50% of the loaded dose of the powder composition. In some embodiments, the FPD ranges from about 53% to about 77% or from about 60% to about 65%.

[0017] In some embodiments, the aerosol comprises a jet dose (ED) of 72% or greater. In some embodiments, the ED ranges from about 79% to about 89%.

[0018] In some embodiments, the aerosol contains a mass average aerodynamic diameter (MMAD) of less than 5 µm. In some embodiments, the MMAD ranges from about 0.75 µm to about 3.0 µm or from about 0.8 µm to about 2.0 µm.

[0019] In some embodiments, the powder composition comprises particles, at least a portion of which comprises: (i) a compound or stereoisomer of formula (I) or a pharmaceutically acceptable salt; (ii) leucine; and (iii) trehalose, mannitol, or a combination thereof, wherein the average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the D10 of the particles is about 0.3 µm. In some embodiments, the D50 of the particles is about 1.7 µm. In some embodiments, the D90 of the particles is about 3.8 µm. In one embodiment, the powder composition is a spray-dried powder composition.

[0020] In one embodiment, the stereoisomer is a diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the stereoisomer is a diastereomer of the compound of formula (I). In yet another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of the compound of formula (I).

[0021] In one embodiment, R 1 It is tetradecyl. In another embodiment, R 1 It is a straight-chain tetradecyl group.

[0022] In one embodiment, R 1 It is a pentadecyl group. In another embodiment, R 1 It is a straight-chain pentadecyl group.

[0023] In one embodiment, R 1 It is a heptadecanyl group. In another embodiment, R... 1 It is a straight-chain heptadecanyl group.

[0024] In one embodiment, R 1 It is octadecyl. In another embodiment, R 1 It is a straight-chain octadecyl group.

[0025] In one embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0026] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In another embodiment, R 1It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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.

[0027] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 4 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0028] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 3.5 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0029] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 3 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0030] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 1.5 wt% to about 4 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0031] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 0.8 wt% to about 4 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0032] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 0.8 wt% to about 3.3 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1It is a straight-chain hexadecyl group.

[0033] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 2 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0034] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 1.5 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0035] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 1 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0036] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 2 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0037] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 3 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0038] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 4 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0039] In one embodiment, leucine is present at about 20 wt% to about 40 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are present in about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0040] In another embodiment, leucine is present at about 29 wt% to about 61 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are present in about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0041] In another embodiment, leucine is present at about 25 wt% to about 35 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are present in about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0042] In another embodiment, leucine is present at about 40 wt% to 61 wt% of the total weight of the powder composition. In yet another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In further embodiments, leucine is present at about 45 wt% to 61 wt% of the total weight of the powder composition. In even further embodiments, leucine is present at about 55 wt% to 61 wt% of the total weight of the powder composition.

[0043] In another embodiment, leucine is present at about 28 wt% to about 33 wt% of the total weight of the powder composition. In yet another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0044] In another embodiment, leucine is present at about 25 wt% to about 33 wt% of the total weight of the powder composition, for example, at about 27 wt% to about 33 wt%, about 27 wt% to about 31 wt%, about 27 wt% to about 30 wt%, about 28 wt% to about 30 wt%, or about 30 wt% of the total weight of the powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0045] 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 0.15:1 (leucine:mannitol) to about 1.7:1 (leucine:mannitol).

[0046] In one embodiment, the sugar is mannitol. In another embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0047] In one embodiment, the powder composition comprises: (a) about 1 wt% of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29.3 wt% or about 29.6 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0048] In one embodiment, the powder composition comprises: (a) about 3 wt% of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29.3 wt% or about 29.6 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0049] This disclosure specifies that a powder composition comprises about 160 µg to about 320 µg of a compound of formula (I), wherein R1 is a linear hexadecyl group, and when administered once daily by inhalation via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) of greater than or equal to about 68%, as measured using a next-generation impactor (NGI). In some embodiments, the dry powder inhaler provides an aerosol comprising an FPF ranging from 78% to about 80%. In some embodiments, the dry powder inhaler provides an aerosol comprising an FPF ranging from 68% to about 73%. In some embodiments, the dry powder inhaler provides an aerosol comprising a fine particulate dose (FPD) of greater than or equal to 50% of the loaded dose of the powder composition. In some embodiments, the dry powder inhaler provides an aerosol comprising an FPD ranging from 60% to about 65%. In some embodiments, the dry powder inhaler provides an aerosol comprising an FPF ranging from 53% to about 65%. In some embodiments, the dry powder inhaler provides an aerosol containing a jet dose (ED) of 79% or greater. In some embodiments, the dry powder inhaler provides an aerosol containing an ED ranging from about 79% to about 89%. In some embodiments, the dry powder inhaler provides an aerosol containing a mass average aerodynamic diameter (MMAD) of less than 5 µm. In some embodiments, the dry powder inhaler provides an aerosol containing an MMAD ranging from about 1.0 µm to about 1.3 µm. In some embodiments, the dry powder inhaler provides an aerosol containing an MMAD ranging from about 1.3 µm to about 1.7 µm.

[0050] In another embodiment, the composition comprises a compound of formula (I) selected from the group consisting 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 compound of formula (I) selected from the group consisting of: 80 µg, 160 µg, 240 µg, 320 µg, 400 µg, 480 µg, and 640 µg. The dosage may, for example, be present in one or more dry powder capsules.

[0051] In another aspect of this disclosure, a method for treating pulmonary hypertension (PH) in a patient of need is provided. The method comprises administering an effective amount of the powder composition disclosed herein to the patient's lungs via inhalation through 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, 1200 µg, or 1280 µg of the compound of formula (I).

[0052] In one embodiment, PH is a Group 1 PH as characterized by the World Health Organization (WHO).

[0053] In one embodiment, pulmonary hypertension is pulmonary arterial hypertension (PAH). In one embodiment, PAH is a Class I PAH as characterized by the New York Heart Association (NYHA). In another embodiment, PAH is a Class II PAH as characterized by the NYHA. In another embodiment, PAH is a Class III PAH as characterized by the NYHA. In yet another embodiment, PAH is a Class IV PAH as characterized by the NYHA.

[0054] In another embodiment, the PH is a Group 2 PH as characterized by the WHO. In another embodiment, the PH is a Group 3 PH as characterized by the WHO. In yet another embodiment, the Group 3 PH is a PH associated with interstitial lung disease (ILD). In another embodiment, the PH is a Group 4 PH as characterized by the WHO. In yet another embodiment, the PH is a Group 5 PH as characterized by the WHO.

[0055] In one embodiment of the treatment method described herein, the application is performed once a day or twice a day.

[0056] In another aspect, this disclosure relates to a system for treating pH. The system includes 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 a predicted amount or device-measured amount.

[0057] In some embodiments, the powder composition described herein and used in the methods described herein comprises about 1 wt% to about 5 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the remainder is one or more pharmaceutically acceptable excipients suitable for use in a dry powder inhaler. Attached Figure Description

[0058] Figure 1This is a schematic diagram showing the system setup with a breathing simulator and a next-generation impactor (NGI) before the simulation begins.

[0059] Figure 2A This is a graph showing various simulated inhalation characteristics at different acceleration rates under the condition of a target inspiratory flow rate of 60 LPM (1030 mL / s) and a total inhalation volume of 4 liters. Figure 2B It is a graph showing various simulated inhalation characteristics at two acceleration rates (50 ms vs. 2000 ms) under the condition that the target inspiratory flow rate is 60 LPM (1030 mL / s) and the total inhalation volume is 1L, 2L or 4L. Figure 2C It is a graph showing various simulated inhalation characteristics at two acceleration rates (25 ms vs. 1000 ms) under the condition that the target inhalation flow rate is 30 LPM (510 mL / s) and the total inhalation volume is 1L, 2L or 4L.

[0060] Figures 3A-3B This is a graph showing the characteristics of TP aerosol deposition in the NGI as a function of acceleration rate. The characteristics show the percentage (mean ± SD) of TP recovered from each component of the NGI at each inhalation acceleration rate to reach a peak inhalation flow rate of 60 LPM at a 4 L inhalation volume. Figure 3A 16 mg TPIP capsules. Figure 3B 32 mg TPIP capsules. Acceleration rate: 20 L / s 2 (Blue), 5.88 L / s 2 (Orange), 2 L / s 2 (Gray), 1 L / s 2 (Yellow) and 0.5 L / s 2 (Light blue).

[0061] Figure 4 This graph shows the change in fine particulate dose (FPD) of TP with the inhalation acceleration rate at which the peak inhalation flow rate reaches 60 LPM for a 4 L inhalation dose. The dashed line shows the FPD values ​​for 16 mg TPIP capsules (blue) and 32 mg TPIP capsules (orange) as the acceleration rate increases from 0.5 L / sec. 2 (2000 ms ramp) increased to 20 L / sec 2 (50 ms ramp-up) change. *For comparison of overall inhalation acceleration rate for 16 mg TPIP capsules, p > 0.05, #For comparison of overall inhalation acceleration rate for 32 mg capsules, p < 0.05, which is consistent with the data in Tables 1 and 2.

[0062] Figures 5A-5CThis is a graph showing the characteristics of TP aerosol deposition in NGI as a function of inhalation volume. The characteristics are shown for each inhalation volume at peak inhalation flow rates of 20 and 0.5 L / s at 60 and 30 LPM, respectively. 2 Percentage of TP recovered from each component of NGI at accelerated rates (mean ± SD). Figure 5A The 16 mg TPIP capsules achieved a peak flow rate of 60 LPM at a ramp time of 50 ms for 1 L (blue), 2 L (orange), and 4 L (grey) doses, and at a ramp time of 2000 ms for 1 L (yellow), 2 L (light blue), and 4 L (green) doses. Figure 5B The 32 mg TPIP capsules achieved a peak flow rate of 60 LPM at a ramp time of 50 ms for 1 L (blue), 2 L (orange), and 4 L (gray) doses, and at a ramp time of 2000 ms for 1 L (yellow), 2 L (light blue), and 4 L (green) doses. Figure 5C The 16 mg TPIP capsules achieved a peak flow rate of 30 LPM at a ramp time of 25 ms for 1 L (blue), 2 L (orange), and 4 L (grey) doses, and at a ramp time of 1000 ms for 1 L (yellow), 2 L (light blue), and 4 L (green) doses.

[0063] Figures 6A-6C This is a graph showing the trend line of TP fine particle dose (FPD) as a function of total inhalation volume. The dashed line represents the peak inhalation flow rate at 30 and 60 LPM for a peak inhalation flow rate of 20 L / s. 2 (Blue) and 0.5 L / s 2 (Orange) Acceleration rate, FPD value changes with increasing inhalation volume. Figure 6A 16 mg TPIP capsules at a flow rate of 60 LPM. Figure 6B 32 mg TPIP capsules at a flow rate of 60 LPM. Figure 6C 16 mg TPIP capsules at a flow rate of 30 LPM. *For 1 and 2 L inhalation doses compared to a 4 L inhalation dose, p > 0.05; #For 1 L inhalation dose compared to a 4 L inhalation dose, p < 0.05; †For 20 L / s 2 Acceleration rate (16 mg and 32 mg) and 0.5 L / s 2 Overall comparison of inhaled volume at acceleration rate (16 mg), p > 0.05, and ¥ for 0.5 L / s 2 Overall comparison of inhaled doses at acceleration rate (32 mg), p < 0.05, which is consistent with the data in Tables 3 and 4.

[0064] Figures 7A-7CThis is a graph showing the particle size distribution characteristics of TP aerosol in a next-generation impactor (NGI). The characteristics show the amount of TP recovered from each stage of the NGI relative to the stage cutoff diameter of the NGI (mean ± SD) for ultra-high drag (UHR, blue), high drag (HR, orange), medium drag (MR, gray), and low drag (LR, yellow) devices. Figure 7A 8 mg TPIP capsules. Figure 7B 16 mg TPIP capsules. Figure 7C 32 mg TPIP capsules.

[0065] Figures 8A-8C This shows the fine particle fraction (FPF) of TP ( Figure 8A For 8 mg (blue), 16 mg (orange), and 32 mg (gray) capsule doses, the fine particle dose (FPD) varies with device resistance ( Figure 8B ); and for each device, the variation of TPFPD with capsule dosage ( Figure 8C (Charts) Figure 8C Only the trend lines for UHR and HR DPI are shown. 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.

[0066] Figures 9A-9C This is a graph showing the particle size distribution characteristics of TP aerosol in a next-generation impactor (NGI). The characteristics show the amount of TP recovered from each stage of the NGI relative to the stage cutoff diameter of the NGI for a high drag (HR) device operating at 40 LPM (blue), 60 LPM (orange), and 80 LPM (grey) (mean ± SD). Figure 9A 8 mg TPIP capsules. Figure 9B 16 mg TPIP capsules. Figure 9C 32 mg TPIP capsules. Detailed Implementation

[0067] definition

[0068] Throughout this disclosure, the term “about” may be used in conjunction with numerical values ​​and / or ranges. The term “about” should be understood to mean those values ​​that are close to the listed values. For example, “about 40 [units]” may mean within ±25% of 40 (e.g., 30 to 50), within ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, or any other value or range of values ​​in or below these values.

[0069] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, wherein the non-toxic base or acid comprises an inorganic or organic base and an inorganic or organic acid. The properties of the salt are not critical, the condition being that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or from organic acids. Exemplary pharmaceutical salts are disclosed in the following literature: 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 hereby incorporated herein by reference in their entirety. Specific, 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, aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclic carboxylic acids and sulfonic acids, 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, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylsulfamic acid, alginic acid, 3-hydroxybutyric acid, galactobionic 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 made 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-methylglucosamine), and procaine.

[0070] As used herein, the term "stereoisomer" refers to two molecules having the same molecular formula and a sequence of bound atoms but with different three-dimensional orientations of their atoms in space. A preferred stereoisomer according to this disclosure is a diastereomer. In one embodiment, the stereoisomer is a diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the stereoisomer is a diastereomer of a compound of formula (I). In yet another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of a compound of formula (I). In yet another embodiment, the stereoisomer is a diastereomer of a compound of formula (II). In even another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of a compound of formula (II).

[0071] Throughout this specification, a specific number of numerical ranges are provided. It should be understood that these ranges encompass 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 can be endpoints of the ranges they encompass (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0072] Throughout this specification, numerical ranges are described as covering “about 80% to about 125%” or “about 80-125%” of the range of values. It should be understood that these include 80% of the lowest endpoint of the range to 125% of the highest endpoint of the range and all values ​​therein.

[0073] Term "C" max "This refers to the maximum (or peak) serum concentration of treprostacyclin measured after administration of a compound of formula (I) or (II) or its stereoisomers or pharmaceutically acceptable salts thereof to the lungs of a subject via the powder composition described herein. Additionally, C can be measured after a single administration of a compound of formula (I) or (II) described herein, its stereoisomers or pharmaceutically acceptable salts thereof." max Alternatively, treprostacyclin C can be measured under steady-state conditions. max Unless otherwise stated, C max This refers to the mean treprostacyclin C measured after a single administration in a subject population (e.g., a population of patients with PH). max .

[0074] The term "AUC" refers to the area under the time curve of treprostacyclin plasma concentration, measured from time 0 to a point after administration to the lungs of the subject, calculated using a combination of linear and logarithmic trapezoidal methods (linear ascending / logarithmic descending methods). In some embodiments, AUC can be measured from time 0 to 24 hours after administration.0-24 ), or it can be extrapolated from time 0 to infinity ("AUC") 0-inf The AUC is measured. Alternatively, the AUC of treprostacyclin can be measured either after a single administration or at steady-state values. Unless otherwise stated, AUC refers to the mean AUC measured after a single administration in a subject population (e.g., a population of patients with PH).

[0075] The term "plasma trough concentration" refers to the plasma concentration of treprostacyclin prior to administration of a subsequent dose of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. For example, treprostacyclin plasma trough concentration may be measured 2 hours, 1 hour, or 30 minutes after administration of a subsequent dose. Plasma trough concentration may be measured immediately after a single administration or at steady state. Unless otherwise stated, plasma trough level refers to the mean treprostacyclin trough level measured in a subject population (e.g., a population of patients with PH).

[0076] The term "adult" refers to a human subject, such as a human patient who is at least 18 years of age or older. In some embodiments, an adult is defined as 18-100 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. Ages 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, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, including all values ​​and ranges in between.

[0077] The term "cascade impaction" refers to a method for measuring the performance characteristics of a dry powder inhaler. The cascade impaction measurements discussed herein use a next-generation impactor (NGI). In some embodiments, the NGI has an inspiratory (or interchangeably referred to as gas) flow rate of 30-60 (e.g., 30, 40, 50, or 60) liters per minute (L / min), an inspiratory volume of 1-4 L (e.g., 1, 2, 3, or 4 L), and an inhalation acceleration rate of 0.5-20 L / sec. 2 In a specific embodiment, the NGI has an inspiratory flow rate of 60 L / min, an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5-20 L / sec. 2 In this embodiment, the inhalation flow rate corresponds to an air pressure drop of 4 kPa in the dry powder inhaler.

[0078] Any reference to compounds of formula I in this document includes their pharmaceutically acceptable salts.

[0079] The term "geometric standard deviation" or "GSD" is a measure of the range of aerodynamic particle size distribution.

[0080] A dry powder inhaler (DPI) is a device used to deliver medication to the respiratory tract. After inhalation, the medication is transported to the lungs. In order to inhale medication via a DPI, the compressed drug powder must be broken down using a process called deagglomeration.

[0081] The compositions described herein are referred to as “powders”. Such powders applied using a DPI are generally referred to as dry powders. Therefore, all references to powders, powder compositions or powder formulations as used herein encompass dry powders, dry powder compositions or dry powder formulations.

[0082] The powders used in DPIs are typically prepared by blending active agents and excipients to prevent aggregation. In other words, DPIs often use micronized drugs blended with carrier particles such as lactose to avoid aggregation and provide sufficient flowability. To enhance drug particle aerosolization, fine lactose particles are often added to the carrier lactose to saturate the high-energy binding sites on the carrier lactose and form aggregates that are easily separated from the drug particles.

[0083] When the powder is sprayed from the inhaler, the drug particles separate from the carrier particles and are delivered to the lungs, while the larger carrier particles eventually enter the upper respiratory tract. In this disclosure, it has been surprisingly found that spray-drying treprostacyclin palmitate (e.g., compounds of formulas (I) and (II)) with certain excipients produces free-flowing drug particles with appropriate size and particle size distribution, resulting in more drug particles being delivered to the lungs and thus improving therapeutic efficacy (e.g., a higher FPF) compared to blended formulations. More specifically, blended formulations typically have an FPF of less than 45% (e.g., from about 11% to about 43%), while the spray-dried powder composition of this disclosure has an FPF greater than or equal to about 68%, at an inspiratory flow rate of 60 L / min, an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec. 2 Measured under the conditions.

[0084] The treprostacycline palmitate inhaled powder (TPIP) described herein is produced by spray drying with mannitol and leucine as excipients and is administered via a dry powder inhaler (DPI), such as a high-resistance (HR) DPI, for example, the RS01Berry Global (formerly Plasciape) device. In one embodiment, the TPIP is administered to patients requiring treatment for pulmonary arterial hypertension (PAH) or pulmonary hypertension caused by interstitial lung disease (PH-ILD).

[0085] In one aspect of this disclosure, a powder composition of a treprost prodrug is provided. The powder composition comprises:

[0086] (a) A compound of formula (I) or a pharmaceutically acceptable salt thereof present in about 0.5 wt% to about 5 wt% of the total weight of the powder composition:

[0087] (I),

[0088] Where R 1 It is tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl;

[0089] (b) Leucine, approximately 10 wt% to approximately 61 wt%, with the remainder being...

[0090] (c) Sugars selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%. 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 average diameter of the particles ranges from 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 provides one or more of the following: (i) an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), (ii) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iv) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 when measured using a next-generation impactor (NGI). L / sec 2 .

[0091] In another embodiment, the powder composition contains about 25 wt% to about 61 wt% leucine. In even another embodiment, the powder composition contains about 25 wt% to about 45 wt% leucine. In yet another embodiment, the powder composition contains about 45 wt% to about 61 wt% leucine.

[0092] In some embodiments, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present in amounts of about 0.4 wt%, about 0.5 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.5 wt%, about 1.7 wt%, about 2.0 wt%, about 2.3 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 4 wt%, about 3.5 wt%, or about 5 wt% of the total weight of the 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle has 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0093] The compound of formula (I) and its pharmaceutically acceptable salt are treprostacyclin prodrugs as disclosed in International Application Publication WO 2015 / 061720, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, leucine is present in about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 58 wt%, or about 60 wt% 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 average diameter of the particles ranges from 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 provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0094] In some embodiments, leucine is present at about 25 wt% to about 30 wt%, about 28 wt% to about 30 wt%, about 25 wt% to about 33 wt%, about 27 wt% to about 33 wt%, about 27 wt% to about 31 wt%, about 27 wt% to about 30 wt%, or about 28 wt% to about 30 wt% of the total weight of the powder composition. In some embodiments, leucine is present at about 40 wt% to about 45 wt%, about 44 wt% to about 51 wt%, or about 43 wt% to about 48 wt% of the total weight of the powder composition.

[0095] In one embodiment of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, R 1 It is tetradecyl. In another embodiment, R 1It is a straight-chain tetradecyl group.

[0096] In another embodiment of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, R 1 It is a pentadecyl group. In another embodiment, R 1 It is a straight-chain pentadecyl group.

[0097] In another embodiment of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, R 1 It is a heptadecanyl group. In another embodiment, R... 1 It is a straight-chain heptadecanyl group.

[0098] In another embodiment of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, R 1 It is octadecyl. In another embodiment, R 1 It is a straight-chain octadecyl group.

[0099] In another embodiment of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group, that is, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is a compound of formula (II):

[0100] (II)

[0101] Its stereoisomer or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is the compound of formula (II). R 1 Compound (I) of formula (I) being a straight-chain hexadecyl group is also referred to herein as C16TR or its international non-proprietary name treprostacyclin palmitate. In this application, C16TR and treprostacyclin palmitate are used interchangeably. Similarly, compound (II) is equivalent to compound (I), wherein R... 1 It is a straight-chain hexadecyl group.

[0102] In a preferred embodiment of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, the compound of formula (I) is treprostacyclin palmitate (i.e., R...). 1 (It is a straight-chain hexadecyl group). In another embodiment, treprostacycline palmitate is in crystalline form. The crystalline form of treprostacycline palmitate is described in U.S. Patent No. 10,781,160, which is incorporated herein by reference in its entirety.

[0103] In one embodiment, treprostacyclin palmitate is crystal form I, and its X-ray powder diffraction (XRPD) pattern exhibits 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 treprostacyclin palmitate crystal form 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, treprostacyclin palmitate is crystal form I, and its XRPD spectrum shows a peak at the 2θ reflection angle provided in Table A.

[0104]

[0105] In one embodiment, treprostacyclin palmitate crystal form I has a differential scanning calorimetry (DSC) thermogram containing an endothermic peak with a peak onset temperature of approximately 52.2 ± 1 °C and a peak maximum temperature of approximately 54.5 ± 1 °C.

[0106] In another embodiment, treprostacyclin palmitate is crystal form II, and its XRPD spectrum exhibits 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 spectrum of treprostacyclin palmitate crystal 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, treprostacyclin palmitate is crystal form II, and its XRPD spectrum shows a peak at the 2θ reflection angle provided in Table B.

[0107]

[0108] In one embodiment, treprostacyclin palmitate crystal form II has a DSC thermogram containing an endothermic peak with a peak onset temperature of approximately 54.6 ± 1 °C and a peak maximum of approximately 56.9 ± 1 °C.

[0109] In one embodiment, (a) is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, (a) is a compound of formula (II) or a pharmaceutically acceptable salt thereof. In yet another embodiment, (a) is a compound of formula (II).

[0110] In one embodiment, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 5 wt% 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 at about 1 wt% to about 4.5 wt% of the total weight of the powder composition. In some embodiments, the compound of formula (I) or (II) is present at about 1 wt% to about 4 wt% of the total weight of the powder composition.

[0111] In one embodiment, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 3.5 wt% 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 at about 1 wt% to about 3 wt% of the total weight of the powder composition.

[0112] In one embodiment, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is present in about 1 wt% to about 5 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 4 wt%, about 2 wt%, about 3 wt%, about 4 wt%, or about 5 wt% 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 about 1 wt% to about 5 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 2 wt%, about 2 wt%, or about 4 wt% of the total weight of the powder composition.

[0113] In one embodiment, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is present in about 0.8 wt% to about 3.3 wt%, or about 1 wt% to about 3 wt%, or about 1 wt% to about 2 wt%, or about 1 wt% to about 1.5% of the total weight of the powder composition.

[0114] In one embodiment, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is present at about 1 wt% 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 at about 1.5 wt% of the total weight of the powder composition.

[0115] In one embodiment, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is present at about 0.8 wt% to about 1.5 wt% 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 at about 2.7 wt% to about 4 wt% 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 at about 2.7 wt% to about 3.5 wt% of the total weight of the powder composition, for example, at about 2.8 wt% to about 3.2 wt% or about 2.9 wt% to about 3.1 wt%.

[0116] In one embodiment, leucine is present at about 25 wt% to about 61 wt% of the total weight of the powder composition. In another embodiment, leucine is present at about 25 wt% to about 50 wt% of the total weight of the powder composition. In another embodiment, leucine is present at about 25 wt% to about 40 wt% of the total weight of the powder composition. In another embodiment, leucine is present at about 20 wt% to about 33 wt% of the total weight of the powder composition, for example, at about 20 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, or about 33 wt%. In another embodiment, leucine is present at about 25 wt% to about 33 wt% of the total weight of the powder composition. In another embodiment, leucine is present at about 27 wt% to about 33 wt% of the total weight of the powder composition. In another embodiment, leucine is present at about 27 wt% to about 31 wt% of the total weight of the powder composition. In another embodiment, leucine is present at about 27 wt% to about 30 wt% of the total weight of the powder composition. In another embodiment, leucine is present at about 28 wt% to about 30 wt% of the total weight of the powder composition.

[0117] In another embodiment, leucine is present at approximately 30 wt% of the total weight of the powder composition.

[0118] In yet another embodiment, leucine is present at about 45 wt% to about 61 wt% of the total weight of the powder composition, for example, at about 45 wt% to about 55 wt% or about 50 wt% to about 55 wt%. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at about 3 wt% to about 4 wt% of the total weight of the powder composition. In even further embodiments, R 1 It is a hexadecyl group, for example, a straight-chain hexadecyl group.

[0119] In some embodiments, the sugar in the powder composition is trehalose. In another embodiment, the sugar in the powder composition is mannitol.

[0120] In one embodiment, the composition has the weight percentages set forth in Table C below. In another embodiment, the composition has ±5% weight percentages of each component set forth in Table C below. In yet another embodiment, the composition has the leucine:mannitol weight ratio set forth in Table C (“leucine:mannitol” or “leucine to mannitol”).

[0121]

[0122] In one embodiment, the powder composition has the components and weight percentages set forth in Table D.

[0123]

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

[0125] In another embodiment, the sugar is mannitol, and the leucine:mannitol weight ratio is from about 0.75:1 (leucine:mannitol) to 0.9:1 (leucine:mannitol). In another embodiment, the composition comprises about 0.5 wt% to about 4 wt% of the total weight of the powder composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the leucine:mannitol weight ratio is from 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 from about 0.75:1 (leucine:trehalose) to 0.9:1 (leucine:trehalose). In another embodiment, the composition comprises about 1 wt% to about 4 wt% of the total weight of the powder composition of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, the leucine:trehalose weight ratio is about 0.8:1 (leucine:trehalose) to 0.9:1 (leucine:trehalose). In one embodiment, the leucine is L-leucine.

[0126] In yet another embodiment, the sugar is mannitol, and the leucine:mannitol weight ratio is from about 1.5:1 (leucine:mannitol) to 1.7:1 (leucine:mannitol). In another embodiment, the composition comprises about 0.5 wt% to about 4 wt% of the total weight of the powder composition of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In yet another embodiment, the leucine:mannitol weight ratio is from 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 from about 1.5:1 (leucine:trehalose) to 1.7:1 (leucine:trehalose). In yet another embodiment, the composition comprises about 0.5 wt% to about 4 wt% of the total weight of the powder composition of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 0.5 wt% to about 3 wt% of the total weight of the powder composition of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 0.5 wt% to about 2 wt% of the total weight of the powder composition of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 0.5 wt% to about 1.5 wt% of the total weight of the powder composition of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, the leucine:mannitol weight ratio is about 1.6:1 (leucine:trehalose) to 1.7:1 (leucine:trehalose).

[0127] In another embodiment, the powder composition comprises: (a) about 1-2 wt% of a compound of formula (I) or (II), its stereoisomers or a pharmaceutically acceptable salt thereof; (b) about 29 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, (a) in the powder composition is about 1 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0128] In another embodiment, (a) of the powder composition is about 1 wt% to about 1.5 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, (a) of the powder composition is about 2 wt% to about 4 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, (a) of the powder composition is about 3 wt% to about 4 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, (a) of the powder composition is about 2 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0129] In another embodiment, the powder composition comprises: (a) about 1 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29.6 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0130] In another embodiment, the powder composition comprises: (a) about 1.5 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof; (b) about 29.6 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0131] In another embodiment, the powder composition comprises: (a) about 1 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29 wt% or about 30 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0132] In another embodiment, the powder composition comprises: (a) about 1.5 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29 wt% or about 30 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1It is a straight-chain hexadecyl group in compound (I).

[0133] In another embodiment, the powder composition comprises: (a) about 2 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29 wt% or about 30 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0134] In another embodiment, the powder composition comprises: (a) about 3 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29 wt% or about 30 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0135] In another embodiment, the powder composition comprises: (a) about 4 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29 wt% or about 30 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0136] In one embodiment, the powder composition comprises: (a) about 0.5 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, the powder composition comprises: (a) about 1 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol. In yet another embodiment, the powder composition comprises: (a) about 1.5 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol. In one embodiment, the powder composition comprises: (a) about 2 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol. In one embodiment, the powder composition comprises: (a) about 3 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol. In one embodiment, the powder composition comprises: (a) about 4 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol.

[0137] In another embodiment, the powder composition comprises: (a) about 0.5 wt% of a compound of formula (I) or (II), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, the powder composition comprises: (a) about 1 wt% of a compound of formula (I) or (II), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, the powder composition comprises: (a) about 1.5 wt% of a compound of formula (I) or (II), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, the powder composition comprises: (a) about 2 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, the powder composition comprises: (a) about 3 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, the powder composition comprises: (a) about 4 wt% of a compound of formula (I) or (II), wherein R1 is a linear hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol.

[0138] In some embodiments, the powder composition does not include distearate phosphoethanolamine-polyethylene glycol 2000 (DPSE-PEG2000).

[0139] In one embodiment, the powder composition comprises about 80 µg to about 700 µg of a compound of formula (I) or (II), for example, 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, about 210 µg, about 220 µg, about 225 µg, about 230 µg, about 240 µg, about 250 µg, about 260 µg, about 270 µg, about 280 µg, about 290 µg, about 300 µg, about 310 µg, about 320 µg, about 330 µg, about 340 µg, about 350 µg, about 360 µg, about 370 µg, about 370 µg, about 380 µg, about 380 µg, about 390 µg, about 300 µg, about 300 µg, about 370 µg, about 380 µg, about 390 µg, about 30 ... µg, approximately 380 µg, approximately 390 µg, approximately 400 µg, approximately 410 µg, approximately 420 µg, approximately 430 µg, approximately 440 µg, approximately 450 µg, approximately 460 µg, approximately 470 µg, approximately 480 µg, approximately 490 µg, approximately 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, approximately 610 µg, approximately 620 µg, approximately 630 µg, approximately 640 µg, approximately 650 µg, approximately 660 µg, approximately 670 µg, approximately 675 µg, approximately 680 µg, approximately 690 µg, or approximately 700 µg µg of compounds of formula (I) and (II), their stereoisomers or pharmaceutically acceptable salts thereof, including all values ​​and ranges thereof.In one embodiment, the powder composition comprises about 80 µg to about 1280 µg of a compound of formula (I) or (II), for example, 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, about 210 µg, about 220 µg, about 225 µg, about 230 µg, about 240 µg, about 250 µg, about 260 µg, about 270 µg, about 280 µg, about 290 µg, about 300 µg, about 310 µg, about 320 µg, about 330 µg, about 340 µg, about 350 µg, about 360 µg, about 370 µg, about 38 ... µg, approximately 380 µg, approximately 390 µg, approximately 400 µg, approximately 410 µg, approximately 420 µg, approximately 430 µg, approximately 440 µg, approximately 450 µg, approximately 460 µg, approximately 470 µg, approximately 480 µg, approximately 490 µg, approximately 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, approximately 610 µg, approximately 620 µg, approximately 630 µg, approximately 640 µg, approximately 650 µg, approximately 660 µg, approximately 670 µg, approximately 675 µg, approximately 680 µg, approximately 690 µg, approximately 700 µg, approximately 720 µg About 740 µg, about 760 µg, about 780 µg, about 800 µg, about 820 µg, about 840 µg, about 860 µg, about, about 880 µg, about 900 µg, about 920 µg, about 940 µg, about 960 µg, about 980 µg, about 1000 µg, about 1020 µg, about 1040 µg, about 1060 µg, about 1080 µg, about 1100 µg, about 1120 µg, about 1140 µg, about 1160 µg, about 1180 µg, about 1200 µg, about 1240 µg, about 1260 µg or about 1280 µg of compounds of formula (I) or (II), their stereoisomers or pharmaceutically acceptable salts thereof, including all values ​​and ranges thereof. In one embodiment, the powder composition comprises about 80 µg to about 700 µg of a compound of formula (I) or (II). In one embodiment, the powder composition comprises about 80 µg to about 1280 µg of a compound of formula (I) or (II). In one embodiment, the powder composition comprises about 80 µg to about 640 µg of a compound of formula (I) or (II).In one embodiment, the powder composition comprises about 80 µg to about 320 µg of a compound of formula (I) or (II). In one 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). In one embodiment, the composition comprises 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 a compound of formula (I) or (II). In one embodiment, the composition may be contained in one powder capsule or multiple (two or more) powder capsules. When present in multiple capsules, the compound of formula (I) or (II) in one of the aforementioned doses is dispensed between the capsules. In one embodiment, the capsules are HPMC capsules of size #3.

[0140] Examples of TPIP compositions with different unit strengths are provided in Table E below. It should be understood that the unit strength of the components provided herein can be calculated based on the weight percentage of the component and the desired dosage. For example, for an 80 µg dose of TP, each component is multiplied by 80 to obtain the unit strength of each component.

[0141]

[0142] In one embodiment, the powder composition comprises about 80 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides one or more of the following: (i) an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), (ii) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iv) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 when measured using a next-generation impactor (NGI). L / sec 2 .

[0143] In one embodiment, the powder composition comprises about 160 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0144] In another embodiment, the powder composition comprises about 240 µg of a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0145] In one embodiment, the powder composition comprises about 320 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0146] In another embodiment, the powder composition comprises about 400 µg of a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0147] In another embodiment, the powder composition comprises about 480 µg of a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0148] In one embodiment, the powder composition comprises about 640 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0149] In one embodiment, the powder composition comprises about 720 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0150] In one embodiment, the powder composition comprises about 800 µg of a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0151] In one embodiment, the powder composition comprises about 880 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0152] In one embodiment, the powder composition comprises about 960 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0153] In one embodiment, the powder composition comprises about 1040 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0154] In one embodiment, the powder composition comprises about 1120 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0155] In one embodiment, the powder composition comprises about 1200 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0156] In one embodiment, the powder composition comprises about 1280 µg of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 It is hexadecyl. In even other embodiments of the compound of formula (I), R 1It is a straight-chain hexadecyl group. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0157] In a preferred embodiment of the powder composition provided herein, the leucine is L-leucine. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0158] On the other hand, this disclosure provides a powder composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, which provides specific pharmacokinetic characteristics upon once-daily administration. Advantageously, the pharmacokinetic characteristics have a lower Cp compared to the current treprostacyclin inhalation solution Tyvaso®. max And a longer half-life.

[0159] In one embodiment, a powder composition exhibiting one of the pharmacokinetic characteristics described herein is a composition described in U.S. Patent Application Publications No. 2020 / 0338005 and No. WO 2022 / 094100, which are incorporated herein by reference in their entirety for all purposes.

[0160] In another embodiment, the powder composition exhibiting one of the pharmacokinetic characteristics described herein comprises: (a) about 1 wt% to about 5 wt% of a compound of formula (I) or (II) by weight of the total powder composition; (b) about 25 wt% to about 61 wt% of leucine; and the remainder being (c) a sugar selected from trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0161] Example 5 of WO 2022 / 094100 shows that the pharmacokinetic (PK) characteristics measured for compounds of formula (I) or (II), their stereoisomers, or pharmaceutically acceptable salts thereof are linear in the dose range of 112.5 µg to 675 µg. Based on this data, a person skilled in the art can determine the pharmacokinetic parameters for doses outside the range or for doses within the range not specifically tested in Example 5 of WO 2022 / 094100. For example, to find the pharmacokinetic parameters at specific doses, Cp can be plotted against specific doses (112.5 µg, 225 µg, 450 µg, and / or 675 µg). max And AUC. The scatter plot can be fitted to a straight line, y = mx + b, where m is the slope of the line, b is the y-intercept, and the values ​​of the unknown pharmacokinetic parameters (y) can be calculated by interpolating the dose x. Additionally, when R... 1When the compound is hexadecyl (i.e., compound (II)), the dosage range of 112.5 µg to 675 µg is based on the molecular weight of compound (I). The equivalent doses of other treprostacyclin prodrugs (when R...) 1 (When it is tetradecyl, pentadecyl, heptadecanyl, or octadecyl) the molecular weight of the treprostacycline prodrug of interest can be used to calculate. For example, when R... 1 When it is tetradecyl, it is equivalent to 112.5 µg of compound II (R). 1 The dosage of compound (I) of formula (hexadecyl) can be determined by multiplying 112.5 µg by the molecular weight of compound (II) (614.95 µg / mol) and when R 1 The calculation is based on the ratio of the molecular weight (586.9 µg / mol) of the compound of formula (I) when it is tetradecyl.

[0162] In the embodiments, the powder compositions of this disclosure are formulated for once-daily administration to the lungs of a subject by means of an inhalation dose ranging from about 80 µg to about 1280 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and provide at least one of the following properties:

[0163] (a) Maximum plasma concentration of treprostacyclin (C max The range is from about 14 pg / mL to about 3000 pg / mL; or

[0164] (b) The area under the plasma concentration curve (AUC) for prostacyclin ranges from approximately 500 pg*h / mL to approximately 20000 pg*h / mL.

[0165] In another 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). In another embodiment, R 1The compound is hexadecyl, for example, a linear hexadecyl. In one embodiment, the powder composition may be present in one or more dry powder capsules. When present in multiple capsules, the compound of formula (I) in one of the aforementioned dosages is dispensed between the capsules. Such multiple capsules may be used to administer a composition comprising one of the aforementioned dosages (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). 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0166] In the embodiments, the powder compositions of this disclosure are formulated for once-daily administration to the lungs of a subject by means of an inhalation dose ranging from about 80 µg to about 675 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and provide at least one of the following properties:

[0167] (a) Maximum plasma concentration of treprostacyclin (C max The range is from about 14 pg / mL to about 1430 pg / mL; or

[0168] (b) The area under the plasma concentration curve (AUC) for prostacyclin ranges from approximately 500 pg*h / mL to approximately 10000 pg*h / mL.

[0169] In another 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, or about 675 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another 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), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment of the compound of formula (I), R 1 The compound is hexadecyl, for example, a straight-chain hexadecyl. In one embodiment, the powder composition may be present in one or more dry powder capsules. When present in multiple capsules, the compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, one of the aforementioned dosages, is dispensed between the capsules. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0170] In the embodiments, the powder compositions of this disclosure are formulated for once-daily administration to the lungs of a subject (e.g., a patient) via an inhalation dose ranging from about 80 µg to about 1280 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and provide at least one of the following properties:

[0171] (a) Maximum plasma concentration of treprostacyclin (C max The range is from about 14 pg / mL to about 3000 pg / mL; or

[0172] (b) The area under the plasma concentration curve (AUC) for prostacyclin ranges from approximately 380 pg*h / mL to approximately 20,000 pg*h / mL.

[0173] In another 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), its stereoisomers, or a pharmaceutically acceptable salt thereof. In one embodiment, the composition may be present in one powder capsule or multiple (two or more) powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, is dispensed between the capsules. Thus, multiple capsules may be administered to achieve one of the aforementioned doses.

[0174] In the embodiments, the powder compositions of this disclosure are formulated for once-daily administration to the lungs of a subject (e.g., a patient) via an inhalation dose ranging from about 80 µg to about 640 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and provide at least one of the following properties:

[0175] (a) Maximum plasma concentration of treprostacyclin (C max The range is from about 14 pg / mL to about 1430 pg / mL; or

[0176] (b) The area under the plasma concentration curve (AUC) for prostacyclin ranges from approximately 380 pg*h / mL to approximately 10000 pg*h / mL.

[0177] In another 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), its stereoisomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the composition may be contained in one powder capsule or multiple (two or more) powder capsules. When contained in multiple capsules, one of the aforementioned doses of the compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is dispensed between the capsules.

[0178] In one embodiment, the powder composition is formulated for once-daily administration to the lungs of a subject (e.g., a patient) via an inhalation dose ranging from about 112.5 µg to about 675 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and provides at least one of the following properties:

[0179] (a) Maximum plasma concentration of treprostacyclin (C max The range is from about 17 pg / mL to about 1370 pg / mL; or

[0180] (b) The area under the plasma concentration curve (AUC) for prostacyclin ranges from approximately 700 pg*h / mL to approximately 7800 pg*h / mL.

[0181] In another 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), its stereoisomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the composition may be contained in one powder capsule or multiple (two or more) powder capsules. When contained in multiple capsules, one of the aforementioned doses of the compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is dispensed between the capsules.

[0182] In the examples, 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 stereoisomers or a pharmaceutically acceptable salt thereof (e.g. about 80 µg to about 1200 µg or about 320 µg to about 1280 µg) and provides the pharmacokinetic characteristics described herein. In one embodiment, a powder composition having one of the pK characteristics described herein comprises 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, about 210 µg, about 220 µg, about 225 µg, about 230 µg, about 240 µg, about 250 µg, about 260 µg, about 270 µg, about 280 µg, about 290 µg, about 300 µg, about 310 µg, about 320 µg, about 330 µg, about 340 µg, about 350 µg, about 360 µg, about 370 µg, about 380 µg, about 390 µg, or about 300 µg. µg, approximately 400 µg, approximately 410 µg, approximately 420 µg, approximately 430 µg, approximately 440 µg, approximately 450 µg, approximately 460 µg, approximately 470 µg, approximately 480 µg, approximately 490 µg, approximately 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, approximately 610 µg, approximately 620 µg, approximately 630 µg, approximately 640 µg, approximately 650 µg, approximately 660 µg, approximately 670 µg, approximately 675 µg, approximately 680 µg, approximately 690 µg, approximately 700 µg, approximately 720 µg, approximately 740 µg, approximately 760 µg About 780 µg, about 800 µg, about 820 µg, about 840 µg, about 860 µg, about, about 880 µg, about 900 µg, about 920 µg, about 940 µg, about 960 µg, about 980 µg, about 1000 µg, about 1020 µg, about 1040 µg, about 1060 µg, about 1080 µg, about 1100 µg, about 1120 µg, about 1140 µg, about 1160 µg, about 1180 µg, about 1200 µg, about 1240 µg, about 1260 µg, or about 1280 µg of compounds of formula (I) or (II), their stereoisomers, or pharmaceutically acceptable salts thereof, including all values ​​and ranges thereof. In further embodiments, R 1The component is hexadecyl, for example, a straight-chain 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 average diameter of the particles ranges from 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 provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0183] In the examples, 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 a stereoisomer thereof or a pharmaceutically acceptable salt thereof (e.g., about 80 µg to about 640 µg or about 112.5 µg to about 675 µg) and provides the pharmacokinetic characteristics described herein. In one embodiment, a powder composition having one of the pK characteristics described herein comprises 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, about 210 µg, about 220 µg, about 225 µg, about 230 µg, about 240 µg, about 250 µg, about 260 µg, about 270 µg, about 280 µg, about 290 µg, about 300 µg, about 310 µg, about 320 µg, about 330 µg, about 340 µg, about 350 µg, about 360 µg, about 370 µg, about 380 µg, about 390 µg, or about 300 µg. About 400 µg, about 410 µg, about 420 µg, about 430 µg, about 440 µg, about 450 µg, about 460 µg, about 470 µg, about 480 µg, about 490 µg, about 500 µg, about 510 µg, about 520 µg, about 530 µg, about 540 µg, about 550 µg, about 560 µg, about 570 µg, about 580 µg, about 590 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 of a compound of formula (I) or a pharmaceutically acceptable salt thereof, including all values ​​and ranges thereof. In another embodiment, R 1 It is a hexadecyl group, for example, a straight-chain hexadecyl group.

[0184] In some embodiments, following once-daily administration of a dry powder composition comprising about 80 µg to about 1280 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, the powder composition or method of application provides a maximum treprostacyclin plasma concentration (C0) ranging from about 10 pg / mL to about 3000 pg / mL. maxFor example, approximately 10 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, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 10 ... pg / mL, approximately 210 pg / 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, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / 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 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 / mL, approximately 590 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL, approximately 750 pg / mL, approximately 800 pg / mL, approximately 850 pg / mL, approximately 900 pg / mL pg / mL, approximately 950 pg / mL, approximately 1000 pg / mL, approximately 1050 pg / mL, approximately 1100 pg / mL, approximately 1150 pg / mL, approximately 1200 pg / mL, approximately 1250 pg / mL, approximately 1300 pg / mL, approximately 1350 pg / mLpg / mL, approximately 1400 pg / mL, approximately 1450 pg / mL, approximately 1500 pg / mL, approximately 1550 pg / mL, approximately 1600 pg / mL, approximately 1650 pg / mL, approximately 1700 pg / mL, approximately 1750 pg / mL, approximately 1800 pg / mL, approximately 1850 pg / mL, approximately 1900 pg / mL, approximately 2000 pg / mL, approximately 2050 pg / mL, approximately 2100 pg / mL, approximately 2150 pg / mL, approximately 2200 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 pg / mL, about 2650 pg / mL, about 2700 pg / mL, about 2750 pg / mL, about 2800 pg / mL, about 2850 pg / mL, about 2900 pg / mL, or about 3000 pg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0185] In some embodiments, following once-daily administration of a powder composition comprising 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) of a compound of formula (I) or (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the powder composition or method of application provides a maximum treprostacyclin plasma concentration (C0) ranging from about 10 pg / mL to about 2000 pg / mL. maxFor example, approximately 10 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, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, etc. pg / mL, approximately 210 pg / 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, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / 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 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 / mL, approximately 590 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL, approximately 750 pg / mL, approximately 800 pg / mL, approximately 850 pg / mL pg / mL, about 900 pg / mL, about 950 pg / mL, about 1000 pg / mL, about 1050 pg / mL, about 1100 pg / mL, about 1150 pg / mL, about 1200 pg / mL, about 1250 pg / mL, about 1300 pg / mL, about 1350pg / mL, about 1400 pg / mL, about 1450 pg / mL, about 1500 pg / mL, about 1550 pg / mL, about 1600 pg / mL, about 1650 pg / mL, about 1700 pg / mL, about 1750 pg / mL, about 1800 pg / mL, about 1850 pg / mL, about 1900 pg / mL, or about 2000 pg / mL, including all values ​​and ranges therein. In one embodiment, the powder composition is a spray-dried powder composition.

[0186] In some embodiments, following a once-daily administration of about 80 µg to about 1280 µg µg (e.g., about 80 µg to about 640 µg or about 360 µg to about 1280 µg) of a compound of formula (I) or (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the powder composition or method of application provides an area under the plasma concentration curve (AUC) ranging from 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, about 1100 pg*h / mL, about 1200 pg*h / mL, about 1300 pg*h / mL, about 1400 pg*h / mL, etc. pg*h / mL, approximately 1500 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 ng*h / mL, approximately 2800 ng*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, 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*hr / mL, approximately 5200 pg*hr / mL, approximately 5300 pg*hr / mL, approximately 5400 pg*h / mL pg*hr / mL, approximately 5500 pg*hr / mL, approximately 5600 pg*hr / mL, approximately 5700 pg*hr / mL, approximately 5800 pg*hr / mL, approximately 5900 pg*hr / mL, approximately 6000 pg*hr / mL, approximately 6100 pg*hr / mL, approximately 6200 pg*hr / mLpg*hr / mL, approximately 6300 pg*h / mL*hr / mL, approximately 6400 pg*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 8200 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, approximately 11700 pg*hr / mL, approximately 11800 pg*hr / mL, approximately 11900 pg*hr / mL 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 / mLpg*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 / mL, approximately 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, 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 pg*hr / mL, approximately 18100 pg*hr / mL, approximately 18200 pg*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 / mLpg*hr / mL, about 19000 pg*hr / mL, about 19100 pg*hr / mL, about 19200 pg*hr / mL, about 19300 pg*hr / mL, about 19400 pg*hr / mL, about 19500 pg*hr / mL, about 19600 pg*hr / mL, about 19700 pg*hr / mL, about 19800 pg*hr / mL, about 19900 pg*hr / mL, or about 20000 pg*hr / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0187] In some embodiments, following a once-daily administration 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) of a compound of formula (I) or (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the powder composition or its method of application provides an area under the plasma concentration curve (AUC) ranging from about 300 pg*h / mL to about 11000 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, about 1100 pg*h / mL, about 1200 pg*h / mL, about 1300 pg*h / mL, about 1400 pg*h / mL, etc. pg*h / mL, approximately 1500 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 ng*h / mL, approximately 2800 ng*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, 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*hr / mL, approximately 5200 pg*hr / mL, approximately 5300 pg*hr / mL, approximately 5400 pg*h / mL pg*hr / mL, about 5500 pg*hr / mL, about 5600 pg*hr / mL, about 5700 pg*hr / mL, about 5800 pg*hr / mL, about 5900 pg*hr / mL, about 6000 pg*hr / mL, about 6100 pg*hr / mL, about 6200pg*hr / mL, approximately 6300 pg*h / mL, approximately 6400 pg*h / mL, approximately 6500 pg*h / 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 8200 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, about 10200 pg*hr / mL, about 10300 pg*hr / mL, about 10400 pg*hr / mL, about 10500 pg*hr / mL, about 10600 pg*hr / mL, about 10700 pg*hr / mL, about 10800 pg*hr / mL, about 10900 pg*hr / mL, or about 11000 pg*hr / mL, including all values ​​and ranges therein. In one embodiment, the powder composition is a spray-dried powder composition.

[0188] In some embodiments, the powder composition or its method of application achieves treprostinil plasma trough concentrations during the administration period of the powder composition. In some embodiments, the plasma trough level is sufficient to provide a sustained therapeutic response during the administration period.

[0189] In some embodiments, the powder composition or method of application comprises about 80 µg to about 1280 µg of a compound of formula (I) or (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and after once-daily administration, the plasma trough concentration of treprostacyclin ranges from 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, 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 10 ... pg / mL, approximately 100 pg / mL, approximately 105 pg / mL, approximately 110 pg / mL, approximately 115 pg / mL, approximately 120 pg / mL, approximately 125 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 145 pg / mL, approximately 150 pg / mL, approximately 155 pg / mL, approximately 160 pg / mL, approximately 165 pg / mL, approximately 170 pg / mL, approximately 175 pg / mL, approximately 180 pg / mL, approximately 185 pg / mL, approximately 190 pg / mL, approximately 195 pg / mL, approximately 200 pg / mL, approximately 200 pg / mL, approximately 205 pg / mL, approximately 210 pg / mL, approximately 215 pg / mL, approximately 220 pg / mL, approximately 225 pg / mL, about 230 pg / mL, about 235 pg / mL, about 240 pg / mL, about 245 pg / mL, or about 250 pg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol containing a fine particulate fraction (FPF) of greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) of greater than or equal to 50% 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 a jet dose (ED) of greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0190] In some embodiments, the powder composition or method of use thereof comprises about 80 µg to about 675 µg of a compound of formula (I) or a stereoisomer thereof (e.g., wherein R 1 The powder composition is hexadecyl (e.g., linear hexadecyl), and after once-daily administration, the powder composition provides or the subject (e.g., the patient) has the following treprostacyclin plasma trough concentrations: 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. pg / mL, 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, approximately 200 pg / mL, including all values ​​and ranges therein.

[0191] In some embodiments, the powder composition or method of application comprises about 80 µg to about 640 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and after once-daily administration, the plasma trough concentration of treprostacyclin ranges from 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, 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 10 ... pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, including all values ​​and ranges therein. In some embodiments, the powder composition comprises about 80 µg to about 640 µg of a compound of formula (II), and the treprostacyclin plasma trough concentration ranges from about 10 pg / mL to about 100 pg / mL.

[0192] In some embodiments, after once-daily administration of a powder composition comprising about 80 µg to about 675 µg of a compound of formula (I) or (II), its stereoisomers, or its pharmaceutically acceptable salts, the powder composition or its method of use provides or the subject (e.g., a patient) has at least one of the following characteristics:

[0193] (a) Maximum treprostacyclin plasma concentration (C maxWithin about 80% to about 125% of the range from about 17 pg / mL to about 1150 pg / mL, for example, about 13 pg / mL, 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 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL. pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / 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, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL 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, 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, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL pg / mL, about 750 pg / mL, about 800 pg / mL, about 850 pg / mL, about 900 pg / mL, about 950 pg / mL, about 1000 pg / mL, about 1050 pg / mL, about 1100 pg / mL, about 1150pg / mL, approximately 1200 pg / mL, approximately 1250 pg / mL, approximately 1300 pg / mL, approximately 1350 pg / mL, approximately 1400 pg / mL, or approximately 1430 pg / mL, including all values ​​and ranges thereof; or

[0194] (b) Area under the plasma concentration curve for prostacyclin (AUC) 0-infWithin approximately 80% to 125% of the 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 1700 pg*h / mL. 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 ng*h / mL, approximately 2800 ng*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL pg*h / mL, about 3800 pg*h / mL, about 3900 pg*h / mL, about 4000 pg*h / mL, about 4100 pg*h / mL, about 4200 pg*h / mL, about 4300 pg*h / mL, about 4400 pg*h / mL, about 4500 pg*h / mL, about 4600 pg*h / mL, about 4700 pg*h / mL, about 4800 pg*h / mL, about 4900 pg*h / mL, about 5000 pg*h / mL, about 5100 pg*hr / mL, about 5200 pg*hr / mL, about 5300 pg*hr / mL, about 5400 pg*hr / mL, about 5500 pg*hr / mL, about 5600 pg*hr / mL, about 5700 pg*hr / mL, approximately 5800 pg*hr / mL, approximately 5900 pg*hr / mL, approximately 6000 pg*hr / mL, approximately 6100 pg*hr / mL, approximately 6200 pg*hr / mL, approximately 6300 pg*hr / mL, approximately 6400 pg*hr / mL, approximately 6500 pg*hr / mL, approximately 6600 pg*hr / mL, approximately 6700 pg*hr / mLpg*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 8200 pg*hr / mL, approximately 8300 pg*h / mL, approximately 8400 pg*h / mL, approximately 8500 pg*h / mL, approximately 8600 pg*hr / mL 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, or approximately 10000 pg*hr / mL, including all values ​​and ranges therein.

[0195] 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, and provides treprostacyclin C ranging from about 14 pg / mL to about 155 pg / mL. maxFor example, 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 105 pg / mL, approximately 110 pg / mL, approximately 115 pg / mL, approximately 120 pg / mL, approximately 125 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 145 pg / mL, approximately 150 pg / mL pg / mL and about 155 pg / mL, including all values ​​and ranges therein. In some embodiments, about 80 µg of a compound of formula (I) or (II), its stereoisomers or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 17 pg / mL to about 125 pg / mL. max In some embodiments, about 80 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 35 pg / mL to about 105 pg / mL. maxIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0196] 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 provides about 80% to about 125% of treprostacyclin C in the range of about 78.4 (72.9) pg / mL. max(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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0197] 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 provides treprostacyclin C ranging from about 30 pg / mL to about 335 pg / mL. maxFor example, 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 105 pg / mL, approximately 110 pg / mL, approximately 115 pg / mL, approximately 120 pg / mL, approximately 125 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 145 pg / mL, approximately 150 pg / mL, approximately 155 pg / mL, approximately 160 pg / mL, approximately 165 pg / mL, approximately 170 pg / mL. pg / mL, approximately 175 pg / mL, approximately 180 pg / mL, approximately 1850 pg / mL, approximately 190 pg / mL, approximately 195 pg / mL, approximately 200 pg / mL, approximately 205 pg / mL, approximately 210 pg / mL, approximately 215 pg / mL, approximately 220 pg / mL, approximately 225 pg / mL, approximately 230 pg / mL, approximately 235 pg / mL, approximately 240 pg / mL, approximately 245 pg / mL, approximately 250 pg / mL, approximately 255 pg / mL, approximately 260 pg / mL, approximately 265 pg / mL, approximately 270 pg / mL, approximately 275 pg / mL, approximately 280 pg / mL, approximately 285 pg / mL, approximately 290 pg / mL, approximately 295 pg / mL, approximately 300 pg / mL, approximately 305 pg / mL, about 310 pg / mL, about 315 pg / mL, about 320 pg / mL, about 325 pg / mL, about 330 pg / mL, about 335 pg / mL, about 340 pg / mL, about 345 pg / mL, or about 350 pg / mL, including all values ​​and ranges therein. In some embodiments, about 160 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 35 pg / mL to about 270 pg / mL. max In some embodiments, about 160 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 76 pg / mL to about 230 pg / mL. maxIn 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 average diameter of the particles ranges from 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 provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0198] 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, and provides about 80% to about 125% of treprostacyclin C in the range of about 287 (46.6) pg / mL. max 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 provides about 80% to about 125% of steady-state treprostacyclin C in the range of about 193 (32.9) pg / mL. max 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, and provides about 80% to about 125% of steady-state treprostacyclin C in the range of about 228 (46.4) pg / mL. max(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 average diameter of the particles ranges from 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 provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0199] 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 provides treprostacyclin C in the range of about 45 pg / mL to about 520 pg / mL. maxFor example, approximately 45 pg / mL, approximately 50 pg / mL, approximately 60 pg / mL, approximately 70 pg / mL, approximately 80 pg / mL, approximately 90 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, 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, approximately 200 pg / mL, approximately 210 pg / 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. 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, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / 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 therein. In some embodiments, about 240 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 55 pg / mL to about 415 pg / mL. max In some embodiments, about 240 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 115 pg / mL to about 355 pg / mL. maxIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0200] 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, and provides treprostacyclin C in the range of about 60 pg / mL to about 700 pg / mL. maxFor example, approximately 60 pg / mL, approximately 70 pg / mL, approximately 80 pg / mL, approximately 90 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 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, approximately 200 pg / mL, approximately 210 pg / 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. 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, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / 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, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL pg / mL, about 580 pg / mL, about 590 pg / mL, about 600 pg / mL, about 610 pg / mL, about 620 pg / mL, about 630 pg / mL, about 640 pg / mL, about 650 pg / mL, about 660 pg / mL, about 670 pg / mL, about 680 pg / mL, about 690 pg / mL, or about 700 pg / mL, including all values ​​and ranges therein. In some embodiments, about 320 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 80 pg / mL to about 560 pg / mL. max In some embodiments, about 320 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 160 pg / mL to about 480 pg / mL. maxIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0201] 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 provides treprostacyclin C in the range of about 80 pg / mL to about 885 pg / mL. maxFor example, approximately 80 pg / mL, approximately 90 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 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, approximately 200 pg / mL, approximately 210 pg / 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. pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / 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, 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 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 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 pg / mL, approximately 870 pg / mL, or approximately 880 pg / mL, including all values ​​and ranges thereof.In some embodiments, about 400 µg of a compound of formula (I) or (II), its stereoisomer or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 100 pg / mL to about 705 pg / mL. max In some embodiments, about 400 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 200 pg / mL to about 605 pg / mL. max 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0202] 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, and provides about 80% to about 125% of treprostacyclin C in the range of about 387 (38.6) pg / mL. maxIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0203] 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 provides treprostacyclin C in the range of about 95 pg / mL to about 1065 pg / mL. maxFor example, approximately 95 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 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, approximately 200 pg / mL, approximately 210 pg / 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. pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / 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, 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 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 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 pg / mL, approximately 880 pg / mL, approximately 890 pg / mL, approximately 900 pg / mL, approximately 910 pg / mL, approximately 920 pg / mL, approximately 930 pg / mL, approximately 940 pg / mL, approximately 950 pg / mL, approximately 960 pg / mL, approximately 970 pg / mLpg / mL, about 980 pg / mL, about 1000 pg / mL, about 1010 pg / mL, about 1020 pg / mL, about 1030 pg / mL, about 1040 pg / mL, about 1050 pg / mL, about 1060 pg / mL, or about 1065 pg / mL, including all values ​​and ranges therein. In some embodiments, about 480 µg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% treprostacyclin C at about 120 pg / mL to about 855 pg / mL. max In some embodiments, about 480 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 240 pg / mL to about 730 pg / mL. max 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0204] 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 provides treprostacyclin C ranging from about 130 pg / mL to about 1430 pg / mL. maxFor example, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 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, approximately 200 pg / mL, approximately 210 pg / 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, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL. pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / 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, 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, approximately 630 pg / mL, approximately 640 pg / mL pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, 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, approximately 880 pg / mL, approximately 890 pg / mL, approximately 900 pg / mL, approximately 910 pg / mL pg / mL, approximately 920 pg / mL, approximately 930 pg / mL, approximately 940 pg / mL, approximately 950 pg / mL, approximately 960 pg / mL, approximately 970 pg / mL, approximately 980 pg / mL, approximately 1000 pg / mL, approximately 1010 pg / mL, approximately 1020 pg / mLpg / mL, approximately 1030 pg / mL, approximately 1040 pg / mL, approximately 1050 pg / mL, approximately 1060 pg / mL, approximately 1070 pg / mL, approximately 1080 pg / mL, approximately 1090 pg / mL, approximately 1100 pg / mL, approximately 1110 pg / mL, approximately 1120 pg / mL, approximately 1130 pg / mL, approximately 1140 pg / mL, approximately 1150 pg / mL, approximately 1160 pg / mL, approximately 1170 pg / mL, approximately 1180 pg / mL, approximately 1190 pg / mL, approximately 1200 pg / mL, approximately 1210 pg / mL, approximately 1220 pg / mL, approximately 1230 pg / mL, approximately 1240 pg / mL, approximately 1250 pg / mL, approximately 1260 pg / mL 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 thereof. In some embodiments, about 640 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 160 pg / mL to about 1140 pg / mL. max In some embodiments, about 640 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%–125% treprostacyclin C at a concentration ranging from about 325 pg / mL to about 980 pg / mL. maxIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0205] 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, and provides about 80% to about 125% of treprostacyclin C in the range of about 717 (52.8) pg / mL. maxIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0206] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 185 pg / mL to about 1300 pg / mL. max This includes all values ​​and ranges therein. 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 provides about 80% to about 125% of treprostacyclin C ranging from about 368 pg / mL to about 1105 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0207] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 200 pg / mL to about 1430 pg / mL. max This includes all values ​​and ranges therein. 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 provides about 80% to about 125% of treprostacyclin C ranging from about 400 pg / mL to about 1230 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0208] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 225 pg / mL to about 1580 pg / mL. max This includes all values ​​and ranges therein. 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 provides about 80% to about 125% of treprostacyclin C ranging from about 450 pg / mL to about 1360 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0209] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 240 pg / mL to about 1720 pg / mL. max This includes all values ​​and ranges therein. 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 provides about 80% to about 125% of treprostacyclin C ranging from about 490 pg / mL to about 1480 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0210] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 530 pg / mL to about 1605 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0211] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 280 pg / mL to about 2020 pg / mL. max This includes all values ​​and ranges therein. 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 provides about 80% to about 125% of treprostacyclin C ranging from about 575 pg / mL to about 1730 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0212] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 300 pg / mL to about 2165 pg / mL. max This includes all values ​​and ranges therein. 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 provides about 80% to about 125% of treprostacyclin C ranging from about 615 pg / mL to about 1855 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0213] 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 provides about 80% to about 125% of treprostacyclin C ranging from about 325 pg / mL to about 2310 pg / mL. max This includes all values ​​and ranges therein. 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 provides about 80% to about 125% of treprostacyclin C ranging from about 660 pg / mL to about 1980 pg / mL. maxThis includes all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0214] 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, and provides treprostacyclin AUC ranging from about 375 pg*h / mL to about 1800 pg*h / mL. 0-inf 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 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, about 1600 pg*h / mL, about 1700 pg*h / mL, or about 1800 pg*h / mL, including all values ​​and ranges therein. In some embodiments, about 80 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of the treprostacyclin AUC in the range of about 475 pg*h / mL to about 1430 pg*h / mL. 0-infIn 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 its method of application provides about 80%-125% of the AUC of treprostacyclin at a rate of about 660 pg*h / mL to about 1240 pg*h / mL. 0-inf 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0215] 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, and provides about 80% to about 125% of treprostacyclin AUC ranging from about 1090 (91.8) pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0216] 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 provides treprostacyclin AUC ranging from about 630 pg*h / mL to about 3000 pg*h / mL. 0-infFor example, 630 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 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 2600 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 26 ... pg*h / mL, about 2700 pg*h / mL, about 2800 pg*h / mL, about 2900 pg*h / mL, or about 3000 pg*h / mL, including all values ​​and ranges therein. 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 provides about 80%-125% of treprostacyclin AUC in the range of about 785 pg*h / mL to about 2370 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 1100 pg*h / mL to about 2050 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0217] 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, and provides about 80% to about 125% of the AUC in the range of about 2130 (30.0) ng*h / mL. 0-inf 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, and provides about 80% to about 125% of the steady-state treprostacyclin AUC in the range of about 1680 (28.7) ng*h / mL. 0-24 (CV%). 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, and provides about 80% to about 125% of the steady-state treprostacyclin AUC ranging from about 1790 (39.6) ng*h / mL. 0-24(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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0218] 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, and provides about 80% to about 125% of treprostacyclin AUC in the range of about 4040 (27.4) pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0219] 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 provides treprostacyclin AUC ranging from about 880 pg*h / mL to about 4130 pg*h / mL. 0-infFor example, approximately 800 pg*h / mL, approximately 900 pg*h / mL, approximately 950 pg*h / mL, approximately 1000 pg*h / mL, approximately 1050 pg*h / mL, approximately 1100 pg*h / mL, approximately 1150 pg*h / mL, approximately 1200 pg*h / mL, approximately 1250 pg*h / mL, approximately 1300 pg*h / mL, approximately 1350 pg*h / mL, approximately 1400 pg*h / mL, approximately 1450 pg*h / mL, approximately 1500 pg*h / mL, approximately 1550 pg*h / mL, approximately 1600 pg*h / mL, approximately 1650 pg*h / mL, approximately 1700 pg*h / mL, approximately 1750 pg*h / mL, approximately 1800 pg*h / mL, approximately 1850 pg*h / mL, approximately 1850 pg*h / mL. pg*h / mL, about 1950 pg*h / mL, about 2000 pg*h / mL, about 2050 pg*h / mL, about 2100 pg*h / mL, about 2150 pg*h / mL, about 2200 pg*h / mL, about 2250 pg*h / mL, about 2300 pg*h / mL, about 2350 pg*h / mL, about 2400 pg*h / mL, about 2450 pg*h / mL, about 2500 pg*h / mL, about 2550 pg*h / mL, about 2600 pg*h / mL, about 2650 pg*h / mL, about 2700 pg*h / mL, about 2750 pg*h / mL, about 2800 pg*h / mL, about 2850 pg*h / mL, about 2950 pg*h / mL, about 3000 pg*h / mL, about 3050 pg*h / mL, about 3100 pg*h / mL, about 3150 pg*h / mL, about 3200 pg*h / mL, about 3250 pg*h / mL, about 3300 pg*h / mL, about 3350 pg*h / mL, about 3400 pg*h / mL, about 3450 pg*h / mL, about 3500 pg*h / mL, about 3550 pg*h / mL, about 3600 pg*h / mL, about 3650 pg*h / mL, about 3700 pg*h / mL, about 3750 pg*h / mL, about 3800 pg*h / mL, about 3850 pg*h / mL, about 3950 pg*h / mL, about 4000 pg*h / mL, approximately 4050 pg*h / mL, approximately 4100 pg*h / mL, approximately 4130 pg*h / mL, including all values ​​and ranges therein.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 provides about 80%-125% of treprostacyclin AUC in the range of about 1100 pg*h / mL to about 3305 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 1540 pg*h / mL to about 2865 pg*h / mL. 0-inf 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0220] 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, and provides treprostacyclin AUC ranging from about 1130 pg*h / mL to about 5310 pg*h / mL. 0-infFor example, approximately 1130 pg*h / mL, approximately 1200 pg*h / mL, approximately 1300 pg*h / mL, approximately 1400 pg*h / mL, approximately 1450 pg*h / mL, approximately 1500 pg*h / mL, approximately 1550 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 2800 pg*h / mL. pg*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, 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 pg*h / mL, about 4900 pg*h / mL, about 5000 pg*h / mL, about 5100 pg*h / mL, about 5200 pg*h / mL, about 5300 pg*h / mL, about 5300 pg*h / mL, or about 5310 pg*h / mL, including all values ​​and ranges therein. 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, and provides about 80%-125% of treprostacyclin AUC in the range of about 1400 pg*h / mL to about 4250 pg*h / mL. 0-inf In some embodiments, about 320 µg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once daily, providing about 80%-125% of the treprostacyclin AUC in the range of about 1975 pg*h / mL to about 3680 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0221] 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 provides treprostacyclin AUC ranging from about 1380 pg*h / mL to about 6480 pg*h / mL. 0-infFor example, approximately 1380 pg*h / mL, approximately 1400 pg*h / mL, approximately 1450 pg*h / mL, approximately 1500 pg*h / mL, approximately 1550 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, approximately 3000 pg*h / mL. pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, 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 pg*h / mL, approximately 5100 pg*h / mL, 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 therein. 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 provides about 80%-125% of treprostacyclin AUC in the range of about 1725 pg*h / mL to about 5180 pg*h / mL. 0-infIn 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 provides about 80%-125% of treprostacyclin AUC in the range of about 2415 pg*h / mL to about 4490 pg*h / mL. 0-inf 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0222] 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 provides treprostacyclin AUC ranging from about 1630 pg*h / mL to about 7650 pg*h / mL. 0-infFor example, approximately 1630 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, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL. pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, 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 5400 pg*h / mL, approximately 5500 pg*h / mL 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, 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 pg*h / mL or about 7650 pg*h / mL, including all values ​​and ranges therein. 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 provides about 80%-125% of treprostacyclin AUC in the range of about 2040 pg*h / mL to about 6120 pg*h / mL. 0-infIn 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 provides about 80%-125% of treprostacyclin AUC in the range of about 2855 pg*h / mL to about 5310 pg*h / mL. 0-inf 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0223] 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 provides treprostacyclin AUC ranging from about 2130 pg*h / mL to about 10000 pg*h / mL. 0-infFor example, approximately 2130 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, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL. pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, 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 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 pg*h / mL, approximately 6100 pg*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, approximately 7600 pg*h / mL, approximately 7700 pg*h / mL, approximately 7800 pg*h / mL, approximately 8000 pg*h / mL, approximately 8100 pg*h / mL, approximately 8200 pg*h / mL, approximately 8300 pg*h / mL, approximately 8400 pg*h / mL, approximately 8500 pg*h / mL, approximately 8600 pg*h / mL, approximately 8700 pg*h / mL, approximately 8800 pg*h / mL, approximately 8900 pg*h / mL, approximately 9000 pg*h / mL, approximately 9100 pg*h / mL, approximately 9200 pg*h / mL, approximately 9300 pg*h / mLpg*h / mL, about 9350 pg*h / mL, about 9400 pg*h / mL, about 9450 pg*h / mL, about 9500 pg*h / mL, about 9600 pg*h / mL, about 9700 pg*h / mL, about 9800 pg*h / mL, about 9900 pg*h / mL, or about 10000 pg*h / mL, including all values ​​and ranges therein. 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 provides about 80%-125% of treprostacyclin AUC in the range of about 2650 pg*h / mL to about 8000 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 3730 pg*h / mL to about 6935 pg*h / mL. 0-inf 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0224] 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, and provides about 80% to about 125% of treprostacyclin AUC in the range of about 5480 (13.8) pg*h / mL. 0-24 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0225] 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 provides about 80%-125% of treprostacyclin AUC in the range of about 2975 pg*h / mL to about 8940 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 4170 pg*h / mL to about 7750 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0226] 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 provides about 80%-125% of treprostacyclin AUC in the range of about 3290 pg*h / mL to about 9900 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 4600 pg*h / mL to about 8560 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0227] 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 provides about 80%-125% of treprostacyclin AUC in the range of about 3605 pg*h / mL to about 10815 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 5045 pg*h / mL to about 9380 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0228] 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 its method of application provides about 80%-125% of the AUC of treprostacyclin in the range of about 3900 pg*h / mL to about 11800 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 5485 pg*h / mL to about 10190 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0229] 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 provides about 80%-125% of treprostacyclin AUC in the range of about 4230 pg*h / mL to about 12700 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 5920 pg*h / mL to about 11000 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0230] 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 provides about 80%-125% of treprostacyclin AUC in the range of about 4500 pg*h / mL to about 13650 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 6360 pg*h / mL to about 11815 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0231] 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 provides about 80%-125% of treprostacyclin AUC in the range of about 4850 pg*h / mL to about 14600 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 6795 pg*h / mL to about 12630 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0232] 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 provides about 80%-125% of treprostacyclin AUC in the range of about 5150 pg*h / mL to about 15550 pg*h / mL. 0-inf 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 provides about 80%-125% of treprostacyclin AUC in the range of about 7235 pg*h / mL to about 13445 pg*h / mL. 0-infIn 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0233] In some embodiments, the powder composition comprises about 80 µg to about 1280 µg of a compound of formula (I) or (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides, or, after once daily administration, a subject (e.g., a patient) with a plasma trough concentration of treprostacyclin ranging from about 3 pg / mL to about 250 mg / mL, such as 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, 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 95 pg / mL. pg / mL, approximately 100 pg / mL, approximately 100 pg / mL, approximately 105 pg / mL, approximately 110 pg / mL, approximately 115 pg / mL, approximately 120 pg / mL, approximately 125 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 145 pg / mL, approximately 150 pg / mL, approximately 155 pg / mL, approximately 160 pg / mL, approximately 165 pg / mL, approximately 170 pg / mL, approximately 175 pg / mL, approximately 180 pg / mL, approximately 185 pg / mL, approximately 190 pg / mL, approximately 195 pg / mL, approximately 200 pg / mL, approximately 200 pg / mL, approximately 205 pg / mL, approximately 210 pg / mL, approximately 215 pg / mL, approximately 220 pg / mL, about 225 pg / mL, about 230 pg / mL, about 235 pg / mL, about 240 pg / mL, about 245 pg / mL, or about 250 pg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol containing a fine particulate fraction (FPF) of greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) of greater than or equal to 50% 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 a jet dose (ED) of greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0234] 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, and the powder composition provides or, after once daily administration, a subject (e.g., a patient) with a plasma trough concentration of treprostacyclin ranging from about 3 pg / mL to about 150 mg / mL, such as 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, 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 105 pg / mL, about 110 pg / mL, about 115 pg / mL, about 120 pg / mL, about 125 pg / mL, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 145 pg / mL, or about 150 pg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0235] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from 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. In another embodiment, the treprostacyclin plasma trough concentration ranges from 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle has 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 provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0236] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from 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. In one embodiment, the powder composition is a spray-dried 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0237] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostinil plasma trough concentration ranging from 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. In other embodiments, the treprostinil plasma trough concentration ranges from about 10 pg / mL to about 30 mg / mL or from 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle has 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0238] 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, or, after once daily administration, a subject (e.g., a patient) with a plasma trough concentration of treprostacyclin ranging from 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. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the D10 of the particles is about 0.3 µm, the D50 is about 1.7 µm, and / or the D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0239] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 7 pg / mL to about 50 mg / mL, such as 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. In some embodiments, the treprostacyclin 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 comprises particles. In some embodiments, the average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle has 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0240] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 9 pg / mL to about 65 mg / mL, such as 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. In some embodiments, the treprostacyclin plasma trough concentration ranges from about 15 pg / mL to about 50 mg / mL or from 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 comprises particles. In some embodiments, the average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle's D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0241] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 10 pg / mL to about 80 mg / mL, such as 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. In some embodiments, the treprostacyclin plasma trough concentration ranges from about 35 pg / mL to about 70 mg / mL or from 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 comprises particles. In some embodiments, the average diameter of the particles ranges from 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0242] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 30 pg / mL to about 75 mg / mL, such as 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. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0243] 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 or, after once daily administration, a subject (e.g., a patient) with a plasma trough concentration of treprostacyclin ranging from about 13 pg / mL to about 95 mg / mL, such as 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. In some embodiments, the treprostacyclin plasma trough concentration ranges from about 25 pg / mL to about 75 mg / mL or from 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 comprises particles. In some embodiments, the average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0244] 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 provides, or, after once daily administration, a subject (e.g., a patient) with a plasma trough concentration of treprostacyclin ranging from about 15 pg / mL to about 125 mg / mL, such as 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, about 110 pg / mL, about 115 mg / mL, about 125 mg / mL. pg / mL, about 120 pg / mL, or about 125 pg / mL, including all values ​​and ranges therein. In some embodiments, the treprostacyclin plasma trough concentration ranges from about 35 pg / mL to about 100 mg / mL or from 50 pg / mL to about 90 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0245] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 50 pg / mL to about 100 mg / mL, such as 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. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle has 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 provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0246] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 20 pg / mL to about 135 mg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0247] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 21 pg / mL to about 150 mg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0248] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 25 pg / mL to about 180 mg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol containing a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% 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 a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0249] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 28 pg / mL to about 195 mg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0250] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 30 pg / mL to about 209 mg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0251] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 32 pg / mL to about 224 mg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0252] 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, or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 34 pg / mL to about 238 mg / mL, including all values ​​and ranges therein. 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 average diameter of the particles ranges from about 1.0 µm to about 2.0 µm. In some embodiments, the particle D10 is about 0.3 µm, D50 is about 1.7 µm, and / or D90 is about 3.8 µm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of the following: (i) a fine particulate dose (FPD) greater than or equal to 50% of the loaded dose of the powder composition (e.g., about 53% to about 77%, or about 60% to about 65%), (ii) an aerosol comprising a jet dose (ED) greater than or equal to 72% (e.g., about 79% to about 89%), or (iii) a mass-average aerodynamic diameter (MMAD) 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), an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0253] In some embodiments, one or more pharmaceutically acceptable excipients suitable for use in dry powder inhalers comprise sugars, amino acids, and optionally distearate-PEG2000 (DPSE-PEG2000). In some embodiments of the powder compositions or methods described herein, the powder composition comprises about 25 wt% to about 61 wt% 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 include distearate-PEG2000 (DPSE-PEG2000).

[0254] Aerosolized Composition

[0255] In some embodiments, the powder compositions described herein are aerosolized via DPI to provide an aerosolized composition. In one embodiment, the powder composition is a spray-dried powder composition.

[0256] The aerosolized composition is administered to a patient requiring treatment for PH (e.g., PAH or PH-ILD associated with interstitial lung disease (PH-ILD)). In one embodiment, the aerosolized composition is administered to a patient requiring treatment for pulmonary fibrosis (e.g., PH-ILD, where ILD is pulmonary fibrosis). The aerosolized composition can be characterized using certain parameters known to those skilled in the art, such as fine particle fraction (FPF), fine particle dose (FPD), ejection dose (ED), mass median aerodynamic diameter (MMAD), and / or particle size and distribution. In an embodiment, these parameters are measured by NGI. In an embodiment, NGI uses a flow rate corresponding to an air pressure drop of 3 kPa to 4.5 kPa, which is related to the drag of the DPI. In an embodiment, the pressure drop is 4 kPa. For example, the performance of ultra-high drag (UHR), high drag (HR), and medium drag (MR) devices can be evaluated by drawing 4 L of air (corresponding to an air pressure drop of 4 kPa) via the DPI at flow rates of 40, 60, and 85 LPM, respectively. Aerosol characterization data for the above parameters can be compared between different DPI devices (with varying resistance). In this embodiment, the average inhaler resistance for achieving the high-resistance DPI parameters described herein ranges from 0.025 kPa. 1 / 2 (L / min -1 ) -1 Up to 0.040 kPa 1 / 2 (L / min -1 ) -1 In the embodiments, the average inhaler resistance used to achieve the high resistance DPI described herein ranges from 0.030 kPa. 1 / 2 (L / min -1 ) -1 to 0.040 kPA 1 / 2 (L / min -1 ) -1 In the embodiments, the average inhaler resistance for achieving the high resistance DPI described herein ranges from approximately 0.034 kPa. 1 / 2 (L / min -1 ) -1 To approximately 0.036 kPa 1 / 2 (L / min -1 ) -1 .

[0257] (i) Fine particle fraction (FPF)

[0258] "Fine Particle Fraction" or "FPF" refers to the fraction of aerosols with a particle diameter less than 5 µm, as measured by cascade impaction (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).

[0259] In some embodiments, the powder composition is in the form of an aerosol comprising particles with an FPF of 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%. In some embodiments, the powder composition is in the form of an aerosol comprising particles with 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 thereof. In one embodiment, the aerosolized powder composition comprises particles with 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.

[0260] In some embodiments, the FPF of the aerosolized powder composition is 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 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 any range thereof, and when measured using a next-generation impactor (NGI), the inspiratory flow rate is 30-60 liters per minute (L / min), the inspiratory volume is 1-4 L, and the inhalation acceleration rate is 0.5-20 L / sec. 2 .

[0261] In one embodiment, the powder composition exhibiting one of the FPF characteristics provided above comprises mannitol. In another embodiment, the powder composition exhibiting the FPF characteristics provided above comprises trehalose.

[0262] In some embodiments, the powder composition comprises: (a) about 0.5 wt% to about 5 wt% of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl; (b) about 10 wt% to about 61 wt% of leucine; and (c) trehalose, mannitol, or a combination thereof, wherein the sum of (a), (b), and (c) is 100%. When the powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68%, an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0263] In some embodiments, for a 16 mg TPIP capsule (containing 160 µg TP), the FPF of the aerosolized powder composition ranges from 78% to 80% at an inspiratory flow rate of 4 L and an inspiratory flow rate of 60 LPM. In some embodiments, for a 16 mg TPIP capsule (containing 160 µg TP), the FPF of the powder composition ranges from 76% to 80% at an inspiratory flow rate of 1 L or 2 L and an inspiratory flow rate of 60 LPM. In some embodiments, for a 16 mg TPIP capsule (containing 160 µg TP), the FPF of the powder composition ranges from 74% to 76% at an inspiratory flow rate of 1 L or 2 L and an inspiratory flow rate of 30 LPM.

[0264] In some embodiments, for a 32 mg TPIP capsule (containing 320 µg TP), the FPF of the aerosolized powder composition ranges from 68% to about 73% at an inspiratory volume of 4 L and an inspiratory flow rate of 60 LPM. In some embodiments, for a 32 mg TPIP capsule, the FPF of the powder composition ranges from 63% to about 68% at an inspiratory volume of 1 L or 2 L and an inspiratory flow rate of 60 LPM.

[0265] (ii) Fine particle dose (FPD)

[0266] As used herein, the term "fine particle dose" or "FPD" refers to the mass of a drug in an aerosol with a particle diameter less than 5 µm, such as as measured by cascade impaction. FPD can be expressed as a percentage or by mass. In this disclosure, FPD is expressed as a percentage.

[0267] In some embodiments, the FPD of the aerosolized powder composition 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% of the loading dose of the powder composition, with an inspiratory flow rate of 30-60 liters per minute (L / min), an inspiratory volume of 1-4 L, and an inhalation acceleration rate of 0.5-20 L / sec when measured using a next-generation impactor (NGI). 2 In some embodiments, the FPD of the aerosolized powder composition is about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more of the loaded amount of the powder composition, or any range thereof, when measured using a next-generation impactor (NGI), with an inspiratory flow rate of 30-60 liters per minute (L / min), an inspiratory volume of 1-4 L, and an inhalation acceleration rate of 0.5-20 L / sec. 2 .

[0268] In some embodiments, for 16 or 32 mg TPIP capsules, the FPD of the aerosolized powder composition ranges from 53% to about 77% under different inhalation flow rates, different acceleration rates and inhalation volumes taught herein.

[0269] In some embodiments, the FPD range of the aerosolized powder composition is from 53% to 65% for 32 mg TPIP capsules (containing 320 µg TP) and from 60% to 65% for 16 mg TPIP capsules (containing 160 µg TP), with an inspiratory flow rate of 30–60 L / min, an inspiratory volume of 1–4 L, and an inhalation acceleration rate of 0.5–20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0270] (iii) Expectoration dose (ED)

[0271] As used herein, the term “jet dose” or “ED” refers to the percentage of drug recovered in the NGI relative to the total drug recovery. ED is an indication of drug delivery from a suitable inhaler device following a dispensing or diffusion event. For powder compositions, ED is a measure of the percentage 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 of the DPI placed prior to dispensing).

[0272] In some embodiments, the ED of the aerosolized powder composition is greater than or equal to 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%, with an inspiratory flow rate of 30-60 liters per minute (L / min), an inspiratory volume of 1-4 L, and an inhalation acceleration rate of 0.5-20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0273] In some embodiments, the ED of the aerosolized powder composition is about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% or more, including any range thereof, with an inspiratory flow rate of 30-60 liters per minute (L / min), an inspiratory volume of 1-4 L, and an inhalation acceleration rate of 0.5-20 L / sec when measured using a next-generation impactor (NGI). 2 .

[0274] In some embodiments, the ED of the aerosolized powder composition is greater than or equal to about 79% for 16 or 32 mg TPIP capsules at 60 LPM, and greater than or equal to about 72% for 16 mg TPIP capsules at 30 LPM.

[0275] In some embodiments, the ED range of the aerosolized powder composition is from about 79% to about 89% for 16 or 32 mg TPIP capsules at 60 LPM. In some embodiments, the ED range of the aerosolized powder composition is from about 72% to about 76% for 16 mg TPIP capsules at 30 LPM.

[0276] (iv) Median Mass Diameter (MMD) and Median Mass Aerodynamic Diameter (MMAD)

[0277] As used herein, the term "mass median diameter" or "MMD" refers to the average particle diameter in an aerosol based on the mass of the particles in the aerosol. MMD is determined by cascade impaction.

[0278] The term "mass median aerodynamic diameter" or "MMAD" is the MMD normalized relative to the aerodynamic separation of aerosol droplets. MMAD is determined by cascade impaction. The mass median aerodynamic diameter (MMAD) is the aerodynamic diameter of a given aerosol where 50% of the mass is associated with particles smaller than the median aerodynamic diameter (MAD) and 50% of the mass is associated with particles larger than the MAD.

[0279] For dry powder inhalers, oral deposition is primarily determined by inertial impaction and is therefore characterized by the Stokes number of the aerosol (DeHaan et al., Journal of Aerosol Science, 35(3), 309-331, 2003). For equivalent inhaler geometry, breathing patterns, and oral cavity geometry, the Stokes number and oral deposition are primarily influenced by the aerodynamic size of the inhaled powder. Therefore, factors contributing to oral deposition of powder include the size distribution of individual particles and the dispersibility of the powder. If the MMAD of individual particles is too large, for example, exceeding 5 µm, then the percentage of powder deposited in the oral cavity will increase. Similarly, if the powder dispersibility is poor, it indicates that particles will leave the dry powder inhaler and enter the oral cavity as agglomerates. Agglomerate powder will aerodynamically behave like individual particles of similar size to the agglomerates, so even if individual particles are small (e.g., MMAD of about 5 µm or less), the size distribution of the inhaled powder may have an MMAD greater than about 5 µm, resulting in enhanced oral deposition. As discussed herein, this disclosure is based in part on the surprising discovery that the spray-dried compositions described herein do not agglomerate and pr...

Claims

1. A powder composition comprising: (a) about 0.5 wt% to about 5 wt% of compound (I) or its stereoisomers or pharmaceutically acceptable salts, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl. (b) Leucine, approximately 10 wt% to approximately 61 wt%, and (c) Trehalose, mannitol, or a combination thereof, The sum of (a), (b), and (c) is 100%; and When administered via a dry powder inhaler, the inhaler provides an aerosol containing an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and a flow rate of 0.5–20 L / sec when using a next-generation impactor (NGI). 2 The fine particulate fraction (FPF) is greater than or equal to approximately 68% as measured at the inhalation acceleration rate.

2. The powder composition according to claim 1, wherein the FPF ranges from 68% to about 73%.

3. The powder composition according to claim 1, wherein the FPF ranges from 78% to about 80%.

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

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

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

7. The powder composition according to any one of claims 1 to 6, wherein the aerosol contains a spray dose (ED) of 72% or more.

8. The powder composition according to claim 7, wherein the ED ranges from about 79% to about 89%.

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

10. The powder composition of claim 9, wherein the MMAD ranges from about 0.75 µm to about 3.0 µm.

11. The powder composition of claim 9, wherein the MMAD ranges from about 0.8 µm to about 2.0 µm.

12. The powder composition according to any one of claims 1 to 11, comprising particles, at least a portion of said particles comprising: (i) A compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt, (ii) Leucine, and (iii) Trehalose, mannitol, or a combination thereof, The average diameter of the particles ranges from about 1.0 µm to about 2.0 µm.

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

14. The powder composition of claim 12, wherein the D50 of the particles is about 1.7 µm.

15. The powder composition according to claim 12, wherein the particle D90 is 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 straight-chain hexadecyl group.

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

19. The powder composition according to claim 18, wherein R1 is a straight-chain tetradecyl group.

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

21. The powder composition according to claim 20, wherein R1 is a straight-chain pentadecyl group.

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

23. The powder composition according to claim 22, wherein R1 is a straight-chain hexadecyl group.

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

25. The powder composition according to claim 24, wherein R1 is a straight-chain heptadecanyl group.

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

27. The powder composition according to claim 26, wherein R1 is a straight-chain octadecyl group.

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 about 0.5 wt% to about 4.5 wt% 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 about 1 wt% to about 4.5 wt% 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 about 1 wt% to about 4 wt% 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 about 1 wt% to about 3.5 wt% 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 about 1 wt% to about 3 wt% 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 about 1 wt% to about 2.5 wt% 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 about 1 wt% to about 2 wt% 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 about 1 wt% to about 1.5 wt% 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 about 2 wt% to about 4 wt% 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 about 2 wt% to about 3.5 wt% 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 about 2 wt% to about 3 wt% 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 about 2 wt% to about 2.5 wt% 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 about 3 wt% to about 4.5 wt% 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 about 3 wt% to about 4 wt% 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 about 3 wt% to about 3.5 wt% 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 about 0.5 wt% to about 2 wt% 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 about 0.5 wt% to about 1.5 wt% 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 about 0.5 wt% to about 1 wt% 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 about 3.5 wt% to about 4.5 wt% 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 about 4 wt% to about 4.5 wt% 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 about 0.5 wt% 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 about 1 wt% 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 about 1.5 wt% 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 about 2 wt% 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 about 2.5 wt% 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 about 3 wt% 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 about 3.5 wt% 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 about 4 wt% 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 a compound of formula (II).

57. The powder composition according to any one of claims 1 to 56, wherein the leucine is present in about 25 wt% to about 61 wt% 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 about 40 wt% to about 61 wt% 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 about 50 wt% to about 61 wt% 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 about 55 wt% to about 61 wt% 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 about 58 wt% to about 61 wt% 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 about 40 wt% to about 45 wt% 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 about 44 wt% to about 51 wt% 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 about 43 wt% to about 48 wt% 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 about 25 wt% to about 30 wt% 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 about 28 wt% to about 30 wt% 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 about 25 wt% to about 33 wt% 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 about 27 wt% to about 33 wt% 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 about 27 wt% to about 31 wt% 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 about 27 wt% to about 30 wt% 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 about 28 wt% to about 30 wt% 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 at about 30 wt% 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 at about 45 wt% 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 at about 60 wt% 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, wherein the powder is selected from one of the following compositions:

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

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

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

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

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

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

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

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

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

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

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

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

90. The powder composition according to any one of claims 78 to 87, comprising about 3 wt% to about 4 wt% of the compound of formula (I) 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 straight-chain hexadecyl group.

92. The powder composition according to claim 1, comprising: (a) about 0.5 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 29 wt% to about 30 wt% of leucine; and the remainder being (c) mannitol.

93. The powder composition according to claim 1, comprising: (a) about 1 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 29 wt% to about 30 wt% of leucine; and the remainder being (c) mannitol.

94. The powder composition according to claim 1, comprising: (a) about 1.5 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 29 wt% to about 30 wt% of leucine; and the remainder being (c) mannitol.

95. The powder composition according to claim 1, comprising: (a) about 2 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 29 wt% to about 30 wt% of leucine; and the remainder being (c) mannitol.

96. The powder composition according to claim 1, comprising: (a) about 3 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 29 wt% to about 30 wt% of leucine; and the remainder being (c) mannitol.

97. The powder composition according to claim 1, comprising: (a) about 4 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 29 wt% to about 30 wt% of leucine; and the remainder being (c) mannitol.

98. The powder composition according to claim 1, comprising: (a) about 0.5 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol.

99. The powder composition according to claim 1, comprising: (a) about 1 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol.

100. The powder composition according to claim 1, comprising: (a) about 1.5 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol.

101. The powder composition according to claim 1, comprising: (a) about 2 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol.

102. The powder composition according to claim 1, comprising: (a) about 3 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol.

103. The powder composition according to claim 1, comprising: (a) about 4 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 60 wt% to about 61 wt% of leucine; and the remainder being (c) mannitol.

104. The powder composition according to claim 1, comprising: (a) about 0.5 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol.

105. The powder composition according to claim 1, comprising: (a) about 1 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol.

106. The powder composition according to claim 1, comprising: (a) about 1.5 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol.

107. The powder composition according to claim 1, comprising: (a) about 2 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol.

108. The powder composition according to claim 1, comprising: (a) about 3 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and the remainder being (c) mannitol.

109. The powder composition according to claim 1, comprising: (a) about 4 wt% of the compound of formula (I), wherein R1 is a straight-chain hexadecyl group; (b) about 43 wt% to about 45 wt% of leucine; and 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. The powder composition according to any one of claims 1 to 110, comprising about 80 µg to about 360 µg of the compound of formula (I).

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

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

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

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

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

117. The powder composition according to claim 111, comprising about 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate fraction (FPF) greater than or equal to about 68% 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, wherein the dry powder inhaler provides an aerosol comprising an amount ranging from 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising an amount ranging from 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particulate dose (FPD) greater than or equal to 50% 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising about 60% to 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising from 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a spray dose (ED) of greater than or equal to 72%.

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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a mass average aerodynamic diameter (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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising 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), wherein R1 is a straight-chain hexadecyl, and when administered once daily by a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the MMAD in the range of about 1.3 µm to about 1.7 µm.

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

130. The method of claim 129, wherein administration comprises (i) aerosolizing the powder composition by means of the DPI to provide an aerosolized powder composition, and (ii) administering the aerosolized powder composition to the lungs of the patient by inhalation of 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 two or more different doses of the compound of formula (I) are administered to the patient during the administration period.

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

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

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

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

137. The method according to any one of claims 132 to 136, wherein the lower dose is administered to the patient for two or more consecutive days prior to 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 lower dose is administered to the patient for three or more consecutive days prior to 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 WHO.

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

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

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

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

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

146. The method of claim 144, wherein the pulmonary hypertension is Class II pulmonary hypertension as characterized by the NYHA.

147. The method of claim 144, wherein the pulmonary hypertension is Class III pulmonary hypertension as characterized by the NYHA.

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

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

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

151. The method of claim 150, wherein the ILD comprises one or more lung diseases selected from the group consisting of: idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia, nonspecific interstitial pneumonia, allergic pneumonia, acute interstitial pneumonia, interstitial pneumonia, connective tissue disease, sarcoidosis, or asbestosis.

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

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

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

155. The method of 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 patient's pulmonary vascular index (PVRI) during the application period compared to the PVRI of the patient prior to the application period.

157. The method of any one of claims 129 to 156, wherein the treatment comprises reducing the patient's mean pulmonary artery pressure during the application period compared to the patient's mean pulmonary artery pressure prior to the application period.

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

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

160. The method of any one of claims 129 to 159, wherein the treatment comprises improving the patient's right ventricular function during the application period compared to the patient's right ventricular function prior to the application period.

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

162. The method of claim 161, wherein athletic ability is measured by a six-minute walk test (6MWT).

163. The method of claim 162, wherein improving motor function comprises increasing the distance the patient walks in 6MWT during the application 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 in 6MWT prior to the application period.

164. The method of claim 162, wherein improving motor function comprises increasing the distance the patient walks in 6MWT during the application period by about 5 meters to about 60 meters, about 5 meters to about 50 meters, about 10 meters to about 50 meters, about 15 meters to about 50 meters, or about 20 meters to about 40 meters, compared to the distance the patient walked in 6MWT before the application period.

165. The method according to any one of claims 129 to 164, wherein the treatment comprises improving the patient's quality of life during the application period compared to the patient's quality of life prior to the application period.

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

167. The method of claim 166, wherein the treatment comprises reducing the patient's CAMPHOR questionnaire score 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 during the application period compared to the patient's CAMPHOR questionnaire score prior to the application period.

168. The method of any one of claims 129 to 167, wherein the treatment comprises increasing the patient's resting peripheral capillary oxygen saturation (SpCh) as assessed by pulse oximetry during the application period compared with the patient's resting peripheral capillary oxygen saturation (SpCh) as assessed by pulse oximetry prior to the application period.

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

170. The method of claim 169, wherein improving the patient's lung function comprises increasing the patient's forced vital capacity (FVC) during the application period compared to the patient's forced vital capacity (FVC) prior to the application period.

171. The method of claim 169, wherein improving the patient's lung function comprises increasing the patient's ppFVC during the application period compared to the patient's predicted percentage of forced vital capacity (ppFVC) prior to the application period.

172. The method of claim 169, wherein improving the patient's lung function comprises increasing the patient's FEV1 during the application period compared to the patient's forced expiratory volume in one second (FEV1) prior to the application period.

173. The method of claim 172, wherein increasing the patient's forced expiratory volume in one second (FEV1) during the administration period comprises increasing the patient's FEV1 by about 5% to about 50%, about 5% to about 40%, or about 5% to about 30% compared to the patient's FEV1 before the administration period.

174. The method of claim 172, wherein increasing the FEV1 comprises increasing by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

175. The method of claim 172, wherein increasing the FEV1 comprises increasing by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.

176. The method of claim 172, wherein increasing the FEV1 comprises increasing by 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%.

177. The method of claim 172, wherein increasing the FEV1 comprises increasing it by at least about 5%.

178. The method of claim 172, wherein increasing the FEV1 comprises increasing by about 5% to about 50%, or about 10% to about 50%, or about 15% to about 50%.

179. The method of claim 172, wherein increasing the FEV1 comprises increasing from about 25 mL to about 500 mL.

180. The method of claim 172, wherein increasing the FEV1 comprises increasing from about 25 mL to about 250 mL.

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

182. The method of claim 170, wherein increasing the patient's forced vital capacity (FVC) during the application period comprises increasing 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%.

183. The method of claim 169, wherein improving the patient's lung function comprises increasing the patient's total vital capacity (TLC) during the application period compared to the patient's total vital capacity (TLC) prior to the application period.

184. The method of claim 183, wherein increasing the patient's total vital capacity (TLC) comprises increasing the patient's TLC by at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% during the application period, compared to the patient's TLC prior to the application period.

185. The method of claim 183, wherein increasing the patient's total vital capacity (TLC) comprises increasing the patient's TLC by about 1% to about 50%, 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% during the application period, compared to the patient's TLC before the application period.

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

187. The method of claim 186, wherein the application period is from about 1 year to about 25 years.

188. The method of claim 186, wherein the application period is from about 5 years to about 30 years.

189. The method of claim 186, wherein the application period is from about 1 year to about 20 years.

190. The method of claim 186, wherein the application period is from about 1 year to about 15 years.

191. The method of claim 186, wherein the application period is from about 1 year to about 10 years.

192. The method of claim 186, wherein the application period is from about 1 year to about 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 between two DPI capsules.

195. A system for treating pulmonary hypertension, the system comprising (i) a powder composition and (ii) a dry powder inhaler, The powder contains: (a) about 0.5 wt% to about 5 wt% of compound (I) or its stereoisomers or pharmaceutically acceptable salts, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl. (b) Leucine, approximately 10 wt% to approximately 61 wt%, and (c) Trehalose, mannitol, or a combination thereof, The sum of (a), (b), and (c) is 100%; and The dry powder inhaler described herein provides an aerosol containing, for example, an inspiratory flow rate of 60 liters per minute (L / min), an inspiratory volume of 4 L, and a flow rate of 0.5–20 L / sec using a next-generation impactor (NGI). 2 The fine particulate fraction (FPF) is greater than or equal to approximately 68% as measured at the inhalation acceleration rate.

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

197. The powder, method, or system according to any one of claims 1 to 196, wherein the resistance of the dry powder inhaler is in the range of about 0.030 kPa. 1 / 2 (L / min -1 ) -1 To approximately 0.040 kPa 1 / 2 (L / min -1 ) -1 .

198. The powder, method, or system according to any one of Examples 1 to 197, wherein the resistance of the dry powder inhaler is in the range of about 0.034 kPa. 1 / 2 (L / min -1 ) -1 To approximately 0.036 kPa 1 / 2 (L / min -1 ) -1 .

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