Spray dried treprostinil formulation

Abstract

The present disclosure provides aerosol properties of a powder composition administered via a dry powder inhaler, as well as spray drying processes. Also provided is a method for treating pulmonary hypertension (PH) in a patient comprising administering once daily to the lungs of a patient an effective amount of the powder composition via inhalation with the dry powder inhaler. A system for treating PH is further provided using the powder composition and the dry powder inhaler.

Description

SPRAY DRIED TREPROSTINIL FORMULATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from 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 OF THE DISCLOSURE

[0002] Pulmonary hypertension is characterized by an abnormally high blood pressure in the lung vasculature. It is a progressive, lethal disease that leads to heart failure and can occur in the pulmonary artery, pulmonary vein, or pulmonary capillaries. Symptomatic patients experience shortness of breath, dizziness, fainting, and other symptoms, all of which are made worse by exertion. There are multiple causes, and can be of unknown origin, idiopathic, and can lead to hypertension in other systems, for example, portopulmonary hypertension in which patients have both portal and pulmonary hypertension.

[0003] Pulmonary hypertension (PH) has been classified into five groups by the World Health Organization (WHO). Group 1 PH is called pulmonary arterial hypertension (PAH), and includes PAH that has no known cause (idiopathic), inherited PAH (z.e., familial PAH or FPAH), PAH that is caused by drugs or toxins, and PAH caused by conditions such as connective tissue diseases, HIV infection, liver disease, and congenital heart disease. Group 2 PH is characterized as pulmonary hypertension associated with left heart disease. Group 3 PH is characterized as PH associated with lung diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases, as well as PH associated with sleep-related breathing disorders (e.g., sleep apnea). Group 4 PH is PH due to chronic thrombotic and / or embolic disease, e.g., PH caused by blood clots in the lungs or blood clotting disorders. Group 5 PH includes PH caused by other disorders or conditions, e.g., blood disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis), and metabolic disorders (e.g., thyroid disease, glycogen storage disease).

[0004] Pulmonary arterial hypertension (PAH) afflicts approximately 200,000 people globally with approximately 30,000-40,000 of those patients in the United States. PAH patients experience constriction of pulmonary arteries which leads to high pulmonary arterial pressures, 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 activity.

[0005] The New York Heart Association (NYHA) has categorized PAH patients into four functional classes to rate the severity of the disease. Class I PAH patients as categorized by the NYHA do not have a limitation of physical activity, as ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. Class II PAH patients as categorized by the NYHA have a slight limitation on physical activity. These patients are comfortable at rest, but ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope. Class III PAH patients as categorized by the NYHA have a marked limitation of physical activity. Although comfortable at rest, class III PAH patients experience undue dyspnoea or fatigue, chest pain or near syncope as a result of less than ordinary physical activity. Class IV PAH patients as categorized by the NYHA are unable to carry out any physical activity without symptoms. Class IV PAH patients might experience dyspnoea and / or fatigue at rest, and discomfort is increased by any physical activity. Signs of right heart failure are often manifested by class IV PAH patients.

[0006] Patients with PAH are treated with an endothelin receptor antagonist (ERA), phosphodiesterase type 5 (PDE-5) inhibitor, a guanylate cyclase stimulator, a prostanoid (e.g., prostacyclin), or a combination 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®). Prostanoids indicated for the treatment of PAH include iloprost (Ventavis®), epoprosentol (Flolan®, Veletri®) and treprostinil (Remodulin®, Tyvaso®). The one approved guanylate cyclase stimulator is riociguat (Adempas®). Additionally, patients are often treated with combinations of the aforementioned compounds.

[0007] Dry powder inhalers (DPIs) may be used to administered drugs to patients via inhalation. Typically, powder formulations are prepared using a blending process to reduce aggregation and provide sufficient flowability, and thus achieve therapeutic benefit. Unfortunately, the fine particle fraction (FPF) - the amount of drug-containing particles that are small enough (< 5 pm) to enter the lungs and provide a clinical effect - is typically low, often less than 50%.

[0008] There is a need for developing powder compositions (e.g., treprostinil palmitil inhalation powder) with improved formulation properties, which are administered via a dry powder inhaler for the treatment of patients with PH and PAH.SUMMARY OF THE DISCLOSURE

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

[0010] In one aspect, the present disclosure relates to a powder composition comprising (a) from about 0.5 wt% to about 5 wt% of a compound of Formula (I):a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl; (b) from about 10 wt% to about 61 wt% of leucine, and the balance being (c) a sugar selected from the group consisting of trehalose and mannitol. The entirety 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 comprising a fine particle fraction (FPF) greater than or equal to about 68%, when measured using a Next Generation Impactor (NGI), with an inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2. The powder composition, in one embodiment, is a spray-dried powder composition.

[0011] In some embodiments, the composition includes from about 29 wt% to about 61 wt% of leucine. In even a further embodiment, the composition comprises 0.5 wt% to about 4 wt% of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0012] 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%.

[0013] In some embodiments, the aerosol comprises a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition. In some embodiments, the FPD ranging from about 53% to about 77% or from about 60% to about 65%.

[0014] In some embodiments, the aerosol comprises an emitted dose (ED) greater than or equal to 72%. In some embodiments, the ED ranges from about 79% to about 89%.

[0015] In some embodiments, the aerosol comprises a mass mean aerodynamic diameter (MMAD) less than 5 pm. In some embodiments, the MMAD ranges from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm.

[0016] In some embodiments, the powder composition comprises particles, at least a portion of the particles comprising: (i) a compound of Formula (I) or stereoisomer or a pharmaceutically acceptable salt, (ii) leucine, and (iii) trehalose, mannitol or a combination thereof, wherein the particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have aD10 of about 0.3 pm. In some embodiments, the particles have a D50 of about 1.7 pm. In some embodiments, the particles have a D90 of about 3.8 pm. The powder composition, in one embodiment, is a spray-dried powder composition.

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

[0018] In one embodiment, R1is tetradecyl. In a further embodiment, R1is linear tetradecyl.

[0019] In one embodiment, R1is pentadecyl. In a further embodiment, R1is linear pentadecyl.

[0020] In one embodiment, R1is heptadecyl. In a further embodiment, R1is linear heptadecyl.

[0021] In one embodiment, R1is octadecyl. In a further embodiment, R1is linear octadecyl.

[0022] In one embodiment, R1is hexadecyl. In a further embodiment, R1is linear hexadecyl.

[0023] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl. In even a further embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is present at from about 2 wt% toabout 4 wt% of the total weight of the powder composition. The powder composition, in one embodiment, is a spray-dried powder composition.

[0024] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0025] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 3.5 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0026] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 3 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0027] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 1.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0028] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 0.8 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0029] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 0.8 wt% to about 3.3 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0030] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is present at from about 1 wt% to about 2 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0031] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is present at from about 1 wt% to about 1.5 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0032] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is present at about 1 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0033] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is present at about 2 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0034] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is present at about 3 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0035] In one embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is present at about 4 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

[0036] In one embodiment, the leucine is present at from about 20 wt% to about 40 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl. In even a further embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0037] In another embodiment, the leucine is present at from about 29 wt% to about 61 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl. In even a further embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0038] In another embodiment, the leucine is present at from about 25 wt% to about 35 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. Ineven a further embodiment, R1is linear hexadecyl. In even a further embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0039] In another embodiment, the leucine is present at about 40 wt% to 61 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl. In even a further embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at about 45 wt% to 61 wt% of the total weight of the powder composition. In even a further embodiment, the leucine is present at about 55 wt% to 61 wt% of the total weight of the powder composition.

[0040] In another embodiment, the leucine is present at from about 28 wt% to about 33 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl. In a further embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

[0041] In another embodiment, the leucine is present at from about 25 wt% to about 33 wt% of the total weight of the powder composition, for example, at from about 27 wt% to about 33 wt%, from about 27 wt% to about 31 wt%, from about 27 wt% to about 30 wt%, from about 28 wt% to about 30 wt%, or at about 30 wt% of the total weight of the powder composition. In a further embodiment, R1is hexadecyl. In even a further embodiment, R1is linear hexadecyl.

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

[0043] In one embodiment, the sugar is mannitol. In a further embodiment, R1is hexadecyl. In a further embodiment, R1is linear hexadecyl.

[0044] In one embodiment, the powder composition includes (a) about 1 wt% of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about29.3 wt% or about 29.6 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is hexadecyl. In a further embodiment, R1is linear hexadecyl.

[0045] In one embodiment, the powder composition includes (a) about 3 wt% of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29.3 wt% or about 29.6 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is hexadecyl. In a further embodiment, R1is linear hexadecyl.

[0046] The present disclosure provides that a powder composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particle fraction (FPF) 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 the FPF that ranges from 78% to about 80%. In some embodiments, the dry powder inhaler provides the dry powder inhaler provides an aerosol comprising the FPF that ranges from 68% to about 73%. In some embodiments, the dry powder inhaler provides an aerosol comprising a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition. In some embodiments, the dry powder inhaler provides an aerosol comprising the FPD that ranges from 60% to about 65%. In some embodiments, the dry powder inhaler provides an aerosol comprising the FPF that ranges from 53% to about 65%. In some embodiments, the dry powder inhaler provides an aerosol comprising an emitted dose (ED) greater than or equal to 79%. In some embodiments, the dry powder inhaler provides an aerosol comprising the ED that ranges from about 79% to about 89%. In some embodiments, the dry powder inhaler provides an aerosol comprising a mass mean aerodynamic diameter (MMAD) less than 5 pm. In some embodiments, the dry powder inhaler provides an aerosol comprising the MMAD that ranges from about 1.0 pm to about 1.3 pm. In some embodiments, the dry powder inhaler provides an aerosol comprising the MMAD that ranges from about 1.3 pm to about 1.7 pm.

[0047] In a further embodiments, the composition comprises a dose selected from the group consisting of 80 pg, 160 pg, 240 pg, 320 pg, 400 pg, 480 pg, 560 pg, 640 pg, 675 pg, 720 pg, 800 pg, 880 pg, 960 pg, 1040 pg , 1120 pg, 1200 pg, and 1280 pg of a compound of Formula (I). In yet a further embodiment, the composition comprises a dose selected from the group consisting of 80 pg, 160 pg, 240 pg, 320 pg, 400 pg, 480 pg and 640 pg of a compound of Formula (I). The dose can be present, e.g., in one dry powder capsule, or multiple capsules.

[0048] In another aspect of the disclosure, a method for treating pulmonary hypertension (PH) in a patient in need thereof is provided. The method includes administering an effective amount of the powder composition disclosed herein to the lungs of the patient by inhalation via a dry powder inhaler. In embodiments, the effective amount comprises 80 pg-1280 pg of a compound of Formula (I). In embodiments, the effective amount comprises 80 pg, 160 pg, 240 pg, 320 pg, 400 pg, 480 pg, 640 pg, 675 pg, 720 pg, 800 pg, 880 pg, 960 pg, 1040 pg , 1120 pg, 1200 pg, of 1280 pg of a compound of Formula (I).

[0049] In one embodiment, the PH is group 1 PH, as characterized by the World Health Organization (WHO).

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

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

[0052] In one embodiment of the treatment methods described herein, the administering is conducted in a once-a-day or twice-a-day.

[0053] In still another aspect, the present 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 single dose or a multidose inhaler. In another embodiment, the DPI is pre-metered or device-metered.

[0054] In some embodiments, the powder composition described herein and used in the methods described herein comprises from about 1 wt% to about 5 wt% of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with the balance being one or more pharmaceutically acceptable excipients which are suitable for use in a dry powder inhaler.BRIEF DESCRIPTION OF THE FIGURES

[0055] FIG. 1 is a schematic diagram showing system setup with breath simulator and Next Generation Impactor (NGI) before simulation started.

[0056] FIG. 2A is a graph showing various simulated inhalation profiles at different acceleration rates with a target inspiratory flow rate of 60 LPM (1030 mL / s) and total inhalation volume of 4 Liters. FIG. 2B is a graph showing various simulated inhalation profiles at two acceleration rates (50 ms vs 2000 ms) with a target inspiratory flow rate of 60 LPM (1030 mL / s) and total inhalation volume of IL, 2L, or 4L. FIG. 2C is a graph showing various simulated inhalation profiles at two acceleration rates (25 ms vs 1000 ms) with a target inspiratory flow rate of 30 LPM (510 mL / s) and total inhalation volume of IL, 2L, or 4L.

[0057] FIGs. 3A-3B are graphs showing TP aerosol deposition profiles in the NGI as a function of acceleration rate. The profiles show the percentage of TP recovered (mean ± SD) from each component of the NGI at each inhalation acceleration rate to reach the 60 LPM peak inspiratory flow rate with a 4 L inhalation volume. FIG. 3A: 16 mg TPIP capsules. FIG. 3B:32 mg TPIP capsules. Acceleration rates are 20 L / s2(blue), 5.88 L / s2(orange), 2 L / s2(gray), 1 L / s2(yellow), and 0.5 L / s2(light blue).

[0058] FIG. 4 is a graph showing TP fine particle dose (FPD) as a function of inhalation acceleration rate to reach the 60 LPM peak inspiratory flow rate for a 4 L inhalation volume. The dotted lines show the change in FPD values for the 16 mg TPIP (blue) and 32 mg TPIP (orange) capsule as the acceleration rate increases from 0.5 L / sec2(2000 ms ramp) to 20 L / sec2(50 ms ramp). *p-value > 0.05 overall inhalation acceleration rate comparison for the 16 mg TPIP capsule, #p-value < 0.05 overall inhalation acceleration rate comparison for the 32 mg capsule associated with data from Tables 1 and 2.

[0059] FIGs. 5A-5C are graphs showing TP aerosol deposition profiles in the NGI as a function of inhaled volume. The profiles show the percentage of TP recovered (mean ± SD) from each component of the NGI for each inhalation volume with 20 and 0.5 L / s2acceleration rates to reach the 60 and 30 LPM peak inspiratory flow rates. FIG 5A: 16 mg TPIP capsules at a 50 ms ramp time for the 1 L (blue), 2 L (orange), and 4 L (gray) volumes, and 2000 ms ramp time for the 1 L (yellow), 2 L (light blue), and 4 L (green) volumes to reach the 60 LPM peak flow rate. FIG 5B:32 mg TPIP capsules at a 50 ms ramp time for the 1 L (blue), 2 L (orange), and 4 L (gray) volumes, and 2000 ms ramp time for the 1 L (yellow), 2 L (light blue), and 4 L (green) volumes to reach the 60 LPM peak flow rate. FIG 5C: 16 mg TPIP capsules at a 25 msramp time for the 1 L (blue), 2 L (orange), and 4 L (gray) volumes, and 1000 ms ramp time for the 1 L (yellow), 2 L (light blue), and 4 L (green) volumes to reach the 30 LPM peak flow rate.

[0060] FIGs. 6A-6C are graphs showing TP fine particle dose (FPD) trend lines as a function of the total inhalation volume. The dotted lines show the change in FPD values as inhalation volume increases for the 20 L / s2(blue) and 0.5 L / s2(orange) acceleration rates at the 30 and 60 LPM peak inspiratory flow rates. FIG. 6A: 16 mg TPIP capsules at the 60 LPM flow rate. FIG. 6B:32 mg TPIP capsules at the 60 LPM flow rate. FIG. 6C: 16 mg TPIP capsules at the 30 LPM flow rate. *p-value > 0.05 for the 1 and 2 L inhalation volumes compared to the 4 L inhalation volume, #p-value < 0.05 for the 1 L inhalation volume compared to the 4 L inhalation volume, fp-value > 0.05 for the overall comparison of inhalation volumes for the 20 L / s2acceleration rate (16 mg and 32 mg) and 0.5 L / s2acceleration rate (16 mg), and ¥p-value <0.05 overall comparison of inhalation volume for the 0.5 L / s2acceleration rate (32 mg) associated with data from Tables 3 and 4.

[0061] FIGs. 7A-7C are graphs showing TP aerosol particle size distribution profiles from the Next Generation Impactor (NGI). The profiles show the recovery of TP (mean ± SD) from each stage of the NGI with respect to its stage cut-off diameter for the ultra-high resistance (UHR, blue), high resistance (HR, orange), medium resistance (MR, gray) and low resistance (LR, yellow) devices. FIG. 7A: 8 mg TPIP capsules. FIG. 7B: 16 mg TPIP capsules. FIG. 7C: 32 mg TPIP capsules.

[0062] FIGs. 8A-8C are graphs showing TP Fine Particle Fraction (FPF) (FIG. 8A); Fine Particle Dose (FPD) as a Function of Device Resistance for the 8 mg (blue), 16 mg (orange), and 32 mg (gray) Capsule Dose (FIG. 8B); and TP FPD as a Function of Capsule Dose for Each Device (FIG. 8C). Trend lines are only shown for the UHR and HR DPIs in FIG. 8C. The ultra-high resistance (UHR), the high resistance (HR), the medium resistance (MR) and the low resistance (LR) devices were tested at 40, 60, 85 and 100 LPM, respectively.

[0063] FIGs. 9A-9C are graphs showing TP aerosol particle size distribution profiles from the Next Generation Impactor (NGI). The profiles show the recovery of TP (mean ± SD) from each stage of the NGI with respect to its stage cut-off diameter for high resistance (HR) device operated at 40 LPM (blue), 60 LPM (orange), and 80 LPM (gray). FIG. 9A: 8 mg TPIP capsules. FIG. 9B: 16 mg TPIP capsules. FIG. 9C: 32 mg TPIP capsules.DETAILED DESCRIPTION OF THE DISCLOSUREDefinitions

[0064] Throughout the present disclosure, the term “about” may be used in conjunction with numerical values and / or ranges. The term “about” is understood to mean those values near to a recited value. For example, “about 40 [units]” may mean within ± 25% of 40 (e.g., from 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 therein or there below.

[0065] The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Exemplary pharmaceutical salts are disclosed in Stahl, P.H., Wermuth, C.G., Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use Verlag Helvetica Chimica Acta / Wiley-VCH: Zurich, 2002, the contents of which are hereby incorporated by reference in their entirety. Specific non-limiting examples of inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, / ?-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hydroxy ethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3 -hydroxybutyric, galactaric or galacturonic acid. Suitable pharmaceutically acceptable salts of free acidcontaining compounds disclosed herein include, without limitation, metallic salts and organic salts. Exemplary metallic salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other physiological 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, for example, tromethamine, diethylamine, tetra-A- methylammonium, A,A’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (A-methylglucamine) and procaine.

[0066] The term “stereoisomer” as used herein refers to two molecules having the same molecular formula and sequence of bonded atoms, but differ in three-dimensional orientations of their atoms in space. One preferred stereoisomer according to the present disclosure is a diastereomer. The stereoisomer, in one embodiment, is a diastereomer of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the stereoisomer is a diastereomer of a compound of Formula (I). In 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).

[0067] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “50-80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60- 70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[0068] Throughout the present specification, numerical ranges are described as encompassing “about 80% to about 125%” or “about 80-125%” of a range of values. It is to be understood that these comprise 80% of the lowest endpoint of the range up to 125% of the highest endpoint of the range, and all values therein.

[0069] The term Cmax means the maximum (or peak) treprostiml serum concentration measured after a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the lungs of a subject via a powder composition described herein. In addition, Cmax may be measured after a single administration of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, described herein, or treprostinil Cmax may be measured at steady state. Unless stated otherwise, Cmax refers to the average treprostinil Cmax measured after a single administration among a population of subjects (e.g., a population of PH patients).

[0070] The term “AUC” means the area under the plasma concentration time curve for treprostinil, measured from time 0 to a certain time post-administration to the lungs of a subject, calculated by a combination of linear and logarithmic trapezoidal methods (Linear up / log down method). In some embodiments, AUC may be measured from time 0 to 24 hours post-administration (“AUC0-24”) or AUC may be measured form from time 0 to extrapolated to infinity (“AUCo-inf”). In addition, treprostinil AUC may be measured after a single administration or at steady state values. Unless stated otherwise, AUC refers to the average AUC measured after a single administration among a population of subjects (e.g., a population of PH patients).

[0071] The term “plasma trough concentration” refers to the treprostinil plasma concentration before administering a subsequent dose of the compounds of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. For example, treprostinil plasma trough concentration may be measured within 2 hours, 1 hour, or 30 minutes of administering a subsequent dose. Plasma trough concentrations may be measured after a single administration or may be measured at steady state. Unless stated otherwise, plasma trough levels refer to the average treprostinil trough level measured among a population of subjects (e.g., a population of PH patients).

[0072] The term “adult” refers to a human subject, e.g., a human patient that is at least 18 years of age or older. In some embodiments, the adult is 18-100 years of age, e.g., 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, 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.

[0073] The term “cascade impaction” refers to a method of measuring performance properties of a dry powder inhaler. Next Generation Impactor (NGI) is used for cascade impaction measurements discussed herein. In some embodiments, the NGI has an inspiratory (also referred to interchangeably as gas) flow rate of 30-60 (e.g., 30, 40, 50, or 60) liter 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 / sec2. In a specific embodiments, the NGI has an inspiratory flow of 60 L / min, an inspiratory volume of 4L, and inhalation accelerate rate of 0.5-20 L / sec2. In embodiments, the inspiratory flow rate corresponds to a 4 kPa air pressure drop for the dry powder inhaler.

[0074] Any reference herein to a compound of Formula I includes a pharmaceutically acceptable salt thereof.

[0075] The term “geometric standard deviation” or “GSD” is a measure of the spread of an aerodynamic particle size distribution.

[0076] Dry powder inhalers (DPIs) are devices that can be used to deliver drugs to the respiratory tract. Upon inhalation, the drugs are transported to the lungs. In order to inhale the drugs via the DPIs, compacted drug powder must be broken up through a process called deagglomeration.

[0077] The composition described herein is referred to as a “powder.” Such powders administered using a DPI are commonly referred to as a dry powder. Thus, all references to a powder, a powder composition, or a powder formulation used herein encompass a dry powder, a dry powder composition or a dry powder formulation.

[0078] Powders used in DPIs are typically formulated by blending the active agent and excipients to prevent aggregation. That is, DPIs typically use a micronized drug blended with carrier particles such as lactose that avoid aggregation and provide sufficient flowability. To enhance the aerosolization of the drug particles, fine lactose particles are often added to the carrier lactose to saturate high-energy binding sites on the carrier lactose and form easily detachable aggregates with the drug particles.

[0079] When the powder is emitted from the inhaler, the drug particles are detached from the carrier particles and delivered into the lungs, while the larger carrier particles end up in the upper respiratory tract. In the present disclosure, it was surprisingly discovered that spray drying treprostinil palmitil (e.g., a compound of Formula (I) and (II)) with certain excipients produces free flowing drug particles of appropriate size and particle size distribution such that more drug particles are delivered into the lungs, resulting in improved therapeutic effects (e.g., higher FPF) compared to blended formulations. More specifically, the FPF of blended formulations were typically less than 45% (for example, about 11% to about 43%), while the spray dried powder compositions of the present disclosure have FPF of greater than or equal to about 68%, measured with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0080] Treprostinil palmitil inhalation powder (TPIP) provided herein is generated by a spray drying process with mannitol and leucine as excipients and is administered via a dry powder inhaler (DPI), such as a high resistance (HR) DPI, e.g., RS01 Berry Global (formerly Plastiape) device. TPIP, in one embodiment, is administered to a patient in need of treatment of pulmonary arterial hypertension (PAH) or pulmonary hypertension due to interstitial lung disease (PH-ILD).

[0081] In one aspect of the present disclosure, a powder composition of a treprostinil prodrug is provided. The powder composition comprises:(a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, present at from about 0.5 wt% to about 5 wt% of the total weight of the powder composition:wherein R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl;(b) from about 10 wt% to about 61 wt% of leucine, and the balance being(c) a sugar selected from the group consisting of trehalose and mannitol. The entirety of (a), (b), and (c) is 100 wt%. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 comprising a fine particle fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about about 78% to about 80%), (ii) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (iii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iv) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0082] In a further embodiment, the powder composition comprises from about 25 wt% to about 61 wt% of leucine. In even a further embodiment, the powder composition comprises from about 25 wt% to about 45 wt% of leucine. In another embodiment, the powder composition comprises from about 45 wt% to about 61 wt% of leucine.

[0083] In some embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is present at about 0.4 wt% about 0.5 wt%, about 1 wt%, abot 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. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0084] The compound of Formula (I) and pharmaceutically acceptable salts thereof are treprostinil 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, the leucine is present at about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 58 wt%, or about 60 wt% of the total weight of the powder composition. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle fraction (FPF) greater than or equal toabout 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about 78% to about 80%), and one or more of (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0085] In some embodiments, the leucine is present at from 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%, from about 27 wt% to about 30 wt%, or from about 28 wt% to about 30 wt% of the total weight of the powder composition. In some embodiments, the leucine is present at from 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.

[0086] In one embodiment of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is tetradecyl. In a further embodiment, R1is linear tetradecyl.

[0087] In another embodiment of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is pentadecyl. In a further embodiment, R1is linear pentadecyl.

[0088] In another embodiment of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is heptadecyl. In a further embodiment, R1is linear heptadecyl.

[0089] In another embodiment of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is octadecyl. In a further embodiment, R1is linear octadecyl.

[0090] In another embodiment of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1is hexadecyl. In a further embodiment, R1is linear hexadecyl, i.e., the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is a compound of Formula (II):a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound of Formula (I) is a compound of Formula (II). The compound of Formula (I) where R1is linear hexadecyl is also referred to herein as C16TR or its international nonproprietary name, treprostinil palmitil. In the present application, C16TR and treprostinil palmitil are used interchangeably. Similarly, a compound of Formula (II) is equivalent to a compound of Formula (I), wherein R1is linear hexadecyl.

[0091] In a preferred embodiment of the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the compound of Formula (I) is treprostinil palmitil (i.e., R1is linear hexadecyl). In a further embodiment, the treprostinil palmitil is in a crystalline form. Crystalline forms of treprostinil palmitil are described in U.S. Patent No. 10,781,160, which is incorporated herein by reference in its entirety.

[0092] In one embodiment, the treprostinil palmitil is a crystal Form I having an X-ray powder diffraction (XRPD) pattern exhibiting peaks at two, three, four, five or all of the following 29 reflection angles: 3.3±0.2°, 6.6±0.2°, 14.2±0.2°, 18.9±0.2°, 21.3±0.2°, and 22.5±0.2°. In another embodiment, the XRPD pattern of treprostinil palmitil crystal Form I further comprises peaks at one, two, three, four, five, six, seven, eight or all of the following 29 reflection angles: 13.8±0.2°, 15.3±0.2°, 16.9±0.2°, 17.8±0.2°, 19.8±0.2°, 29.6±9.2°, 29.9±9.29, 24.4±9.2°, and 24.8±9.2°. In one embodiment, the treprostinil palmitil is a crystal Form I having an XRPD pattern exhibiting peaks at the 29 reflection angles provided in Table A.

[0093] In one embodiment, the treprostinil palmitii crystal Form I has a differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 52.2±1° C. and a peak maximum of approximately 54.5±1° C.

[0094] In another embodiment, the treprostinil palmitii is a crystal Form II having an XRPD pattern exhibiting peaks at two, three, four, five or all of the following 29 reflection angles: 3.4±0.2°, 6.1±0.2°, 9.4±0.2°, 20.3±0.2°, 21.6±0.2°, and 23.4±0.2°. In another embodiment, the XRPD pattern of treprostinil palmitii crystal Form II further comprises peaks at one, two, three, four, five, six, seven, eight or all the following 29 reflection angles: 7.0±0.2°, 9.0±0.2°, 12.2±0.2°, 12.7±0.2°, 17.5±9.2°, 18.0±0.2°, 18.5±9.2°, 19.1±0.2°, and 19.4±9.2°. In one embodiment, the treprostinil palmitii is a crystal Form II having an XRPD pattern exhibiting peaks at the 29 reflection angles provided in Table B.

[0095] In one embodiment the treprostinil palmitil crystal Form II has a DSC thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 54.6±1° C. and a peak maximum of approximately 56.9±1° C.

[0096] In one embodiment, (a) is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, (a) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In a further embodiment, (a) is a compound of Formula (II).

[0097] In one embodiment, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present at from 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 from 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 from about 1 wt% to about 4 wt% of the total weight of the powder composition.

[0098] In one embodiment, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present at from 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 from about 1 wt% to about 3 wt% of the total weight of the powder composition.

[0099] In one embodiment, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 5 wt%, from about 1 wt% to about 4.5 wt%, from about 1 wt% to about 4 wt%, at about 2 wt%, at about 3 wt%, at about 4 wt%, or at 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 from about 1 wt% to about 5 wt%, from about 1 wt% to about 4.5 wt%, from about 1 wt% to about 4 wt%, from about 1 wt% to about 2 wt%, about 2 wt%, or about 4 wt%, of the total weight of the powder composition.

[0100] In one embodiment, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof is present at from about 0.8 wt% to about 3.3 wt%, or from about 1 wt% to about 3 wt%, or from about 1 wt% to about 2 wt%, or from about 1 wt% to about 1.5% of the total weight of the powder composition.

[0101] 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.

[0102] In one embodiment, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present from about 0.8 wt% to about 1.5 wt% of the total weight of the powder composition. In another embodiment, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof is present from about 2.7 wt% to about 4 wt% of the total weight of the powder composition. In one embodiment, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof is present from about 2.7 wt% to about 3.5 wt%, for example, from about 2.8 wt% to about 3.2 wt%, or from about 2.9 wt% to about 3.1 wt% of the total weight of the powder composition.

[0103] In one embodiment, the leucine is present at from about 25 wt% to about 61 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 25 wt% to about 50 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 25 wt% to about 40 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 20 wt% to about 33 wt%, e.g., about 20 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, or about 33 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 25 wt% to about 33 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 27 wt% to about 33 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 27 wt% to about 31 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 27 wt% to about 30 wt% of the total weight of the powder composition. In a further embodiment, the leucine is present at from about 28 wt% to about 30 wt% of the total weight of the powder composition.

[0104] In another embodiment, the leucine is present at about 30 wt% of the total weight of the powder composition.

[0105] In yet another embodiment, the leucine is present at from about 45 wt% to about 61 wt% of the total weight of the powder composition, for example at from about 45 wt% to about 55 wt%, or from about 50 wt% to about 55 wt%. In a further embodiment, the compoundof 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 a further embodiment, R1is hexadecyl, e.g., linear hexadecyl.

[0106] In some embodiments, the sugar in the powder composition is trehalose. In another embodiment, the sugar in the powder composition is mannitol.

[0107] In one embodiment, the composition has the weight percentages set forth in Table C, below. In another embodiment, the composition has the weight percentages set forth in Table C, below, ± 5% for each component. In yet another embodiment, the composition has a leucine-to-mannitol weight ratio (“leucine : mannitol” or “leucine-to-mannitol”) set forth in Table C.

[0108] In one embodiment, the powder composition has the components and weight percentages set forth in Table D.

[0109] The leucine-to-sugar (i.e., mannitol or trehalose) weight ratio in a composition provided herein, in one embodiment, is from about 0.4-to-l (leucine-to-mannitol or -trehalose) to about 1.7-to-l (leucine-to-mannitol -trehalose). In a further embodiment, the composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, the leucine-to-sugar weight ratio is from about 0.4: 1 (leucine-to-mannitol or - trehalose) to 0.9: 1 (leucine-to-mannitol or -trehalose). In even a further embodiment, the leucine-to-sugar weight ratio is from about 0.4: 1 (leucine-to-mannitol or -trehalose) to 0.5: 1 (leucine-to-mannitol or -trehalose). In a further embodiment, the sugar is mannitol. The leucine, in one embodiment, is L-leucine.

[0110] In another embodiment, the sugar is mannitol and the leucine-to-mannitol weight ratio is from about 0.75-to-l (leucine-to-mannitol) to 0.9-to-l (leucine-to-mannitol). In a further embodiment, the composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, the leucine-to-mannitol weight ratio is from about 0.8: 1 (leucine-to-mannitol) to 0.9: 1 (leucine-to-mannitol). In another embodiment, the sugar is trehalose and the leucine-to-trehalose weight ratio is from about 0.75:1 (leucine-to-trehalose) to 0.9: 1 (leucine-to-trehalose). In a further embodiment, the composition comprises a compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, at from about 1 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, the leucine-to- trehalose weight ratio is from about 0.8: 1 (leucine-to- trehalose) to 0.9: 1 (leucine-to-trehalose). The leucine, in one embodiment, is L-leucine.

[0111] In yet another embodiment, the sugar is mannitol and the leucine-to-mannitol weight ratio is from about 1.5: 1 (leucine-to-mannitol) to 1.7: 1 (leucine-to-mannitol). In a further embodiment, the composition comprises a compound of Formula (I), (II), or apharmaceutically acceptable salt thereof, at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, the leucine-to-mannitol weight ratio is from about 1.6: 1 (leucine-to-mannitol) to 1.7: 1 (leucine-to-mannitol). In yet another embodiment, the sugar is trehalose and the leucine-to-trehalose weight ratio is from about 1.5: 1 (leucine-to-trehalose) to 1.7: 1 (leucine-to-trehalose). In a further embodiment, the composition comprises a compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition. In a further embodiment, the composition comprises a compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, at from about 0.5 wt% to about 3 wt% of the total weight of the powder composition. In a further embodiment, the composition comprises a compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, at from about 0.5 wt% to about 2 wt% of the total weight of the powder composition. In a further embodiment, the composition comprises a compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, at from about 0.5 wt% to about 1.5 wt% of the total weight of the powder composition. In a further embodiment, the leucine-to-mannitol weight ratio is from about 1.6: 1 (leucine-to-trehalose) to 1.7:1 (leucine-to-trehalose).

[0112] In another embodiment, the powder composition includes (a) about 1-2 wt% of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, (a) in the powder composition is about 1 wt% of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0113] In another embodiment, (a) in the powder composition is at about 1 wt% to about 1.5 wt% of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. In another embodiment, (a) in the powder composition is at about 2 wt% to about 4 wt% of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. In another embodiment, (a) in the powder composition is at about 3 wt% to about 4 wt% of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. In another embodiment, (a) in the powder composition is at about 2 wt% of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0114] In another embodiment, the powder composition includes (a) about 1 wt% of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29.6 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is linear hexadecyl in the compound of Formula (I).

[0115] In another embodiment, the powder composition includes (a) about 1.5 wt% of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, (b) about 29.6 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is linear hexadecyl in the compound of Formula (I).

[0116] In another embodiment, the powder composition includes (a) about 1 wt% of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% to about 30 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is linear hexadecyl in the compound of Formula (I).

[0117] In another embodiment, the powder composition includes (a) about 1.5 wt% of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% to about 30 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is linear hexadecyl in the compound of Formula (I).

[0118] In another embodiment, the powder composition includes (a) about 2 wt% of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% to about 30 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is linear hexadecyl in the compound of Formula (I).

[0119] In another embodiment, the powder composition includes (a) about 3 wt% of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% to about 30 wt% of the leucine, and the balance being (c) mannitol. In a further embodiment, R1is linear hexadecyl in the compound of Formula (I).

[0120] In another embodiment, the powder composition includes (a) about 4 wt% of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% to about 30 wt% of leucine, and the balance being (c) mannitol. In a further embodiment, R1is linear hexadecyl in the compound of Formula (I).

[0121] In one embodiment, the powder composition includes (a) about 0.5 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol. In one embodiment, the powder composition includes (a) about 1 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol. In another embodiment, the powder composition includes (a) about 1.5 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol. In one embodiment, the powder composition includes (a)about 2 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol. In one embodiment, the powder composition includes (a) about 3 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol. In one embodiment, the powder composition includes (a) about 4 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol.

[0122] In another embodiment, the powder composition includes (a) about 0.5 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol. In another embodiment, the powder composition includes (a) about 1 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol. In another embodiment, the powder composition includes (a) about 1.5 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol. In another embodiment, the powder composition includes (a) about 2 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol. In another embodiment, the powder composition includes (a) about 3 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol. In another embodiment, the powder composition includes (a) about 4 wt% of the compound of Formula (I) or (II), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol.

[0123] In some embodiments, the powder composition does not include distearoyl phosphoethanoamine-polyethylene glycol 2000 (DPSE-PEG2000).

[0124] In one embodiment, the powder composition comprises from about 80 pg to about 700 pg of a compound of Formula (I) or (II), for example, about 80 pg, about 100 pg, about 110 pg, about 112.5 pg, about 120 pg, about 130 pg, about 140 pg, about 150 pg, about 160 pg, about 170 pg, about 180 pg, about 190 pg, about 200 pg, about 210 pg, about 220 pg, about 225 pg, about 230 pg, about 240 pg, about 250 pg, about 260 pg, about 270 pg, about 280 pg, about 290 pg, about 300 pg, about 310 pg, about 320 pg, about 330 pg, about 340 pg, about 350 pg, about 360 pg, about 370 pg, about 380 pg, about 390 pg, about 400 pg, about 410 pg, about 420 pg, about 430 pg, about 440 pg, about 450 pg, about 460 pg, about 470 pg,about 480 pg, about 490 pg, about 500 pg, about 510 pg, about 520 pg, about 530 pg, about 540 pg, about 550 pg, about 560 pg, about 570 pg, about 580 pg, about 590 pg, about 600 pg, about 610 pg, about 620 pg, about 630 pg, about 640 pg, about 650 pg, about 660 pg, about 670 pg, about 675 pg, about 680 pg, about 690 pg, or about 700 pg of a compound of Formula (I), (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, including all values and ranges therein. In one embodiment, the powder composition comprises from about 80 pg to about 1280 pg of a compound of Formula (I) or (II), for example, about 80 pg, about 100 pg, about 110 pg, about 112.5 pg, about 120 pg, about 130 pg, about 140 pg, about 150 pg, about 160 pg, about 170 pg, about 180 pg, about 190 pg, about 200 pg, about 210 pg, about 220 pg, about 225 pg, about 230 pg, about 240 pg, about 250 pg, about 260 pg, about 270 pg, about 280 pg, about 290 pg, about 300 pg, about 310 pg, about 320 pg, about 330 pg, about 340 pg, about 350 pg, about 360 pg, about 370 pg, about 380 pg, about 390 pg, about 400 pg, about 410 pg, about 420 pg, about 430 pg, about 440 pg, about 450 pg, about 460 pg, about 470 pg, about 480 pg, about 490 pg, about 500 pg, about 510 pg, about 520 pg, about 530 pg, about 540 pg, about 550 pg, about 560 pg, about 570 pg, about 580 pg, about 590 pg, about 600 pg, about 610 pg, about 620 pg, about 630 pg, about 640 pg, about 650 pg, about 660 pg, about 670 pg, about 675 pg, about 680 pg, about 690 pg, about 700 pg, about 720 pg, about 740 pg, about 760 pg, about 780 pg, about 800 pg, about 820 pg, about 840 pg, about 860 pg, about, about 880 pg, about 900 pg, about 920 pg, about 940 pg, about 960 pg, about 980 pg, about 1000 pg, about 1020 pg, about 1040 pg, about 1060 pg, about 1080 pg, about 1100 pg, about 1120 pg, about 1140 pg, about 1160 pg, about 1180 pg, about 1200 pg, about 1240 pg, about 1260 pg, or about 1280 pg of a compound of Formula (I), (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, including all values and ranges therein. In one embodiment, the powder composition comprises from about 80 pg to about 700 pg of a compound of Formula (I) or (II). In one embodiment, the powder composition comprises from about 80 pg to about 1280 pg of a compound of Formula (I) or (II). In one embodiment, the powder composition comprises from about 80 pg to about 640 pg of a compound of Formula (I) or (II). In one embodiment, the powder composition comprises from about 80 pg to about 320 pg of a compound of Formula (I) or (II). In one embodiment, the composition comprises about 80 pg, about 160 pg, about 240 pg, about 320 pg, about 400 pg, about 480 pg or about 640 pg of a compound of Formula (I) or (II). In one embodiment, the composition comprises about 80 pg, about 160 pg, about 240 pg, about 320 pg, about 400 pg, about 480 pg, 560 pg, 640 pg, 675 pg, 720 pg, 800 pg, 880 pg, 960 pg, 1040 pg , 1120 pg, 1200 pg, and 1280 pg of a compound of Formula (I) or (II). The composition may be present, in one embodiment, inone powder capsule or a plurality (two or more) powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of Formula (I) or (II) is divided amongst the capsules. The capsule, in one embodiment, is a size #3 HPMC capsule.

[0125] Embodiments of a TPIP composition at different unit strengths are provided in Table E, below. It should be understood that the unit strengths of the components provided herein can be calculated based on the weight percentages of the component and the desired dosage. For example, for an 80 pg dose of TP, each component is multiplied by 80 to obtain the unit strength of each component.

[0126] In one embodiment, the powder composition comprises about 80 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 comprisinga fine particle fraction (FPF) greater than or equal to about 68% (e.g., about 68% to about 80%, about 68% to about 73%, or about about 78% to about 80%), (ii) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (iii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iv) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0127] In one embodiment, the powder composition comprises about 160 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0128] In another embodiment, the powder composition comprises about 240 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-driedpowder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0129] In one embodiment, the powder composition comprises about 320 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0130] In another embodiment, the powder composition comprises about 400 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0131] In another embodiment, the powder composition comprises about 480 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater thanor equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 gm (e.g., from about 0.75 gm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0132] In one embodiment, the powder composition comprises about 640 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 gm. In some embodiments, the particles have a D10 of about 0.3 gm, a D50 of about 1.7 gm, and / or a D90 of about 3.8 gm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 gm (e.g., from about 0.75 gm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0133] In one embodiment, the powder composition comprises about 720 gg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 gm, a D50 of about 1.7 gm, and / or a D90 of about 3.8 gm. In some embodiments, when the spray-dried powder composition is administered via a dry powderinhaler, the dry powder inhaler provides an aerosol comprising a fine particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0134] In one embodiment, the powder composition comprises about 800 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0135] In one embodiment, the powder composition comprises about 880 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in oneembodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0136] In one embodiment, the powder composition comprises about 960 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratoryflow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0137] In one embodiment, the powder composition comprises about 1040 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0138] In one embodiment, the powder composition comprises about 1120 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than orequal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0139] In one embodiment, the powder composition comprises about 1200 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0140] In one embodiment, the powder composition comprises about 1280 pg of the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl. In even a further embodiment of a compound of Formula (I), R1is linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles havea DIO of about 0.3 m, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0141] In a preferred embodiment of the powder composition provided herein, the leucine is L-leucine. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0142] In another aspect, the present disclosure provides a powder composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, which provides a particular pharmacokinetic profile following once daily administration.Advantageously, pharmacokinetic profile has a lower Cmax and longer half-life compared to the current treprostinil inhaled solution, Tyvaso®.

[0143] In one embodiment, the powder composition exhibiting one of the pharmacokinetic profiles described herein is a composition described in U.S. Patent Application Publication No. 2020 / 0338005 and WO 2022 / 094100, incorporated by reference herein in their entirety for all purposes.

[0144] In another embodiment, the powder composition exhibiting one of the pharmacokinetic profiles described herein comprises (a) a compound of Formula (I) or (II) at from about 1 wt% to about 5 wt% of the total weight of the powder composition; (b) from about 25 wt% to about 61 wt% of leucine, and the balance being (c) a sugar selected from trehalose and mannitol. The entirety of (a), (b), and (c) is 100 wt%. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0145] Example 5 of WO 2022 / 094100 presents that the pharmacokinetic (PK) profile measured for the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, was linear over the dose range of 112.5 pg to 675 pg. Based on this data, the skilled artisan can determine the pharmacokinetic parameters of doses outside of the range, or doses inside this range that were not specifically tested in the Example 5 of WO 2022 / 094100. For example, in order to find a pharmacokinetic parameter at a dose, Cmax and AUC associated with specific doses (112.5 pg, 225 pg, 450 pg, and / or 675 pg) may be plotted.The scatter plot may be fit to a straight line, y= mx + b, where m is the slope of the line, b is the y intercept, and the value of an unknown pharmacokinetic parameter (y) may be calculated by plugging in the dose for x. In addition, the dose range of 112.5 pg to 675 pg was based on the molecular weight of the compound of Formula (I) when R1is hexadecyl (i.e., the compound of Formula (II)). Equivalent doses for other treprostinil prodrugs (when R1is tetradecyl, pentadecyl, heptadecyl, or octadecyl) can be calculated using the molecular weight of the treprostinil prodrug of interest. For example, the dose of the compound of Formula (I) when R1is tetradecyl that is equivalent to 112.5 pg of the compound of Formula II (R1is hexadecyl) can be calculated by multiplying 112.5 pg by the ratio of the molecular weight of the compound of Formula (II) (614.95 pg / mol) to the molecular weight of the compound of Formula (I) when R1is tetradecyl (586.9 pg / mol).

[0146] In embodiments, the powder composition of the disclosure is formulated to administer once daily to the lungs of a subject by inhalation a dose ranging from about 80 pg to about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and provide at least one of the following characteristics:(a) a treprostinil maximum plasma concentration (Cmax) ranging from about 14 pg / mL to about 3000 pg / mL; or(b) a treprostinil area under the plasma concentration curve (AUC) ranging from about from about 500 pg*h / mL to about 20000 pg*h / mL.

[0147] In a further embodiment, the powder composition comprises about 80 pg, about 112.5 pg, about 160 pg, about 225 pg, about 240 pg, about 320 pg, about 400 pg, about 450 pg, about 480 pg, about 640 pg, about 675 pg, about 720 pg, about 800 pg, about 960 pg, about 1040 pg, about 1120 pg, about 1200 pg, or about 1280 pg of a compound of Formula (I). In a further embodiment, R1is hexadecyl, e.g., linear hexadecyl. The powder composition may be present, in one embodiment, in one powder capsule or a plurality (two or more) powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of Formula (I) is divided amongst the capsules. This multiple capsules may be used to administer a composition comprising one of the aforementioned doses (e.g., about 480 pg, about 560 pg, about 640 pg, about 675 pg, about 720 pg, about 800 pg, about 960 pg, about 1040 pg, about 1120 pg, about 1200 pg, or about 1280 pg). The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an averagediameter ranging from about 1.0 gm to about 2.0 gm. In some embodiments, the particles have a DIO of about 0.3 gm, a D50 of about 1.7 gm, and / or a D90 of about 3.8 gm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0148] In embodiments, the powder composition of the disclosure is formulated to administer once daily to the lungs of a subject by inhalation a dose ranging from about 80 gg to about 675 gg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and provide at least one of the following characteristics:(a) a treprostinil maximum plasma concentration (Cmax) ranging from about 14 pg / mL to about 1430 pg / mL; or(b) a treprostinil area under the plasma concentration curve (AUC) ranging from about from about 500 pg*h / mL to about 10000 pg*h / mL.

[0149] In a further embodiment, the powder composition comprises about 80 gg, about 112.5 gg, about 160 gg, about 225 gg, about 240 gg, about 320 gg, about 400 gg, about 450 gg, about 480 gg, about 640 gg, or about 675 gg of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In a further embodiment, the composition comprises about 80 gg, about 160 gg, about 240 gg, about 320 gg, about 400 gg, about 480 gg, or about 640 gg of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In a further embodiment of a compound of Formula (I), R1is hexadecyl, e.g., linear hexadecyl. The powder composition may be present, in one embodiment, in one powder capsule or a plurality (two or more) powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of Formula (I) or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is divided amongstthe capsules. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0150] In embodiments, the powder composition of the disclosure is formulated to administer once daily to the lungs of the subject (e.g., patient) by inhalation a dose ranging from about 80 pg to about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and provide at least one of the following characteristics:(a) a treprostinil maximum plasma concentration (Cmax) ranging from about 14 pg / mL to about 3000 pg / mL; or(b) a treprostinil area under the plasma concentration curve (AUC) ranging from about from about 380 pg*h / mL to about 20000 pg*h / mL.

[0151] In a further embodiment, the powder composition comprises about 80 pg, about 112.5 pg, about 160 pg, about 225 pg, about 240 pg, about 320 pg, about 400 pg, about 450 pg, about 480 pg, about 640 pg, about 675 pg, about 720 pg, about 800 pg, about 960 pg, about 1040 pg, about 1120 pg, about 1200 pg, or about 1280 pg of a compound of Formula (I) or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The composition may be present, in one embodiment, in one powder capsule or a plurality (two or more) powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of Formula (I) or (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,is divided amongst the capsules. Thus, multiple capsules may be administered to achieve one of the aforementioned doses.

[0152] In embodiments, the powder composition of the disclosure is formulated to administer once daily to the lungs of the subject (e.g., patient) by inhalation a dose ranging from about 80 pg to about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and provide at least one of the following characteristics:(a) a treprostinil maximum plasma concentration (Cmax) ranging from about 14 pg / mL to about 1430 pg / mL; or(b) a treprostinil area under the plasma concentration curve (AUC) ranging from about from about 380 pg*h / mL to about 10000 pg*h / mL.

[0153] In a further embodiment, the composition comprises about 80 pg, about 160 pg, about 240 pg, about 320 pg, about 400 pg, about 480 pg or about 640 pg of a compound of Formula (I) or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The composition may be present, in one embodiment, in one powder capsule or a plurality (two or more) powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of Formula (I) or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is divided amongst the capsules.

[0154] In one embodiment, the powder composition is formulated to administer once daily to the lungs of the subject (e.g., patient) by inhalation a dose ranging from about 112.5 pg to about 675 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and provide at least one of the following characteristics:(a) a treprostinil maximum plasma concentration (Cmax) ranging from about 17 pg / mL to about 1370 pg / mL; or(b) a treprostinil area under the plasma concentration curve (AUC) ranging from about from about 700 pg*h / mL to about 7800 pg*h / mL.

[0155] In a further embodiment, the composition comprises about 80 pg, about 160 pg, about 240 pg, about 320 pg, about 400 pg, about 480 pg or about 640 pg of a compound of Formula (I) or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The composition may be present, in one embodiment, in one powder capsule or a plurality (two or more) powder capsules. When present in multiple capsules, one of the aforementioned dosesof the compound of Formula (I) or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is divided amongst the capsules.

[0156] In embodiments, the powder composition is formulated to administer once daily to the lungs of the subject (e.g., patient) by inhalation about 80 pg to about 1280 pg of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for example from about 80 pg to about 1200 pg or from about 320 pg to about 1280 pg, and provide a pharmacokinetic profile described herein. In one embodiment, the powder composition having one of the pK profiles described herein comprises about 80 pg, about 100 pg, about 110 pg, about 112.5 pg, about 120 pg, about 130 pg, about 140 pg, about 150 pg, about 160 pg, about 170 pg, about 180 pg, about 190 pg, about 200 pg, about 210 pg, about 220 pg, about 225 pg, about 230 pg, about 240 pg, about 250 pg, about 260 pg, about 270 pg, about 280 pg, about 290 pg, about 300 pg, about 310 pg, about 320 pg, about 330 pg, about 340 pg, about 350 pg, about 360 pg, about 370 pg, about 380 pg, about 390 pg, about 400 pg, about 410 pg, about 420 pg, about 430 pg, about 440 pg, about 450 pg, about 460 pg, about 470 pg, about 480 pg, about 490 pg, about 500 pg, about 510 pg, about 520 pg, about 530 pg, about 540 pg, about 550 pg, about 560 pg, about 570 pg, about 580 pg, about 590 pg, about 600 pg, about 610 pg, about 620 pg, about 630 pg, about 640 pg, about 650 pg, about 660 pg, about 670 pg, about 675 pg, about 680 pg, about 690 pg, about 700 pg, about 720 pg, about 740 pg, about 760 pg, about 780 pg, about 800 pg, about 820 pg, about 840 pg, about 860 pg, about, about 880 pg, about 900 pg, about 920 pg, about 940 pg, about 960 pg, about 980 pg, about 1000 pg, about 1020 pg, about 1040 pg, about 1060 pg, about 1080 pg, about 1100 pg, about 1120 pg, about 1140 pg, about 1160 pg, about 1180 pg, about 1200 pg, about 1240 pg, about 1260 pg, or about 1280 pg of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, including all values and ranges therein. In a further embodiment, R1is hexadecyl, e.g., linear hexadecyl. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than orequal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0157] In embodiments, the powder composition is formulated to administer once daily to the lungs of the subject (e.g., patient) by inhalation about 80 pg to about 675 pg of a compound of Formula (I) or (II), or a stereoisomer or pharmaceutically acceptable salt thereof, for example from about 80 pg to about 640 pg or from about 112.5 pg to about 675 pg, and provide a pharmacokinetic profile described herein. In one embodiment, the powder composition having one of the pK profiles described herein comprises about 80 pg, about 100 pg, about 110 pg, about 112.5 pg, about 120 pg, about 130 pg, about 140 pg, about 150 pg, about 160 pg, about 170 pg, about 180 pg, about 190 pg, about 200 pg, about 210 pg, about 220 pg, about 225 pg, about 230 pg, about 240 pg, about 250 pg, about 260 pg, about 270 pg, about 280 pg, about 290 pg, about 300 pg, about 310 pg, about 320 pg, about 330 pg, about 340 pg, about 350 pg, about 360 pg, about 370 pg, about 380 pg, about 390 pg, about 400 pg, about 410 pg, about 420 pg, about 430 pg, about 440 pg, about 450 pg, about 460 pg, about 470 pg, about 480 pg, about 490 pg, about 500 pg, about 510 pg, about 520 pg, about 530 pg, about 540 pg, about 550 pg, about 560 pg, about 570 pg, about 580 pg, about 590 pg, about 600 pg, about 610 pg, about 620 pg, about 630 pg, about 640 pg, about 650 pg, about 660 pg, about 670 pg, about 675 pg, about 680 pg, about 690 pg, or about 700 pg, of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, including all values and ranges therein. In a further embodiment, R1is hexadecyl, e.g., linear hexadecyl.

[0158] In some embodiments, following once daily administration of a dry powder composition comprising from about 80 pg to about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the powder composition or method of use thereof provides a maximum treprostinil plasma concentration (Cmax) ranging from about 10 pg / mL to about 3000 pg / mL, for example, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 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, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, about 310 pg / mL, about 320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about 370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about 420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about 470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, about 520 pg / mL, about 530 pg / mL, about 540 pg / mL, about 550 pg / mL, about 560 pg / mL, about 570 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, about 700 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 1150 pg / mL, about 1200 pg / mL, about 1250 pg / mL, about 1300 pg / mL, about 1350 pg / 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, about 2000 pg / mL, about 2050 pg / mL, about 2100 pg / mL, about 2150 pg / mL, about 2200 pg / mL, about 2250 pg / mL, about 2300 pg / mL, about 2350 pg / mL, about 2400 pg / mL, about 2450 pg / mL, about 2500 pg / mL, about 2550 pg / mL, about 2600 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. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm orfrom about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0159] In some embodiments, following once daily administration of a powder composition comprising from about 80 pg to about 675 pg (e.g., about 80 pg to about 640 pg, or about 112.5 pg to about 675 pg) of the compound of Formula (I) or (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the powder composition or method of use thereof provides a maximum treprostinil plasma concentration (Cmax) ranging from about 10 pg / mL to about 2000 pg / mL, for example, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL 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, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, about 310 pg / mL, about 320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about 370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about 420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about 470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, about 520 pg / mL, about 530 pg / mL, about 540 pg / mL, about 550 pg / mL, about 560 pg / mL, about 570 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, about 700 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 1150 pg / mL, about 1200 pg / mL, about 1250 pg / mL, about 1300 pg / mL, about 1350 pg / 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. The powder composition, in one embodiment, is a spray-dried powder composition.

[0160] In some embodiments, following once daily administration of about 80 pg to about 1280 pg pg (e.g., about 80 pg to about 640 pg, or about 360 pg to about 1280 pg) of thecompound of Formula (I) or (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the powder composition or method of use thereof 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, about 1500 pg*h / mL, about 1600 pg*h / mL, about 1700 pg*h / mL, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 pg*h / mL, about 2700 ng*h / mL, about 2800 ng*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, about 3100 pg*h / mL, about 3200 pg*h / mL, about 3300 pg*h / mL, about 3400 pg*h / mL, about 3500 pg*h / mL, about 3600 pg*h / mL, about 3700 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, about 5800 pg*hr / mL, about 5900 pg*hr / mL, about 6000 pg*hr / mL, about 6100 pg*hr / mL, about 6200 pg*hr / mL, about 6300 pg*h / mL*hr / mL, about 6400 pg*h / mL, about 6500 pg*h / mL*hr / mL, about 6600 pg*hr / mL, about 6700 pg*hr / mL, about 6800 pg*hr / mL, about 6900 pg*hr / mL, about 7000 pg*hr / mL, about 7100 pg*hr / mL, about 7200 pg*hr / mL, about 7300 pg*hr / mL, about 7400 pg*hr / mL, about 7500 pg*hr / mL, about 7600 pg*hr / mL, about 7700 pg*hr / mL, about 7800 pg*hr / mL, about 7900 pg*hr / mL, about 8000 pg*hr / mL, about 8100 pg*hr / mL, about 8200 pg*hr / mL, about 8300 pg*hr / mL, about 8400 pg*hr / mL, about 8500 pg*hr / mL, about 8600 pg*hr / mL, about 8700 pg*hr / mL, about 8800 pg*hr / mL, about 8900 pg*hr / mL, about 9000 pg*hr / mL, about 9100 pg*hr / mL, about 9200 pg*hr / mL, about 9300 pg*hr / mL, about 9400 pg*hr / mL, about 9500 pg*hr / mL, about 9600 pg*hr / mL, about 9700 pg*hr / mL, about 9800 pg*hr / mL, about 9900 pg*hr / mL, about 10000 pg*hr / mL, about 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, about 11000 pg*hr / mL, about 11100 pg*hr / mL, about 11200 pg*hr / mL, about 11300 pg*hr / mL, about 11400 pg*hr / mL, about 11500 pg*hr / mL, about 11600 pg*hr / mL, about 11700 pg*hr / mL, about 11800 pg*hr / mL, about 11900 pg*hr / mL, about 12000 pg*hr / mL, about 12100 pg*hr / mL, about 12200 pg*hr / mL, about 12300 pg*hr / mL, about 12400pg*hr / mL, about 12500 pg*hr / mL, about 12600 pg*hr / mL, about 12700 pg*hr / mL, about12800 pg*hr / mL, about 12900 pg*hr / mL, about 13000 pg*hr / mL, about 13100 pg*hr / mL, about 13200 pg*hr / mL, about 13300 pg*hr / mL, about 13400 pg*hr / mL, about 13500 pg*hr / mL, about 13600 pg*hr / mL, about 13700 pg*hr / mL, about 13800 pg*hr / mL, about13900 pg*hr / mL, about 14000 pg*hr / mL, about 14100 pg*hr / mL, about 14200 pg*hr / mL, about 14300 pg*hr / mL, about 14400 pg*hr / mL, about 14500 pg*hr / mL, about 14600 pg*hr / mL, about 14700 pg*hr / mL, about 14800 pg*hr / mL, about 14900 pg*hr / mL, about 15000 pg*hr / mL, about 15100 pg*hr / mL, about 15200 pg*hr / mL, about 15300 pg*hr / mL, about 15400 pg*hr / mL, about 15500 pg*hr / mL, about 15600 pg*hr / mL, about 15700 pg*hr / mL, about 15800 pg*hr / mL, about 15900 pg*hr / mL, about 16000 pg*hr / mL, about16100 pg*hr / mL, about 16200 pg*hr / mL, about 16300 pg*hr / mL, about 16400 pg*hr / mL, about 16500 pg*hr / mL, about 16600 pg*hr / mL, about 16700 pg*hr / mL, about 16800 pg*hr / mL, about 16900 pg*hr / mL, about 17000 pg*hr / mL, about 17100 pg*hr / mL, about17200 pg*hr / mL, about 17300 pg*hr / mL, about 17400 pg*hr / mL, about 17500 pg*hr / mL, about 17600 pg*hr / mL, about 17700 pg*hr / mL, about 17800 pg*hr / mL, about 17900 pg*hr / mL, about 18000 pg*hr / mL, about 18100 pg*hr / mL, about 18200 pg*hr / mL, about18300 pg*hr / mL, about 18400 pg*hr / mL, about 18500 pg*hr / mL, about 18600 pg*hr / mL, about 18700 pg*hr / mL, about 18800 pg*hr / mL, about 18900 pg*hr / mL, about 19000 pg*hr / mL, about 19100 pg*hr / mL, about 19200 pg*hr / mL, about 19300 pg*hr / mL, about19400 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. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next GenerationImpactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0161] In some embodiments, following once daily administration of about 80 pg to about 675 pg (e.g., about 80 pg to about 640 pg, or about 112.5 pg to about 675 pg) of the compound of Formula (I) or (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the powder composition or method of use thereof 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, about 1500 pg*h / mL, about 1600 pg*h / mL, about 1700 pg*h / mL, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 pg*h / mL, about 2700 ng*h / mL, about 2800 ng*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, about 3100 pg*h / mL, about 3200 pg*h / mL, about 3300 pg*h / mL, about 3400 pg*h / mL, about 3500 pg*h / mL, about 3600 pg*h / mL, about 3700 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, about 5800 pg*hr / mL, about 5900 pg*hr / mL, about 6000 pg*hr / mL, about 6100 pg*hr / mL, about 6200 pg*hr / mL, about 6300 pg*h / mLg*hr / mL, about 6400 pg*h / mL, about 6500 pg*h / mLg*hr / mL, about 6600 pg*hr / mL, about 6700 pg*hr / mL, about 6800 pg*hr / mL, about 6900 pg*hr / mL, about 7000 pg*hr / mL, about 7100 pg*hr / mL, about 7200 pg*hr / mL, about 7300 pg*hr / mL, about 7400 pg*hr / mL, about 7500 pg*hr / mL, about 7600 pg*hr / mL, about 7700 pg*hr / mL, about 7800 pg*hr / mL, about 7900 pg*hr / mL, about 8000 pg*hr / mL, about 8100 pg*hr / mL, about 8200 pg*hr / mL, about 8300 pg*hr / mL, about 8400 pg*hr / mL, about 8500 pg*hr / mL, about 8600 pg*hr / mL, about 8700 pg*hr / mL, about 8800 pg*hr / mL, about 8900 pg*hr / mL, about 9000 pg*hr / mL, about 9100 pg*hr / mL, about 9200 pg*hr / mL, about 9300 pg*hr / mL, about 9400 pg*hr / mL, about 9500 pg*hr / mL, about 9600 pg*hr / mL, about 9700 pg*hr / mL, about 9800 pg*hr / mL, about 9900 pg*hr / mL, about 10000 pg*hr / mL, about 10100 pg*hr / mL, about 10200 pg*hr / mL, about 10300 pg*hr / mL, about 10400 pg*hr / mL, about 10500 pg*hr / mL, about10600 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. The powder composition, in one embodiment, is a spray-dried powder composition.

[0162] In some embodiments, the powder composition or method of use thereof achieves treprostinil plasma trough concentration during an administration period of the powder composition. In some embodiments, the plasma trough levels are sufficient to provide a sustained therapeutic response during the administration period.

[0163] In some embodiments, the powder composition or method of use comprises from about 80 pg to about 1280 pg of the compound of Formula (I) or (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and following once daily administration, the treprostinil plasma trough concentration 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 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, about 150 pg / mL, about 155 pg / mL, about 160 pg / mL, about 165 pg / mL, about 170 pg / mL, about 175 pg / mL, about 180 pg / mL, about 185 pg / mL, about 190 pg / mL, about 195 pg / mL, about 200 pg / mL, about 200 pg / mL, about 205 pg / mL, about 210 pg / mL, about 215 pg / mL, about 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 some embodiments the powder composition is a spray-dried powder. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter(MMAD) less than 5 pm (e.g., from about 0.75 gm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0164] In some embodiments, the powder composition or method of use thereof comprises from about 80 pg to about 675 pg of the compound of Formula (I) or a stereoisomer thereof (e.g., where R1is hexadecyl, e.g., linear hexadecyl), and following once daily administration, the powder composition provides or the subject (e.g., patient) has a treprostinil plasma trough concentration of 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, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, including all values and ranges therein.

[0165] In some embodiments, the powder composition or method of use comprises from about 80 pg to about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and following once daily administration, the treprostinil plasma trough concentration 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 100 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 from about 80 pg to about 640 pg of the compound of Formula (II), and the treprostinil plasma trough concentration ranges from about 10 pg / mL to about 100 pg / mL.

[0166] In some embodiments, following once daily administration of a powder composition comprising from about 80 pg to about 675 pg of the compound of Formula (I) or (II), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, the powder composition or method of use thereof provides or the subject (e.g., patient) has at least one of the following characteristics:(a) a maximum treprostinil plasma concentration (Cmax) within about 80% to about 125% of the range of 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, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, about 310 pg / mL, about 320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about 370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about 420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about 470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, about 520 pg / mL, about 530 pg / mL, about 540 pg / mL, about 550 pg / mL, about 560 pg / mL, about 570 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, about 700 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 1150 pg / mL, about 1200 pg / mL, about 1250 pg / mL, about 1300 pg / mL, about 1350 pg / mL, about 1400 pg / mL, or about 1430 pg / mL, including all values and ranges therein; or(b) a treprostinil area under the plasma concentration curve (AUCo-inf) within about 80% to about 125% of the range of from about 475 pg*h / mL to about 8000 pg*h / mL, for example, about 370 pg*h / mL, about 400 pg*h / mL, about 450 pg*h / mL, about 500 pg*h / mL, about 550 pg*h / mL, about 600 pg*h / mL, about 650 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, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 pg*h / mL, about 2700 ng*h / mL, about 2800 ng*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, about 3100 pg*h / mL, about 3200 pg*h / mL, about 3300 pg*h / mL, about 3400 pg*h / mL, about 3500 pg*h / mL, about 3600 pg*h / mL, about 3700 pg*h / mL, about 3800 pg*h / mL, about 3900 pg*h / mL, about 4000 pg*h / mL, about 4100pg*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, about 5800 pg*hr / mL, about 5900 pg*hr / mL, about 6000 pg*hr / mL, about 6100 pg*hr / mL, about 6200 pg*hr / mL, about 6300 pg*h / mL, about 6400 pg*h / mL, about 6500 pg*h / mL, about 6600 pg*hr / mL, about 6700 pg*hr / mL, about 6800 pg*hr / mL, about 6900 pg*hr / mL, about 7000 pg*hr / mL, about 7100 pg*hr / mL, about 7200 pg*hr / mL, about 7300 pg*hr / mL, about 7400 pg*hr / mL, about 7500 pg*hr / mL, about 7600 pg*hr / mL, about 7700 pg*hr / mL, about 7800 pg*hr / mL, about 7900 pg*hr / mL, about 8000 pg*hr / mL, about 8100 pg*hr / mL, about 8200 pg*hr / mL, about 8300 pg*h / mL, about 8400 pg*h / mL, about 8500 pg*h / mL, about 8600 pg*hr / mL, about 8700 pg*hr / mL, about 8800 pg*hr / mL, about 8900 pg*hr / mL, about 9000 pg*hr / mL, about 9100 pg*hr / mL, about 9200 pg*hr / mL, about 9300 pg*hr / mL, about 9400 pg*hr / mL, about 9500 pg*hr / mL, about 9600 pg*hr / mL, about 9700 pg*hr / mL, about 9800 pg*hr / mL, about 9900 pg*hr / mL, or about 10000 pg*hr / mL, including all values and ranges therein.

[0167] In some embodiments, the powder composition comprises about 80 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 14 pg / mL to about 155 pg / mL, for example, about 14pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, about 105 pg / mL 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, about 150 pg / mL, and about 155 pg / mL, including all values and ranges therein. In some embodiments, about 80 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax of about 80%-125% of a range from about 17 pg / mL to about 125 pg / mL. In some embodiments, about 80 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax of about 80%-125% of a range from about 35 pg / mL to about 105 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powdercomposition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0168] In some embodiments, the powder composition comprises about 112.5 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and provides a treprostinil Cmax (CV%) ranging from about 80% to about 125% of about 78.4 (72.9) pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0169] In some embodiments, the powder composition comprises about 160 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable saltthereof, is administered once daily, and provides a treprostinil Cmax ranging from about 30 pg / mL to about 335 pg / mL, for example, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, about 105 pg / mL 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, about 150 pg / mL, about 155 pg / mL, about 160 pg / mL, about 165 pg / mL, about 170 pg / mL, about 175 pg / mL, about 180 pg / mL, about 1850 pg / mL, about 190 pg / mL, about 195 pg / mL, about 200 pg / mL, about 205 pg / mL, about 210 pg / mL, about 215 pg / mL, about 220 pg / mL, about 225 pg / mL, about 230 pg / mL, about 235 pg / mL, about 240 pg / mL, about 245 pg / mL, about 250 pg / mL, about 255 pg / mL, about 260 pg / mL, about 265 pg / mL, about 270 pg / mL, about 275 pg / mL, about 280 pg / mL, about 285 pg / mL, about 290 pg / mL, about 295 pg / mL, about 300 pg / mL, about 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 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 35 pg / mL to about 270 pg / mL. In some embodiments, about 160 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 76 pg / mL to about 230 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratoryflow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0170] In some embodiments, the powder composition comprises about 225 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 287 (46.6) pg / mL. In some embodiments, the powder composition comprises about 225 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and provides a steady state treprostinil Cmax ranging from about 80% to about 125% of about 193 (32.9) pg / mL. In some embodiments, the powder composition comprises about 225 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a steady state treprostinil Cmax (CV%) ranging from about 80% to about 125% of about 228 (46.4) pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0171] In some embodiments, the powder composition comprises about 240 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily, and provides a treprostinil Cmax ranging from about 45 pg / mL to about 520 pg / mL, for example, about 45 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, 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, about170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, about 310 pg / mL, about320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, or about 520 pg / mL, including all values and ranges therein. In some embodiments, about 240 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 55 pg / mL to about 415 pg / mL. In some embodiments, about 240 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 115 pg / mL to about 355 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0172] In some embodiments, the powder composition comprises about 320 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 60 pg / mL to about 700 pg / mL, for example, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL,about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, about 310 pg / mL, about 320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about 370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about 420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about 470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, about 520 pg / mL, about 530 pg / mL, about 540 pg / mL, about 550 pg / mL, about 560 pg / mL, about 570 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 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 80 pg / mL to about 560 pg / mL. In some embodiments, about 320 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 160 pg / mL to about 480 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0173] In some embodiments, the powder composition comprises about 400 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80 pg / mL to about 885 pg / mL, for example, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, about 310 pg / mL, about 320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about 370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about 420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about 470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, about 520 pg / mL, about 530 pg / mL, about 540 pg / mL, about 550 pg / mL, about 560 pg / mL, about 570 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, and about 700 pg / mL, about 710 pg / mL, about 720 pg / mL, about 730 pg / mL, about 740 pg / mL, about 750 pg / mL, about 760 pg / mL, about 770 pg / mL, about 780 pg / mL, about 790 pg / mL, about 800 pg / mL, about 810 pg / mL, about 820 pg / mL, about 830 pg / mL, about 840 pg / mL, about 850 pg / mL, about 860 pg / mL, about 870 pg / mL, or about 880 pg / mL, including all values and ranges therein. In some embodiments, about 400 pg of the compound of Formula (I) or(II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range of about 100 pg / mL to about 705 pg / mL. In some embodiments, about 400 pg of the compound of Formula (I), (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 200 pg / mL to about 605 pg / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 about80%), and one or more of (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0174] In some embodiments, the powder composition comprises about 450 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 387 (38.6) pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0175] In some embodiments, the powder composition comprises about 480 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 95 pg / mL to about 1065 pg / mL, for example, about 95 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290pg / mL, about 300 pg / mL, about 310 pg / mL, about 320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about 370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about 420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about 470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, about 520 pg / mL, about 530 pg / mL, about 540 pg / mL, about 550 pg / mL, about 560 pg / mL, about 570 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, and about 700 pg / mL, about 710 pg / mL, about 720 pg / mL, about 730 pg / mL, about740 pg / mL, about 750 pg / mL, about 760 pg / mL, about 770 pg / mL, about 780 pg / mL, about790 pg / mL, about 800 pg / mL, about 810 pg / mL, about 820 pg / mL, about 830 pg / mL, about840 pg / mL, about 850 pg / mL, about 860 pg / mL, about 870 pg / mL, about 880 pg / mL, about890 pg / mL, about 900 pg / mL, about 910 pg / mL, about 920 pg / mL, about 930 pg / mL, about940 pg / mL, about 950 pg / mL, about 960 pg / mL, about 970 pg / mL, about 980 pg / mL, about1000 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 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of about 120 pg / mL to about 855 pg / mL. In some embodiments, about 480 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range from about 240 pg / mL to about 730 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pmto about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0176] In some embodiments, the powder composition comprises about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 130 pg / mL to about 1430 pg / mL, for example, about 130 pg / mL, about 135 pg / mL, about 140 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, about 310 pg / mL, about 320 pg / mL, about 330 pg / mL, about 340 pg / mL, about 350 pg / mL, about 360 pg / mL, about 370 pg / mL, about 380 pg / mL, about 390 pg / mL, about 400 pg / mL, about 410 pg / mL, about 420 pg / mL, about 430 pg / mL, about 440 pg / mL, about 450 pg / mL, about 460 pg / mL, about 470 pg / mL, about 480 pg / mL, about 490 pg / mL, about 500 pg / mL, about 510 pg / mL, about 520 pg / mL, about 530 pg / mL, about 540 pg / mL, about 550 pg / mL, about 560 pg / mL, about 570 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, and about 700 pg / mL, about 710 pg / mL, about 720 pg / mL, about 730 pg / mL, about 740 pg / mL, about 750 pg / mL, about 760 pg / mL, about 770 pg / mL, about780 pg / mL, about 790 pg / mL, about 800 pg / mL, about 810 pg / mL, about 820 pg / mL, about830 pg / mL, about 840 pg / mL, about 850 pg / mL, about 860 pg / mL, about 870 pg / mL, about880 pg / mL, about 890 pg / mL, about 900 pg / mL, about 910 pg / mL, about 920 pg / mL, about930 pg / mL, about 940 pg / mL, about 950 pg / mL, about 960 pg / mL, about 970 pg / mL, about980 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, about 1070 pg / mL, about 1080 pg / mL, about 1090 pg / mL, about 1100 pg / mL, about 1110 pg / mL, about 1120 pg / mL, about 1130 pg / mL, about 1140 pg / mL, about 1150 pg / mL, about 1160 pg / mL, about 1170 pg / mL, about 1180 pg / mL, about 1190 pg / mL, about 1200 pg / mL, about 1210 pg / mL, about 1220 pg / mL, about 1230 pg / mL, about 1240 pg / mL, about 1250 pg / mL, about 1260 pg / mL, about 1270 pg / mL, about 1280 pg / mL, about 1290 pg / mL, about 1300 pg / mL, about 1310 pg / mL, about 1320 pg / mL, about 1330 pg / mL, about 1340 pg / mL, about 1350 pg / mL, about 1360 pg / mL, about 1370 pg / mL, about 1380 pg / mL, about 1390 pg / mL, about 1400 pg / mL, about1410 pg / mL, about 1420 pg / mL, or about 1430 pg / mL, including all values and ranges therein. In some embodiments, about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax from about 80%-125% of a range of about 160 pg / mL to about 1140 pg / mL. In some embodiments, about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once daily and provides a treprostinil Cmax ranging from about 80%-125% of about 325 pg / mL to about 980 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0177] In some embodiments, the powder composition comprises about 675 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 717 (52.8) pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 about80%), and one or more of (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0178] In some embodiments, the powder composition comprises about 720 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 185 pg / mL to about 1300 pg / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 720 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 368 pg / mL to about 1105 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0179] In some embodiments, the powder composition comprises about 800 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% toabout 125% of about 200 pg / mL to about 1430 pg / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 800 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 400 pg / mL to about 1230 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0180] In some embodiments, the powder composition comprises about 880 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 225 pg / mL to about 1580 pg / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 880 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 450 pg / mL to about 1360 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. In some embodiments, when the spray-dried powder composition isadministered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0181] In some embodiments, the powder composition comprises about 960 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 240 pg / mL to about 1720 pg / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 960 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 490 pg / mL to about 1480 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0182] In some embodiments, the powder composition comprises about 1040 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 530 pg / mL to about 1605 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0183] In some embodiments, the powder composition comprises about 1120 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 280 pg / mL to about 2020 pg / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 1120 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 575 pg / mL to about 1730 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprisinga fine particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0184] In some embodiments, the powder composition comprises about 1200 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 300 pg / mL to about 2165 pg / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 1200 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 615 pg / mL to about 1855 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0185] In some embodiments, the powder composition comprises about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 325 pg / mL to about 2310 pg / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil Cmax ranging from about 80% to about 125% of about 660 pg / mL to about 1980 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0186] In some embodiments, the powder composition comprises about 80 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about 375 pg*h / mL to about 1800 pg*h / mL, for example, 375 pg*h / mL, 400 pg*h / mL, 500 pg*h / mL, 600 pg*h / mL, about 700 pg*h / mL, about 800 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 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125%of a range of about 475 pg*h / mL to about 1430 pg*h / mL. In some embodiments, the powder composition comprises about 80 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and upon administration, the powder composition or method of use thereof provides a treprostinil AUCo-inf from about 80%-125% of about 660 pg*h / mL to about 1240 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0187] In some embodiments, the powder composition comprises about 112.5 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about 80% to about 125% of about 1090 (91.8) pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater thanor equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0188] In some embodiments, the powder composition comprises about 160 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about 630 pg*h / mL to about 3000 pg*h / mL, for example, 630 pg*h / mL, about 700 pg*h / mL, about 800 pg*h / mL, about 900 pg*h / mL, about 1000 pg*h / mL, about 1100 pg*h / mL, about 1200 pg*h / mL, about 1300 pg*h / mL, about 1400 pg*h / mL, about 1500 pg*h / mL, about 1600 pg*h / mL, about 1700 pg*h / mL, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 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 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 785 pg*h / mL to about 2370 pg*h / mL. In some embodiments, the powder composition comprises about 160 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 1100 pg*h / mL to about 2050 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%,or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 gm (e.g., from about 0.75 gm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0189] In some embodiments, the powder composition comprises about 225 pg of a compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides an AUCo-inf ranging from about 80% to about 125% of about 2130 (30.0) ng*h / mL. In some embodiments, the powder composition comprises about 225 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a steady state treprostinil AUC0-24 (CV%) ranging from about 80% to about 125% of about 1680 (28.7) ng*h / mL. In some embodiments, the powder composition comprises about 225 gg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a steady state treprostinil AUC0-24 (CV%) ranging from about 80% to about 125% of about 1790 (39.6) ng*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 gm to about 2.0 gm. In some embodiments, the particles have a D10 of about 0.3 gm, a D50 of about 1.7 gm, and / or a D90 of about 3.8 gm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0190] In some embodiments, the powder composition comprises about 450 gg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about80% to about 125% of about 4040 (27.4) pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0191] In some embodiments, the powder composition comprises about 240 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about 880 pg*h / mL to about 4130 pg*h / mL, for example, about 800 pg*h / mL, about 900 pg*h / mL, about950 pg*h / mL, about 1000 pg*h / mL, about 1050 pg*h / mL, about 1100 pg*h / mL, about 1150 pg*h / mL, about 1200 pg*h / mL, about 1250 pg*h / mL, about 1300 pg*h / mL, about 1350 pg*h / mL, about 1400 pg*h / mL, about 1450 pg*h / mL, about 1500 pg*h / mL, about 1550 pg*h / mL, about 1600 pg*h / mL, about 1650 pg*h / mL, about 1700 pg*h / mL, about 1750 pg*h / mL, about 1800 pg*h / mL, about 1850 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 3650pg*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, about 4050 pg*h / mL, about 4100 pg*h / mL, about 4130 pg*h / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 240 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 1100 pg*h / mL to about 3305 pg*h / mL. In some embodiments, the powder composition comprises about 240 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 1540 pg*h / mL to about 2865 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0192] In some embodiments, the powder composition comprises about 320 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about 1130 pg*h / mL to about 5310 pg*h / mL, for example, about 1130 pg*h / mL, about 1200 pg*h / mL, about 1300 pg*h / mL, about 1400 pg*h / mL, about 1450 pg*h / mL, about 1500 pg*h / mL, about 1550 pg*h / mL, about 1600 pg*h / mL, about 1700 pg*h / mL, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600pg*h / mL, about 2700 pg*h / mL, about 2800 pg*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, about 3100 pg*h / mL, about 3200 pg*h / mL, about 3300 pg*h / mL, about 3400 pg*h / mL, about 3500 pg*h / mL, about 3600 pg*h / mL, about 3700 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*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 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 1400 pg*h / mL to about 4250 pg*h / mL. In some embodiments, about 320 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 1975 pg*h / mL to about 3680 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0193] In some embodiments, the powder composition comprises about 400 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about1380 pg*h / mL to about 6480 pg*h / mL, for example, about 1380 pg*h / mL, about 1400 pg*h / mL, about 1450 pg*h / mL, about 1500 pg*h / mL, about 1550 pg*h / mL, about 1600 pg*h / mL, about 1700 pg*h / mL, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 pg*h / mL, about 2700 pg*h / mL, about 2800 pg*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, about 3100 pg*h / mL, about 3200 pg*h / mL, about 3300 pg*h / mL, about 3400 pg*h / mL, about 3500 pg*h / mL, about 3600 pg*h / mL, about 3700 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*h / mL, about 5200 pg*h / mL, about 5300 pg*h / mL, about 5400 pg*h / mL, about 5500 pg*h / mL, about 5600 pg*h / mL, about 5700 pg*h / mL, about 5800 pg*h / mL, about 5900 pg*h / mL, about 6000 pg*h / mL, about 6100 pg*h / mL, about 6200 pg*h / mL, about 6300 pg*h / mL, about 6400 pg*h / mL, or about 6480 pg*h / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 400 pg of the compound of Formula(I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 1725 pg*h / mL to about 5180 pg*h / mL. In some embodiments, the powder composition comprises about 400 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 2415pg*h / mL to about 4490 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm orfrom about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0194] In some embodiments, the powder composition comprises about 480 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about1630 pg*h / mL to about 7650 pg*h / mL, for example, about 1630 pg*h / mL, about 1700 pg*h / mL, about 1800 pg*h / mL, about 1900 pg*h / mL, about 2000 pg*h / mL, about 2100 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 pg*h / mL, about 2700 pg*h / mL, about 2800 pg*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, about 3100 pg*h / mL, about 3200 pg*h / mL, about 3300 pg*h / mL, about 3400 pg*h / mL, about 3500 pg*h / mL, about 3600 pg*h / mL, about 3700 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*h / mL, about 5200 pg*h / mL, about 5300 pg*h / mL, about 5400 pg*h / mL, about 5500 pg*h / mL, about 5600 pg*h / mL, about 5700 pg*h / mL, about 5800 pg*h / mL, about 5900 pg*h / mL, about 6000 pg*h / mL, about 6100 pg*h / mL, about 6200 pg*h / mL, about 6300 pg*h / mL, about 6400 pg*h / mL, about 6500 pg*h / mL, about 6600 pg*h / mL, about 6700 pg*h / mL, about 6800 pg*h / mL, about 6900 pg*h / mL, about 7000 pg*h / mL, about 7100 pg*h / mL, about 7200 pg*h / mL, about 7300 pg*h / mL, about 7400 pg*h / mL, about 7500 pg*h / mL, or about 7650 pg*h / mL, including all values and ranges therein. In some embodiments, the powder composition comprises about 480 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 2040 pg*h / mL to about 6120 pg*h / mL. In some embodiments, the powder composition comprises about 480 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 2855 pg*h / mL to about 5310 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0195] In some embodiments, the powder composition comprises about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf ranging from about 2130 pg*h / mL to about 10000 pg*h / mL, for example, about 2130 pg*h / mL, about 2200 pg*h / mL, about 2300 pg*h / mL, about 2400 pg*h / mL, about 2500 pg*h / mL, about 2600 pg*h / mL, about 2700 pg*h / mL, about 2800 pg*h / mL, about 2900 pg*h / mL, about 3000 pg*h / mL, about 3100 pg*h / mL, about 3200 pg*h / mL, about 3300 pg*h / mL, about 3400 pg*h / mL, about 3500 pg*h / mL, about 3600 pg*h / mL, about 3700 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*h / mL, about 5200 pg*h / mL, about 5300 pg*h / mL, about 5400 pg*h / mL, about 5500 pg*h / mL, about 5600 pg*h / mL, about 5700 pg*h / mL, about 5800 pg*h / mL, about 5900 pg*h / mL, about 6000 pg*h / mL, about 6100 pg*h / mL, about 6200 pg*h / mL, about 6300 pg*h / mL, about 6400 pg*h / mL, about 6500 pg*h / mL, about 6600 pg*h / mL, about 6700 pg*h / mL, about 6800 pg*h / mL, about 6900 pg*h / mL, about 7000 pg*h / mL, about 7100 pg*h / mL, about 7200 pg*h / mL, about 7300 pg*h / mL, about 7400 pg*h / mL, about 7500 pg*h / mL, about 7600 pg*h / mL, about 7700 pg*h / mL, about 7800 pg*h / mL, about 8000 pg*h / mL, about 8100 pg*h / mL, about 8200 pg*h / mL, about 8300 pg*h / mL, about 8400 pg*h / mL, about 8500 pg*h / mL, about 8600 pg*h / mL, about 8700 pg*h / mL, about 8800 pg*h / mL, about 8900 pg*h / mL, about 9000 pg*h / mL, about 9100 pg*h / mL, about 9200 pg*h / mL, about 9300 pg*h / mL, about 9350 pg*h / mL, about 9400pg*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 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 2650 pg*h / mL to about 8000 pg*h / mL. In some embodiments, the powder composition comprises about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 3730 to about 6935 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0196] In some embodiments, the powder composition comprises about 675 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUC0-24 ranging from about 80% to about 125% of about 5480 (13.8) pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. In some embodiments, when the spray-dried powder composition is administered via a dry powderinhaler, the dry powder inhaler provides an aerosol comprising a fine particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0197] In some embodiments, the powder composition comprises about 720 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 2975 pg*h / mL to about 8940 pg*h / mL. In some embodiments, the powder composition comprises about 720 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 4170 pg*h / mL to about 7750 pg*h / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0198] In some embodiments, the powder composition comprises about 800 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 3290 pg*h / mL to about 9900 pg*h / mL. In some embodiments, the powder composition comprises about 800 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 4600 pg*h / mL to about 8560 pg*h / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0199] In some embodiments, the powder composition comprises about 880 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 3605 pg*h / mL to about 10815 pg*h / mL. In some embodiments, the powder composition comprises about 880 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 5045 pg*h / mL to about 9380 pg*h / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3m, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0200] In some embodiments, the powder composition comprises about 960 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and upon administration, the powder composition or method of use thereof provides a treprostinil AUCo-inf from about 80%-125% of a range from about 3900 pg*h / mL to about 11800 pg*h / mL. In some embodiments, the powder composition comprises about 960 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%- 125% of a range from about 5485 pg*h / mL to about 10190 pg*h / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratoryflow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0201] In some embodiments, the powder composition comprises about 1040 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 4230 pg*h / mL to about 12700 pg*h / mL. In some embodiments, the powder composition comprises about 1040 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 5920 pg*h / mL to about 11000 pg*h / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0202] In some embodiments, the powder composition comprises about 1120 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 4500 pg*h / mL to about 13650 pg*h / mL. In some embodiments, the powder composition comprises about 1120 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 6360 pg*h / mL to about 11815 pg*h / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder compositioncomprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0203] In some embodiments, the powder composition comprises about 1200 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 4850 pg*h / mL to about 14600 pg*h / mL. In some embodiments, the powder composition comprises about 1200 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 6795 pg*h / mL to about 12630 pg*h / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measuredusing a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0204] In some embodiments, the powder composition comprises about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 5150 pg*h / mL to about 15550 pg*h / mL. In some embodiments, the powder composition comprises about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered once daily, and provides a treprostinil AUCo-inf from about 80%-125% of a range from about 7235 pg*h / mL to about 13445 pg*h / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0205] In some embodiments, the powder composition comprises from about 80 pg to about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging 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 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, about 150 pg / mL, about 155 pg / mL, about 160 pg / mL, about 165 pg / mL, about 170 pg / mL, about 175 pg / mL, about 180 pg / mL, about 185 pg / mL, about 190 pg / mL, about 195 pg / mL, about 200 pg / mL, about 200 pg / mL, about 205 pg / mL, about 210 pg / mL, about 215 pg / mL, about 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. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0206] In some embodiments, the powder composition comprises from about 80 pg to about 675 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 3 pg / mL to about 150 mg / mL, for example about 4 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL 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. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0207] In some embodiments, the powder composition comprises about 80 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 3 pg / mL to about 25 mg / mL, for example, about 3 pg / mL, about 4 pg / mL 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 a further embodiment, the treprostinil plasma trough concentration ranges from about 6 pg / mL to about 18 mg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 gm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0208] In some embodiments, the powder composition comprises about 112.5 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil 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. The powder composition, in one embodiment, is a spray-dried powder composition. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 gm, a D50 of about 1.7 gm, and / or a D90 of about 3.8 gm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 gm (e.g., from about 0.75 gm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0209] In some embodiments, the powder composition comprises about 160 gg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has 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 a further embodiment, the treprostinil plasma trough concentration rangesfrom about 10 pg / mL to about 30 mg / mL, or from 15 pg / mL to about 25 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0210] In some embodiments, the powder composition comprises from about 225 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration 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. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%,or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 gm to about 3.0 gm or from about 0.8 gm to about 2.0 gm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0211] In some embodiments, the powder composition comprises from about 240 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 7 pg / mL to about 50 mg / mL, for example about 7 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, or about 50 pg / mL, including all values and ranges therein. In some embodiments, the treprostinil plasma trough concentration ranges from about 15 pg / mL to about 50 mg / mL, or from 20 pg / mL to about 45 pg / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0212] In some embodiments, the powder composition comprises about 320 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 9 pg / mL to about 65 mg / mL, for example about 9 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL,about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, or about 65 pg / mL, including all values and ranges therein. In some embodiments, the treprostinil plasma trough concentration ranges from about 15 pg / mL to about 50 mg / mL, or from 20 pg / mL to about 45 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0213] In some embodiments, the powder composition comprises about 400 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 10 pg / mL to about 80 mg / mL, for example about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, or about 80 pg / mL including all values and ranges therein. In some embodiments, the treprostinil plasma trough concentration ranging from about 35 pg / mL to about 70 mg / mL, or from 40 pg / mL to about 65 pg / mL. The powder composition, in one embodiment, is a spray- dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. In some embodiments, when the spray-dried powder composition is administered via a dry powder inhaler, the dry powderinhaler provides an aerosol comprising a fine particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0214] In some embodiments, the powder composition comprises about 450 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 30 pg / mL to about 75 mg / mL, for example about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, and about 75 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0215] In some embodiments, the powder composition comprises about 480 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 13 pg / mL to about 95 mg / mL, for example about 13 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, including all values and ranges therein. In some embodiments, the treprostinil plasma trough concentration ranging from about 25 pg / mL to about 75 mg / mL, or from 30 pg / mL to about 70 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0216] In some embodiments, the powder composition comprises about 640 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 15 pg / mL to about 125 mg / mL, for example about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 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, about110 pg / mL, about 115 pg / mL, about 120 pg / mL, or about 125 pg / mL, including all values and ranges therein. In some embodiments, the treprostinil plasma trough concentration ranging from about 35 pg / mL to about 100 mg / mL, or from 50 pg / mL to about 90 pg / mL. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0217] In some embodiments, the powder composition comprises about 675 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 50 pg / mL to about 100 mg / mL, for example about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, and about 100 pg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particledose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0218] In some embodiments, the powder composition comprises about 720 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 20 pg / mL to about 135 mg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0219] In some embodiments, the powder composition comprises about 800 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 21 pg / mL to about 150 mg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray-dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0220] In some embodiments, the powder composition comprises about 960 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 25 pg / mL to about 180 mg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratoryflow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0221] In some embodiments, the powder composition comprises about 1040 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 28 pg / mL to about 195 mg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0222] In some embodiments, the powder composition comprises about 1120 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 30 pg / mL to about 209 mg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0223] In some embodiments, the powder composition comprises about 1200 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 32 pg / mL to about 224 mg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0224] In some embodiments, the powder composition comprises about 1280 pg of the compound of Formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the powder composition provides or following once daily administration the subject (e.g., patient) has a treprostinil plasma trough concentration ranging from about 34pg / mL to about 238 mg / mL, including all values and ranges therein. The powder composition, in one embodiment, is a spray-dried powder composition. In some embodiments, the spray- dried powder composition comprises particles. In some embodiments, particles have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a DIO of about 0.3 pm, a D50 of about 1.7 pm, and / or a D90 of about 3.8 pm. 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 particle 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 (i) a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition (e.g. about 53% to about 77% or from about 60% to about 65%), (ii) an aerosol comprising an emitted dose (ED) greater than or equal to 72%, e.g., about 79% to about 89%, or (iii) a mass mean aerodynamic diameter (MMAD) less than 5 pm (e.g., from about 0.75 pm to about 3.0 pm or from about 0.8 pm to about 2.0 pm) when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0225] In some embodiments, the one or more pharmaceutically acceptable excipients which are suitable for use in a dry powder inhaler comprise sugar, amino acid, and optionally distearoyl phosphoethanoamine-polyethylene glycol 2000 (DPSE-PEG2000). In some embodiments of the powder compositions or methods described herein, the powder composition comprises from about 25 wt% to about 61 wt% of leucine, with the balance 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 distearoylphosphoethanoamine-polyethylene glycol 2000 (DPSE-PEG2000).Aerosolized compositions

[0226] The powder compositions described herein are in some embodiments, aerosolized via a DPI to provide an aerosolized composition. The powder composition, in one embodiment, is a spray-dried powder composition.

[0227] The aerosolized composition is administered to a patient in need of treatment ofPH, e.g., PAH or PH associated with interstitial lung disease (PH-ILD). In one embodiment, the aerosolized composition is administered to a patient in need of treatment of pulmonaryfibrosis (e.g., PH-ILD where the ILD is pulmonary fibrosis). The aerosolized composition can be characterized by certain parameters known to those of skill in the art, such as fine particle fraction (FPF), fine particle dose (FPD), emitted dose (ED), mass median aerodynamic diameter (MMAD) and / or particle size and distribution. In embodiments, these parameters are measured by NGI. In embodiments, the NGI uses a flow rate corresponding to a 3kPa to 4.5 kPa air pressure drop relative the resistance of the DPI. In embodiments, the pressure drop is 4 kPa. For example, the performance of an ultra high resistance (UHR), high resistance (HR) and medium resistance (MR) devices may be evaluated by drawing 4 L of air through the DPI at a flow rate of 40, 60 and 85 LPM, respectively, corresponding to the 4 kPa air pressure drop. Aerosol characterization data for the above-noted parameters can be compared across different DPI devices (with different resistances). In embodiments, the mean inhaler resistance of a high resistance DPI used to achieve the parameters described herein ranges from 0.025 to 0.040 kPA1 2(L / min'1)'1. In embodiments, the mean inhaler resistance of a high resistance DPI used to achieve the parameters described herein ranges from 0.030 to 0.040 kPA1 2(L / min'1)'1. In embodiments, the mean inhaler resistance of a high resistance DPI used to achieve the parameters described herein ranges from about 0.034 to about 0.036 kPA1 / 2(L / min'1)'1.

[0228] (i) Fine particle fraction (FPF)

[0229] “Fine particle fraction” or “FPF” refers to the fraction of an aerosol having a particle size less than 5 pm in diameter, as measured by cascade impaction, such as NGI. FPF is usually expressed as a percentage. FPF has been demonstrated to correlate to the fraction of the powder that is deposited in the lungs of the subject (e.g., patient).

[0230] 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 a FPF of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, or any value or range therein. In one embodiment, the aerosolized powder composition comprises particles with an FPF of from about 50% to about 100%, from about 60% to about 90%, from about 65% to about 85%, from about 68% to about 80%, from about 68% to about 73%, or from about 78% to about 80%, as measured by NGI.

[0231] In some embodiments, the aerosolized powder composition has an FPF at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least88%, at least 89% or, at least 90%, or any range therein, when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 30-60 liter per minute (L / min), inspiratory volume of 1-4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0232] In one embodiment, the powder composition exhibiting one of the FPF profiles provided above comprises mannitol. In another embodiment, the powder composition exhibiting the FPF profile provided above comprises trehalose.

[0233] In some embodiments, a powder composition comprises (a) about 0.5 wt% to about 5 wt% of a compound of Formula (I), or stereoisomer or a pharmaceutically acceptable salt thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, (b) about 10 wt% to about 61wt% 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 particle fraction (FPF) greater than or equal to about 68%, when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0234] In some embodiments, the aerosolized powder composition has FPF ranges from 78% to about 80% for 16 mg TPIP capsule (containing 160 pg TP) at 4L of inspiratory volume and 60 LPM of inspiratory flow rate. In some embodiments, the powder composition has FPF ranges from 76% to about 80% for 16 mg TPIP capsule (containing 160 pg TP) at IL or 2L of inspiratory volume and 60 LPM of inspiratory flow rate. In some embodiments, the powder composition has FPF ranges from 74% to about 76% for 16 mg TPIP capsule (containing 160 pg TP) at IL or 2L of inspiratory volume and 30 LPM of inspiratory flow rate.

[0235] In some embodiments, the aerosolized powder composition has FPF ranges from 68% to about 73% for 32 mg TPIP capsule (containing 320 pg TP) at 4L of inspiratory volume and 60 LPM of inspiratory flow rate. In some embodiments, the powder composition has FPF ranges from 63% to about 68% for 32 mg TPIP capsule at IL or 2L of inspiratory volume and 60 LPM of inspiratory flow rate.

[0236] (ii) Fine particle dose (FPD)

[0237] The term “fine particle dose” or “FPD”, as used herein, refers to the mass of drug in an aerosol having a particle size less than 5 pm in diameter, as measured by cascade impaction. FPD may be expressed as percentage or mass. In the present disclosure, FPD is expressed as a percentage.

[0238] 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 a loaded dose of the powder composition, when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 30-60 liter per minute (L / min), inspiratory volume of 1-4 L, and inhalation acceleration rate of 0.5-20 L / sec2. In some embodiments, The FPD of the aerosolized powder composition of 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, or any ranges therein, of a loaded dose of the powder composition, when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 30-60 liter per minute (L / min), inspiratory volume of 1-4 L, and inhalation acceleration rate of 0.5- 20 L / sec2.

[0239] In some embodiments, the aerosolized powder composition has FPD ranges from 53% to about 77% for 16 or 32 mg TP IP capsule in different inspiratory flow rates, different acceleration rate and inspiratory volumes taught herein.

[0240] In some embodiments, the aerosolized powder composition has FPD ranges from 53% to about 65% for 32 mg TPIP capsule (containing 320 pg TP) and from 60% to about 65% for 16 mg TPIP capsule (containing 160 pg TP), when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 30-60 liter per minute (L / min), inspiratory volume of 1-4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0241] (iii) Emitted Dose (ED)

[0242] The term “emitted dose” or “ED”, as used herein, refers to the percentage of drug recovered in the NGI relative to the total recovery of drug. The ED is an indication of the delivery of a drug from a suitable inhaler device after a firing or dispersion event. For powder compositions, the ED is a measure of the percentage of powder that is drawn out of a unit dose package. The ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e. the mass of powder per unit dose placed into the DPI prior to firing).

[0243] In some embodiments, the aerosolized powder composition has an ED 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%, when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 30-60 liter per minute (L / min), inspiratory volume of 1-4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0244] In some embodiments, the aerosolized powder composition has an ED of 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 ranges therein, when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 30-60 liter per minute (L / min), inspiratory volume of 1-4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

[0245] In some embodiments, the aerosolized powder composition has ED greater than or equal to about 79% for 16 or 32 mg TP IP capsule at 60 LPM and about 72% for 16 mg TPIP capsule at 30 LPM.

[0246] In some embodiments, the aerosolized powder composition has ED ranges from about 79% to about 89% for 16 or 32 mg TPIP capsule at 60 LPM. In some embodiments, the aerosolized powder composition has ED ranges from about 72% to about 76% for 16 mg TPIP capsule at 30 LPM.

[0247] (iv) Mass Median Diameter (MMD) and Mass Median Aerodynamic Diameter (MMAD)

[0248] The term “mass median diameter” or “MMD”, as used herein, 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.

[0249] The term “mass median aerodynamic diameter” or “MMAD” is the MMD normalized with respect to the aerodynamic separation of aerosol droplets. MMAD is determined by cascade impaction. Mass median aerodynamic diameter (MMAD) is the value of aerodynamic diameter for which 50% of the mass in a given aerosol is associated with particles smaller than the median aerodynamic diameter (MAD), and 50% of the mass is associated with particles larger than the MAD.

[0250] For dry powder inhalers, oral cavity deposition is dominated by inertial impaction and so characterized by the aerosol’s Stokes number (DeHaan et al. Journal of Aerosol Science, 35 (3), 309-331, 2003). For equivalent inhaler geometry, breathing pattern and oral cavity geometry, the Stokes number, and so the oral cavity deposition, is primarily affected by the aerodynamic size of the inhaled powder. Hence, factors that contribute to oral deposition of a powder include the size distribution of the individual particles and the dispersibility of the powder. If the MMAD of the individual particles is too large, e.g. above 5 pm, then an increasing percentage of powder will deposit in the oral cavity. Likewise, if a powder has poor dispersibility, it is an indication that the particles will leave the dry powder inhaler and enter the oral cavity as agglomerates. Agglomerated powder will perform aerodynamically like an individual particle as large as the agglomerate, therefore even if the individual particles are small (e.g., MMAD of about 5 pm or less), the size distribution of the inhaled powder may have an MMAD of greater than about 5 pm, leading to enhanced oral cavity deposition. As discussed herein, the present disclosure is based, in part, on the surprising discovery the spray dried composition described herein does not agglomerate and produces a high percentage of small particles that can be delivered to the deep lung regions such as the alveolar spaces.

[0251] Powder particles with an MMAD of about 1 pm to about 3 pm can be effectively delivered to the deep lung regions such as the alveolar spaces. Larger aerodynamic diameters, for example, from about 3 pm to about 5 pm can be delivered to the central and upper airways.

[0252] In some embodiments, the aerosolized powder composition comprises particles with an MMAD of from about 1 pm to about 10 pm, from about 1 pm to about 7 pm, from about 1 pm to about 5 pm, or from about 1 pm to about 4 pm, or from about 1.5 pm to about 3.5 pm, or from about 2 pm to about 3 pm, as measured by NGI. In some embodiments, the present disclosure relates to a powder composition with MMAD of 5 pm or less, e.g. between about 1 pm to 5 pm (e.g., about 1 pm, about 2 pm, about 3 pm, about 4 pm, or about 5 pm).

[0253] In other embodiments, the aerosolized powder composition comprises a mass mean aerodynamic diameter (MMAD) less than 5 pm. In other embodiments, the aerosolized powder composition has the MMAD ranges from about 0.75 pm to about 3.0 pm (e.g., about 0.75 pm, about 1.0 pm, about 1.25 pm, about 1.5 pm, about 1.75 pm, about 2.0 pm, about 2.25 pm, about 2.5 pm, about 2.75 pm, or about 3.0 pm). In other embodiments, the aerosolized powder composition has the MMAD ranges from about 0.8 pm to about 2.0 pm.

[0254] In one embodiment, the powder composition exhibiting one of the MMAD profiles provided above comprises mannitol. In another embodiment, the powder composition exhibiting the MMAD profile provided above comprises trehalose.

[0255] (v) Particle size and distribution

[0256] In some embodiments, the powder composition comprises particles that have an average diameter ranging from about 1.0 pm to about 2.0 pm. In some embodiments, the particles have a D10 of about 0.3 pm. In some embodiments, the particles have a D50 of about 1.7 pm. In some embodiments, the particles have a D90 of about 3.8 pm. In some embodiments, these particle size distribution values distinguish the disclosed spray-dried powder compositions from similar compositions prepared by blending.

[0257] The present disclosure teaches the powder composition taught herein comprises from about 80 pg to about 1280 pg, from about 80 pg to about 640 pg, or from about 160 pg to about 1280 pg, or about 160 pg to about 640 pg of the compound of Formula (I).

[0258] In some embodiments, the powder composition taught herein comprises from about 80 pg to about 360 pg, from about 80 pg to about 320 pg, or from about 160 pg to about 320 pg of the compound of Formula (I).

[0259] In some embodiments, the powder composition taught herein comprises about 80 pg, 160 pg, 240 pg, 320 pg, 400 pg, 480 pg, 640 pg, 675 pg, 720 pg, 800 pg, 880 pg, 960 pg, 1040 pg , 1120 pg, 1200 pg, or 1280 pg of the compound of Formula (I), which is treprostinil palmitil. In other embodiments, the powder composition taught herein comprises about 80 pg, 160 pg, 240 pg, or 320 pg of the compound of Formula (I), which is treprostinil palmitil.

[0260] The present disclosure provides a powder composition comprising from about 80 pg to about 1280 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and wherein upon once daily inhalation administration via a dry powder inhaler, wherein the drypowder inhaler provides an aerosol comprising a fine particle fraction (FPF) greater than or equal to about 68%, as measured using a Next Generation Impactor (NGI).

[0261] The present disclosure also provides a powder composition comprising from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and wherein upon once daily inhalation administration via a dry powder inhaler, wherein the dry powder inhaler provides an aerosol comprising a fine particle fraction (FPF) greater than or equal to about 68%, as measured using a Next Generation Impactor (NGI).

[0262] In some embodiments, the powder composition comprises about 160 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the FPF that ranges from 78% to about 80%.

[0263] In some embodiments, the powder composition comprises about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the FPF that ranges from 68% to about 73%.

[0264] In some embodiments, the powder composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition.

[0265] In some embodiments, the powder composition comprises about 160 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the FPD that ranges from 60% to about 65%.

[0266] In some embodiments, the powder composition comprises about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the FPF that ranges from 53% to about 65%.

[0267] In some embodiments, the powder composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising an emitted dose (ED) greater than or equal to 72%.

[0268] In some embodiments, the powder composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the ED that ranges from about 79% to about 89%.

[0269] In some embodiments, the powder composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a mass mean aerodynamic diameter (MMAD) less than 5 pm.

[0270] In some embodiments, the powder composition comprises about 160 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the MMAD that ranges from about 1.0 pm to about 1.3 pm.

[0271] In some embodiments, the powder composition comprises about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the MMAD that ranges from about 1.3 pm to about 1.7 pm.Production of Powder compositions

[0272] The powder compositions of the present disclosure may be produced from liquid compositions using lyophilization or spray-drying techniques. In one embodiment, spray-drying methods are performed to arrive at the powder compositions described herein. When lyophilization is used, the lyophilized composition may be milled to obtain the finely divided powder containing particles within the desired size range described above. When spray-drying is used, the process is carried out under conditions that result in a finely divided powder containing particles within the desired size range described above. Exemplary methods of preparing dry powder forms of pharmaceutical compositions are disclosed in WO 96 / 32149, WO 97 / 41833, WO 98 / 29096, and U.S. Patent Nos. 5,976,574, 5,985,248, and 6,001,336, the disclosure of each of which is incorporated herein by reference in their entireties. Exemplary spray drying methods are described in U.S. Application Publication No. 2020 / 0338005, and U.S. Patent Nos. 6,848,197 and 8,197,845, the disclosure of each of which is incorporated herein by reference in their entireties.

[0273] In some embodiments, the powder composition of the present disclosure is prepared by the following process. A stock solution of a compound of Formula (I) or (II), astereoisomer thereof, or a pharmaceutically acceptable salt thereof is prepared using an organic solvent, such as an alcohol (e.g., 1 -propanol). Aqueous stock solutions of a sugar (e.g., mannitol or trehalose) and leucine are also prepared. Afterwards required amounts of the above stock solutions are added to a mixture of water and the organic solvent to form a spray drying feed solution. In the spray drying feed solution, the volume ratio of water to the organic solvent may be from about 3 :2 to about 1 : 1.

[0274] Spray drying is initiated by starting the drying gas flow and heating up the drying gas by setting the desired inlet temperature at, for example, from about 120 °C to about 180 °C, or from about 135 °C to about 150 °C. After the spray dryer outlet temperature reaches a suitable temperature, for example, at from about 55 °C to about 65 °C, the liquid skid inlet is set to allow blank solvents to be atomized with the aid of nitrogen into the spray dryer, and the system is allowed to cool and stabilize. Product filter pulsing is initiated, and product filter purge flow is set, for example, to 10 to 20 scfh. After the system stabilizes, the liquid skid inlet is switched to the feed solution prepared above and the process is continued till the feed solution runs out. At the point when the feed solution runs out, the liquid skid inlet is switched back to blank solvents, which are allowed to spray for from about 5 to about 20 minutes. At this point, powder is collected at the bottom of the product filter. After spraying the blank solvent for from about 5 to about 20 minutes, the system is shut down by shutting down the liquid lines, atomization gas, drying gas heater, drying gas inlet and finally the exhaust.Dry powder inhaler (DPI)

[0275] The powder compositions of the present disclosure are delivered to the lungs of a subject (e.g., patient) via inhalation using a dry powder inhaler (DPI). In one embodiment, the dry powder inhaler is a single dose dry powder inhaler. A propellant-free device, a DPI delivers powder to the lungs of a subject (e.g., patient) using the subject (e.g., patient) inspiration. The unit dose of a powder composition used in a DPI device is often a dry powder blister disc of hard capsule. Exemplary DPI devices suitable for delivering the powder compositions of the present disclosure include the devices described in the following paragraphs, as well as the DPIs described in U.S. Patent Nos. 6,766,799, 7,278,425 and 8,496,002, the disclosure of each of which is herein incorporated by reference in their entireties.

[0276] The DPI in one embodiment, is a capsule based DPI. In a further embodiment, the capsule based DPI is manufactured by Plastiape. In even a further embodiment, the capsule based DPI is a RS01 monodose dry powder inhaler developed by Plastiape, which features aI l lcompact size and a simple and effective perforation system and is suited for both gelatin and HMPC capsules.

[0277] Four Plastiape RS01 Model 7 DPIs (Plastiape S. p. A., Osnago, Italy) differ with respect to their device resistance: Ultra-high Resistance (UHR, code 239700005AA), High Resistance (HR, code 239700002 AA), Medium Resistance (MR, code 239700006 AA) and Low Resistance (LR, code 239700001AB). The pressure drop across each device containing an empty capsule was measured as a function of flow rate between 30 and 120 L / min (LPM). The present disclosure teaches that the high resistance DPI device is selected for evaluation and use. A peak inspiratory flow rate of 80 LPM, 60 LPM, 40 LPM, or 30 LPM corresponds to a pressure drop of 5.4 kPa, 4 kPa , 1.4 kPa, or 0.89 kPa, respectively, for the high resistance DPI.

[0278] Other dry powder inhalers are also available to the public and known to those skilled in the art, which may be used for the powder compositions of the present disclosure. A number of DPIs are available, such as, the inhalers disclosed is U.S. Pat. Nos. 4,995,385 and 4,069,819.

[0279] The AIR® inhaler (Alkermes) includes a small, breath-activated system that delivers porous powder from a capsule. The porous particles have an aerodynamic diameter of 1-5 pm. See International Patent Application Publication Nos. WO 99 / 66903 and WO 00 / 10541, the disclosure of each of which is incorporated herein by reference in their entireties.

[0280] Aerolizer™ (Novartis) is a single dose dry powder inhaler. In this device, dry powder medicament is stored in a capsule and released by piercing the capsule wall with TEFLON-coated steel pins. See U.S. Patent Nos. 6,488,027 and 3,991,761, the disclosure of each of which is incorporated herein by reference in their entireties.

[0281] Bang Olufsen provides a breath actuated inhaler using blister strips with up to sixty doses. The dose is made available only during the inhalation by a novel trigger mechanism. The device is equipped with a dose counter and can be disposed of after all doses have been used. See EP 1522325, the disclosure of which is incorporated herein by reference in its entirety.

[0282] Clickhaler® (Innovata PLC) is a large reservoir breath-activated multidose device. See U.S. Pat. 5,437,270, the disclosure of which is incorporated herein by reference in its entirety.

[0283] DirectHaler™ (Direct-Haler A / S) is a single dose, pre-metered, pre-filled, disposable DPI device made from polypropylene. See U.S. Patent No. 5,797,392, the disclosure of which is incorporated herein by reference in its entirety.

[0284] Diskus™ (GlaxoSmithKline) is a disposable small DPI device that holds up to 60 doses contained in double foil blister strips to provide moisture protection. See GB2242134, the disclosure of which is incorporated herein by reference in its entirety.

[0285] Eclipse™ (Aventis) is a breath actuated re-usable capsule device capable of delivering up to 20 mg of a powder composition. The powder is sucked from the capsule into a vortex chamber where a rotating ball assists in powder disaggregation as a subject (e.g., patient) inhales. See U.S. Pat. 6,230,707 and WO 9503846, the disclosure of each of which is incorporated herein by reference in their entireties.

[0286] Flexhaler® is a plastic breath-activated dry powder inhaler and is amenable for use with the powder compositions provided herein.

[0287] FlowCaps® (Hovione) is a capsule-based, re-fillable, re-usable passive drypowder inhaler that holds up to 14 capsules. The inhaler itself is moisture-proof. See U.S. Pat. 5,673,686, the disclosure of which is incorporated herein by reference in its entirety.

[0288] Gyrohaler® (Vectura) is a passive disposable DPI containing a strip of blisters. See GB2407042, the disclosure of which is incorporated herein by reference in its entirety.

[0289] The HandiHaler® (Boehringer Ingelheim GmbH) is a single dose DPI device. It can deliver up to 30 mg of a powder composition in capsules. See International Patent Application Publication No. WO 04 / 024156, the disclosure of which is incorporated herein by reference in its entirety.

[0290] MicroDose DPI (Microdose Technologies) is a small electronic DPI device. It uses piezoelectric vibrator (ultrasonic frequencies) to deaggragate the drug powder in an aluminum blister (single or multiple dose). See U.S. Patent No. 6,026,809, the disclosure of which is incorporated herein by reference in its entirety.

[0291] Nektar Dry Powder Inhaler® (Nektar) is a palm-sized and easy-to-use device. It provides convenient dosing from standard capsules and flow-rate-independent lung deposition.

[0292] Nektar Pulmonary Inhaler® (Nektar) efficiently removes powders from the packaging, breaks up the particles and creates an aerosol cloud suitable for deep lung delivery.It enables the aerosolized particles to be transported from the device to the deep lung during a subject’s (e.g., patient’s) breath, reducing losses in the throat and upper airways. Compressed gas is used to aerosolize the powder. See AU...

Claims

CLAIMS1. A powder composition comprising:(a) about 0.5 wt% to about 5 wt% of a compound of Formula (I)salt thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl,(b) about 10 wt% to about 61wt% leucine, and(c) trehalose, mannitol or a combination thereof, wherein the sum of (a), (b), and (c) is 100%; and when administered via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particle fraction (FPF) greater than or equal to about 68%, when measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4 L, and inhalation acceleration rate of 0.5-20 L / sec2.

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

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

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

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

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

7. The powder composition of any one of claims 1-6, wherein the aerosol comprises an emitted dose (ED) greater than or equal to 72%.

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

9. The powder composition of any one of claims 1-8, wherein the aerosol comprises a mass mean aerodynamic diameter (MMAD) less than 5 pm.

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

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

12. The powder composition of any one of claims 1-11, comprising particles, at least a portion of the particles comprising:(i) a compound of Formula (I) or stereoisomer or a pharmaceutically acceptable salt,(ii) leucine, and(iii) trehalose, mannitol or a combination thereof, wherein the particles have an average diameter ranging from about 1.0 pm to about 2.0 pm.

13. The powder composition of claim 12, wherein the particles have a DIO of about 0.3 pm.

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

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

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

17. The powder composition of claim 16, wherein R1 is linear hexadecyl.

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

19. The powder composition of claim 18, wherein R1 is linear tetradecyl.

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

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

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

23. The powder composition of claim 22, wherein R1 is linear hexadecyl.

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

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

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

27. The powder composition of claim 26, wherein R1 is linear octadecyl.

28. The powder composition of any one of claims 1-27, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 4.5 wt% of the total weight of the powder composition.

29. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 4.5 wt% of the total weight of the powder composition.

30. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 4 wt% of the total weight of the powder composition.

31. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 3.5 wt% of the total weight of the powder composition.

32. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 3 wt% of the total weight of the powder composition.

33. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 2.5 wt% of the total weight of the powder composition.

34. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 2 wt% of the total weight of the powder composition.

35. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 1 wt% to about 1.5 wt% of the total weight of the powder composition.

36. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof is present at from about 2 wt% to about 4 wt% of the total weight of the powder composition.

37. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 2 wt% to about 3.5 wt% of the total weight of the powder composition.

38. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 2 wt% to about 3 wt% of the total weight of the powder composition.

39. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 2 wt% to about 2.5 wt% of the total weight of the powder composition.

40. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 3 wt% to about 4.5 wt% of the total weight of the powder composition.

41. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 3 wt% to about 4 wt% of the total weight of the powder composition.

42. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 3 wt% to about 3.5 wt% of the total weight of the powder composition.

43. The powder composition of claim 28, wherein the compound of Formula (I), or apharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 2 wt% of the total weight of the powder composition.

44. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 1.5 wt% of the total weight of the powder composition.

45. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 0.5 wt% to about 1 wt% of the total weight of the powder composition.

46. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 3.5 wt% to about 4.5 wt% of the total weight of the powder composition.

47. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at from about 4 wt% to about 4.5 wt% of the total weight of the powder composition.

48. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof is present at from about 0.5 wt% of the total weight of the powder composition.

49. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 1 wt% of the total weight of the powder composition.

50. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 1.5 wt% of the total weight of the powder composition.

51. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 2 wt% of the total weight of the powder composition.

52. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 2.5 wt% of the total weight of the powder composition.

53. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 3 wt% of the total weight of the powder composition.

54. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 3.5 wt% of the total weight of the powdercomposition.

55. The powder composition of claim 28, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present at about 4 wt% of the total weight of the powder composition.

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

57. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 25 wt% to about 61 wt% of the total weight of the powder composition.

58. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 40 wt% to about 61 wt% of the total weight of the powder composition.

59. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 50 wt% to about 61 wt% of the total weight of the powder composition.

60. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 55 wt% to about 61 wt% of the total weight of the powder composition.

61. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 58 wt% to about 61 wt% of the total weight of the powder composition.

62. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 40 wt% to about 45 wt% of the total weight of the powder composition.

63. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 44 wt% to about 51 wt% of the total weight of the powder composition.

64. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 43 wt% to about 48 wt% of the total weight of the powder composition.

65. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 25 wt% to about 30 wt% of the total weight of the powder composition.

66. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 28 wt% to about 30 wt% of the total weight of the powder composition.

67. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 25 wt% to about 33 wt% of the total weight of the powder composition.

68. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 27 wt% to about 33 wt% of the total weight of the powder composition.

69. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 27 wt% to about 31 wt% of the total weight of the powder composition.

70. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 27 wt% to about 30 wt% of the total weight of the powder composition.

71. The powder composition of any one of claims 1-56, wherein the leucine is present at from about 28 wt% to about 30 wt% of the total weight of the powder composition.

72. The powder composition of any one of claims 1-56, wherein the leucine is present at about 30 wt% of the total weight of the powder composition.

73. The powder composition of any one of claims 1-56, wherein the leucine is present at about 45 wt% of the total weight of the powder composition.

74. The powder composition of any one of claims 1-56, wherein the leucine is present at about 60 wt% of the total weight of the powder composition.

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

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

77. The powder composition of claim 1, selected from one of the following compositions:

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

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

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

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

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

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

84. The powder composition of any one of claims 78-83, comprising the compound of Formula (I) at from about 0.5 wt% to about 4 wt% of the total weight of the powder composition.

85. The powder composition of any one of claims 78-83, comprising the compound of Formula (I) at from about 0.5 wt% to about 3 wt% of the total weight of the powder composition.

86. The powder composition of any one of claims 78-83, comprising the compound of Formula (I) at from about 0.5 wt% to about 2 wt% of the total weight of the powder composition.

87. The powder composition of any one of claims 78-83, comprising the compound of Formula (I) at from about 0.5 wt% to about 1.5 wt% of the total weight of the powder composition.

88. The powder composition of any one of claims 78-87, comprising the compound of Formula (I) at from about 1 wt% to about 1.5 wt% of the total weight of the powder composition.

89. The powder composition of any one of claims 78-87, comprising the compound of Formula (I) at from about 2 wt% to about 4 wt% of the total weight of the powder composition.

90. The powder composition of any one of claims 78-87, comprising the compound of Formula (I) at from about 3 wt% to about 4 wt% of the total weight of the powder composition.

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

92. The powder composition of claim 1, comprising (a) about 0.5 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 29 wt% to about 30 wt% leucine, and the balance being (c) mannitol.

93. The powder composition of claim 1, comprising (a) about 1 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 29 wt% to about 30 wt% leucine, and the balance being (c) mannitol.

94. The powder composition of claim 1, comprising (a) about 1.5 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 29 wt% to about 30 wt% leucine, and the balance being(c) mannitol.

95. The powder composition of claim 1, comprising (a) about 2 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 29 wt% to about 30 wt% leucine, and the balance being (c) mannitol.

96. The powder composition of claim 1, comprising (a) about 3 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 29 wt% to about 30 wt% leucine, and the balance being (c) mannitol.

97. The powder composition of claim 1, comprising (a) about 4 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 29 wt% to about 30 wt% leucine, and the balance being (c) mannitol.

98. The powder composition of claim 1, comprising (a) about 0.5 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol.

99. The powder composition of claim 1, comprising (a) about 1 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol.

100. The powder composition of claim 1, comprising (a) about 1.5 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol.

101. The powder composition of claim 1, comprising (a) about 2 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol.

102. The powder composition of claim 1, comprising (a) about 3 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol.

103. The powder composition of claim 1, comprising (a) about 4 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 60 wt% to about 61 wt% leucine, and the balance being (c) mannitol.

104. The powder composition of claim 1, comprising (a) about 0.5 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol.

105. The powder composition of claim 1, comprising (a) about 1 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol.

106. The powder composition of claim 1, comprising (a) about 1.5 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol.

107. The powder composition of claim 1, comprising (a) about 2 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol.

108. The powder composition of claim 1, comprising (a) about 3 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol.

109. The powder composition of claim 1, comprising (a) about 4 wt% of the compound of Formula (I), wherein R1 is linear hexadecyl, (b) about 43 wt% to about 45 wt% leucine, and the balance being (c) mannitol.

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

111. The powder composition of any one of claims 1-110, comprising from about 80 pg to about 360 pg of the compound of Formula (I).

112. The powder composition of claim 111, comprising from about 80 pg to about 320 pg of the compound of Formula (I).

113. The powder composition of claim 111, comprising from about 160 pg to about 320 pg of the compound of Formula (I).

114. The powder composition of claim 111, comprising about 80 pg of the compound of Formula (I).

115. The powder composition of claim 111, comprising about 160 pg of the compound of Formula (I).

116. The powder composition of claim 111, comprising about 240 pg of the compound of Formula (I).

117. The powder composition of claim 111, comprising about 320 pg of the compound of Formula (I).

118. The powder composition of any one of claims 1-117, wherein the composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particle fraction (FPF) greater than or equal to about 68%, as measured using a Next Generation Impactor (NGI).

119. The powder composition of any one of claims 1-118, wherein the composition comprises about 160 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, wherein the dry powder inhaler provides an aerosol comprisingthe FPF that ranges from 78% to about 80%.

120. The powder composition of any one of claims 1-118, wherein the composition comprises about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the FPF that ranges from 68% to about 73%.

121. The powder composition of any one of claims 1-120, wherein the composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a fine particle dose (FPD) greater than or equal to 50% of a loaded dose of the powder composition.

122. The powder composition of any one of claims 1-121, wherein the composition comprises about 160 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the FPD that ranges from 60% to about 65%.

123. The powder composition of any one of claims 1-121, wherein the composition comprises about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the FPD that ranges from 53% to about 65%.

124. The powder composition of any one of claims 1-123, wherein the composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising an emitted dose (ED) greater than or equal to 72%.

125. The powder composition of any one of claims 1-124, wherein the composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the ED that ranges from about 79% to about 89%.

126. The powder composition of any one of claims 1-125, wherein the composition comprises from about 160 pg to about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising a mass mean aerodynamic diameter (MMAD) less than 5 pm.

127. The powder composition of any one of claims 1-126, wherein the composition comprises about 160 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the MMAD that ranges from about 1.0 pm to about 1.3 pm.

128. The powder composition of any one of claims 1-126, wherein the composition comprises about 320 pg of a compound of Formula (I), wherein R1 is linear hexadecyl, and upon once daily inhalation administration via a dry powder inhaler, the dry powder inhaler provides an aerosol comprising the MMAD that ranges from about 1.3 pm to about 1.7 pm.

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

130. The method of claim 129, wherein administering comprises (i) aerosolizing the powder composition via the DPI to provide an aerosolized powder composition, and (ii) administering the aerosolized powder composition to the lungs of the patient via inhalation with the DPI.

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

132. The method of any one of claims 129-131, wherein the patient is administered two or more different dosages of the compound of Formula (I) during the administration period.

133. The method of claim 132, wherein the patient is administered two different dosages of the compound of Formula (I) during the administration period.

134. The method of claim 132, wherein the patient is administered three different dosages of the compound of Formula (I) during the administration period.

135. The method of claim 132, wherein the patient is administered four different dosages of the compound of Formula (I) during the administration period.

136. The method of claim 132, wherein the patient is administered five different dosages of the compound of Formula (I) during the administration period.

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

138. The method of any one of claims 132-136, wherein prior to receiving a higher dosage of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the patient is administered a lower dosage for three or more consecutive days.

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

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

141. The method of any one of claims 129-138, wherein the PH is group 3 PH, as classified by theWHO.

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

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

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

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

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

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

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

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

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

151. The method of claim 150, wherein the ILD comprises one or more lung conditions selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, hypersensitivity pneumonitis, acute interstitial pneumonitis, 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 of any one of claims 129-155, wherein treating comprises reducing the pulmonary vascular index (PVRI) of the patient during the administration period, compared to the patient’s PVRI prior to the administration period.

157. The method of any one of claims 129-156, wherein treating comprises reducing the mean pulmonary artery pressure of the patient during the administration period, compared to the mean pulmonary artery pressure of the patient prior to the administration period.

158. The method of any one of claims 129-157, wherein treating comprises increasing the hypoxemiascore of the patient during the hypoxemia score of the patient prior to the administration period.

159. The method of any one of claims 129-158, wherein decreasing the oxygenation index of the patient during the administration period, compared to the oxygenation index of the patient prior to the administration period.

160. The method of any one of claims 129-159, wherein treating comprises improving the right heart function of the patient during the administration period, compared to the right heart function of the patient prior to the administration period.

161. The method of any one of claims 129-160, wherein treating comprises improving exercise capacity of the patient during the administration period, compared to the exercise capacity of the patient prior to the administration period.

162. The method of claim 161, wherein exercise capacity is measured by the six-minute walk test (6MWT).

163. The method of claim 162, wherein improving exercise capacity comprises increasing the patient’s distance walked in the 6MWT 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 during the administration period, compared to the patient’s distance walked in the 6MWT prior to the administration period.

164. The method of claim 162, wherein improving exercise capacity comprises increasing the patient’s distance walked in the 6MWT by from about 5 meters to about 60 meters, by from about 5 meters to about 50 meters, by from about 10 meters to about 50 meters, by from about 15 meters to about 50 meters, or by from about 20 meters to about 40 meters, during the administration period, compared to the patient’s distance walked in the 6MWT prior to the administration period.

165. The method of any one of claims 129-164, wherein treating comprises improving the quality of life of the patient during the administration period, compared to the quality of life of the patient prior to the administration period.

166. The method of claim 165, wherein the quality of life of the patient is measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Questionnaire.

167. The method of claim 166, wherein treating comprises decreasing the patient’s CAMPHOR Questionnaire score during the administration period by from 1 to about 10, from 1 to about 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3 or from 1 to 2, compared to the patient’s CAMPHOR Questionnaire score prior to the administration period.

168. The method of any one of claims 129-167, wherein treating comprises increasing the patient’s saturation of peripheral capillary oxygenation (SpCh) at rest assessed by pulse oximetry, during the administration period, compared to the patient’s SpCh at rest assessed by pulse oximetry prior to theadministration period.

169. The method of any one of claims 129-167, wherein treating comprises improving the patient’s lung function during the administration period, as compared to the patient’s lung function prior to the administration 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 administration period, compared to the patient’s PVC prior to the administration period.

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

172. The method of claim 169, wherein improving the patient’s lung function comprises increasing the patient’s the patient’s forced expiratory volume in 1 second (FEVi) during the administration period, compared to the patient’s FEVi prior to the administration period.

173. The method of claim 172, wherein increasing the patient’ s the patient’ s forced expiratory volume in 1 second (FEVi) during the administration period comprises increasing the patient’s FEVI by from about 5% to about 50%, from about 5% to about 40% or from about 5% to about 30%, compared to the patient’s FEVi prior to the administration period.

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

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

176. The method of claim 172, wherein increasing the FEVi comprises increasing by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30%, by about 5% to about 20%, by about 10 to about 50%, by about 15% to about 50%, by about 20% to about 50% or by about 25% to about 50 .177 The method of claim 172, wherein increasing the FEVi comprises increasing by of at least about 5178 The method of claim 172, wherein increasing the FEVi comprises increasing by from about 5% to about 50%, or from about 10% to about 50%, or from about 15% to about 50%.179 The method of claim 172, wherein increasing the FEVi comprises increasing by about 25 mL to about 500 mL.180 The method of claim 172, wherein increasing the FEVi comprises increasing by about 25 mL toabout 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%, by about 2%, by about 3%, by about 4%, by about 5%, by about 6%, by about 7%, by about 8%, by about 9%, by about 10%, by about 11%, by about 12%, by about 13%, by about 14%, by about 15%, by about 16%, by about 17%, by about 18%, by about 19%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, by about 55%, by about 60%, by about 65%, by about 70%, by about 75%, by about 80%, by about 85% or by about 90%, as compared to a FVC of the patient prior to the administration period.

182. 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 from about 1% to about 20%, from about 1% to about 15%, from about 1% to about 10%, from about 1% to about 5%, from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, from about 5% to about 20%, from about 10% to about 50%, from about 15% to about 50%, from about 20% to about 50%, or from about 25% to about 50%, as compared to a FVC of the patient prior to the administration period.

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

184. The method of claim 183, wherein increasing the patient’s total lung 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 by at least about 50% during the administration period, compared to the patient’s TLC prior to the administration period.

185. The method of claim 183, wherein increasing the patient’s total lung capacity (TLC) comprises increasing the patient’s TLC by from about 1% to about 50%, by from about 5% to about 50%, by from about 5% to about 40%, by from about 5% to about 30%, by from about 5% to about 20%, by from about 10% to about 50%, by from about 15% to about 50%, by from about 20% to about 50%, or by from about 25% to about 50%. during the administration period, compared to the patient’s TLC prior to the administration period.

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

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

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

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

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

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

192. The method of claim 186, wherein the administration period is from about 1 year to about 5 years.

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

194. The method of any one of claims 129-192, wherein the dry powder inhaler (DPI) is a capsulebased DPI, and the composition is split between two DPI capsules.

195. A system for treating pulmonary hypertension, comprising (i) a powder composition and (ii) a dry powder inhaler, the powder comprising:(a) from about 0.5 wt% to about 5 wt% of a compound of Formula (I)thereof, wherein R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl,(b) from about 10 wt% to about 61wt% leucine, and(c) trehalose, mannitol or a combination thereof, wherein the sum of (a), (b), and (c) is 100%; and wherein the dry powder inhaler provides an aerosol comprising fine particle fraction (FPF) greater than or equal to about 68%, as measured using a Next Generation Impactor (NGI), with a inspiratory flow rate of 60 liter per minute (L / min), inspiratory volume of 4L, and inhalation acceleration rate of 0.5-20 L / sec2.

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

197. The powder, method or system of any one of claims 1-196, wherein the dry powder inhaler has a resistance ranging from about 0.030 to about 0.040 kPA1 / 2(L / min'1)'1.

198. The powder, method or system of any one of embodiments 1-197, wherein the dry powder inhaler has a resistance ranging from about 0.034 to about 0.036 kPA1 / 2(L / rnin'1)'1.

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