Dry powder compositions of a treprostinil prodrug and methods of using the same

Abstract

This disclosure provides a dry powder composition of treprostol prodrug and a method of treating pulmonary hypertension (e.g., pulmonary arterial hypertension or PH associated with interstitial lung disease) in patients in need using said dry powder composition. The dry powder composition comprises: (a) about 0.5 wt% to about 5 wt% of a compound, its stereoisomers, or a pharmaceutically acceptable salt thereof; (b) about 10 wt% to about 61 wt% of leucine; and the remainder is (c) a sugar selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%, and R1 is tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl. The method of treating PH comprises administering an effective amount of the dry powder composition to the lungs of the patient by inhalation via a dry powder inhaler during an administration period.

Description

[0001] Cross-referencing related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 106,818, filed on October 28, 2020, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] Pulmonary hypertension (PH) is characterized by abnormally high blood pressure in the pulmonary vessels. It is a progressive and fatal condition that can lead to heart failure and can occur in the pulmonary arteries, pulmonary veins, or pulmonary capillaries. Symptomatic patients may experience shortness of breath, dizziness, syncope, and other symptoms, all of which are exacerbated by exertion. The disease can have various causes, including those of unknown origin and idiopathic conditions, and may lead to hypertension in other systems, such as portal pulmonary hypertension (PVH) where the patient also has portal hypertension and pulmonary hypertension.

[0004] The World Health Organization (WHO) has classified pulmonary hypertension into five groups. Group 1, known as pulmonary arterial hypertension (PAH), includes PAH of unknown cause (idiopathic), hereditary PAH (i.e., familial PAH or FPAH), PAH caused by drugs or toxins, and PAH caused by conditions such as connective tissue diseases, HIV infection, liver disease, and congenital heart disease. Group 2 pulmonary hypertension is characterized by pulmonary hypertension associated with left ventricular heart disease. Group 3 pulmonary hypertension is characterized by PH associated with lung diseases such as chronic obstructive pulmonary disease and interstitial lung disease, as well as PH associated with sleep-related breathing disorders (e.g., sleep apnea). Group 4 PH is caused by chronic thrombotic and / or embolic diseases, such as PH caused by blood clots in the lungs or blood clotting disorders. Group 5 includes PH caused by other conditions or symptoms, such as hematologic disorders (e.g., polycythemia vera, spontaneous thrombocythemia), systemic diseases (e.g., sarcoidosis, vasculitis), and metabolic disorders (e.g., thyroid disease, glycogen storage disease).

[0005] Approximately 200,000 people worldwide suffer from pulmonary arterial hypertension (PAH), with about 30,000-40,000 of them in the United States. PAH patients experience pulmonary artery constriction, which makes it difficult for the heart to pump blood to the lungs. Patients suffer from shortness of breath and fatigue, which often severely limits their ability to perform physical activities.

[0006] The New York Heart Association (NYHA) categorizes patients with paroxysmal arterial hypertension (PAH) into four functional categories to assess the severity of the disease. Patients with PAH classified by the NYHA have no limitation of physical activity because normal physical activity does not cause excessive dyspnea or fatigue, chest pain, or near-syncope. Patients with PAH classified by the NYHA have slightly limited physical activity. These patients feel comfortable at rest, but normal physical activity causes excessive dyspnea or fatigue, chest pain, or near-syncope. Patients with PAH classified by the NYHA have significantly limited physical activity. Although they feel comfortable at rest, they experience excessive dyspnea or fatigue, chest pain, or near-syncope due to less physical activity than usual. Patients with PAH classified by the NYHA cannot perform any physical activity without symptoms. Patients with PAH may experience dyspnea and / or fatigue at rest, and any physical activity increases discomfort. Patients with PAH often show signs of right heart failure.

[0007] Patients with PAH can be treated with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE-5) inhibitors, guanylate cyclase stimulants, prostaglandins (e.g., prostacyclin), or combinations thereof. ERAs contain ampexentan. Sitathan, Bosentan and Maciten The indicated PDE-5 inhibitors used to treat PAH include sildenafil. and Tadalafil The prostaglandins used to treat PAH include iloprost, eprostol, and treprostol. One approved guanylate cyclase stimulant is leocygua. In addition, patients are often treated with a combination of the aforementioned compounds.

[0008] This invention addresses the need for novel treatment options for pulmonary hypertension (PH) (including pulmonary arterial hypertension (PAH) and PH associated with interstitial lung disease), portal pulmonary hypertension (PPH), and pulmonary fibrosis by providing a dry powder composition of treprostol prodrug that can be administered to the lungs and a method for administering the dry powder composition to a patient in need of treatment. Summary of the Invention

[0009] In one aspect, this disclosure relates to a dry powder composition comprising: (a) about 0.5 wt% to about 5 wt% of a compound of formula (I):

[0010]

[0011] Its stereoisomer or its pharmaceutically acceptable salt, wherein R 1The composition comprises (a) tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl; (b) about 10 wt% to about 61 wt% leucine; and the remainder comprises (c) a sugar selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%. In another embodiment, the composition comprises about 29 wt% to about 61 wt% leucine. In even further embodiments, the composition comprises 0.5 wt% to about 4 wt% of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment, the stereoisomer is a diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the stereoisomer is a diastereomer of the compound of formula (I). In yet another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of the compound of formula (I).

[0013] In one embodiment, R 1 It is tetradecyl. In another embodiment, R 1 It is a straight-chain tetradecyl group.

[0014] In one embodiment, R 1 It is a pentadecyl group. In another embodiment, R... 1 It is a straight-chain pentadecyl group.

[0015] In one embodiment, R 1 It is a heptadecanyl group. In another embodiment, R... 1 It is a straight-chain heptadecanyl group.

[0016] In one embodiment, R 1 It is octadecyl. In another embodiment, R 1 It is a straight-chain octadecyl group.

[0017] In one embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0018] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 0.5 wt% to about 4 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at about 2 wt% to about 4 wt% of the total weight of the dry powder composition.

[0019] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 4 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0020] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 3.5 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0021] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 3 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0022] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 1.5 wt% to about 4 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0023] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 0.8 wt% to about 4 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0024] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 0.8 wt% to about 3.3 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0025] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 2 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0026] In one embodiment, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

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

[0028] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present at about 2 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

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

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

[0031] In one embodiment, leucine is present at about 20 wt% to about 40 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are present at about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0032] In another embodiment, leucine is present at about 29 wt% to about 61 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are present at about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0033] In another embodiment, leucine is present at about 25 wt% to about 35 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are present at about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0034] In another embodiment, leucine is present at about 40 wt% to 61 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In even further embodiments, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts are present at about 1 wt% to about 4 wt% of the total weight of the dry powder composition. In further embodiments, leucine is present at about 45 wt% to 61 wt% of the total weight of the dry powder composition. In even further embodiments, leucine is present at about 55 wt% to 61 wt% of the total weight of the dry powder composition.

[0035] In another embodiment, leucine is present at about 28 wt% to about 33 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0036] In another embodiment, leucine is present at about 25 wt% to about 33 wt% of the total weight of the dry powder composition, for example, at about 27 wt% to about 33 wt%, about 27 wt% to about 31 wt%, about 27 wt% to about 30 wt%, about 28 wt% to about 30 wt% or about 30 wt% of the total weight of the dry powder composition. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0037] In one embodiment, the dry powder composition provided herein has a leucine:mannitol weight ratio of about 0.40:1 (leucine:mannitol) to about 0.50:1 (leucine:mannitol). In another embodiment, the dry powder composition provided herein has a leucine:mannitol weight ratio of about 0.75:1 (leucine:mannitol) to about 0.90:1 (leucine:mannitol). In yet another embodiment, the dry powder composition provided herein has a leucine:mannitol weight ratio of about 0.15:1 (leucine:mannitol) to about 1.7:1 (leucine:mannitol).

[0038] In one embodiment, the sugar is mannitol. In another embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0039] In one embodiment, the dry powder composition comprises: (a) about 1 wt% of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29.3 wt% or about 29.6 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0040] In one embodiment, the dry powder composition comprises (a) about 3 wt% of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, (b) about 29.3 wt% or about 29.6 wt% of leucine, and the remainder as (c) mannitol. In another embodiment, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group.

[0041] In another aspect of the invention, a method for treating pulmonary hypertension (PH) in a patient in need is provided. The method comprises administering an effective amount of the dry powder composition disclosed herein to the patient's lungs via inhalation through a dry powder inhaler.

[0042] In one embodiment, PH is a Group 1 PH as characterized by the World Health Organization (WHO).

[0043] In one embodiment, pulmonary hypertension is pulmonary arterial hypertension (PAH). In one embodiment, PAH is a Class I PAH as characterized by the New York Heart Association (NYHA). In another embodiment, PAH is a Class II PAH as characterized by the NYHA. In another embodiment, PAH is a Class III PAH as characterized by the NYHA. In yet another embodiment, PAH is a Class IV PAH as characterized by the NYHA.

[0044] In another embodiment, the PH is a Group 2 PH as characterized by the WHO. In another embodiment, the PH is a Group 3 PH as characterized by the WHO. In yet another embodiment, the Group 3 PH is a PH associated with interstitial lung disease (ILD). In another embodiment, the PH is a Group 4 PH as characterized by the WHO. In yet another embodiment, the PH is a Group 5 PH as characterized by the WHO.

[0045] In one embodiment of the treatment method described herein, the application is performed once a day or twice a day.

[0046] In another aspect, this disclosure relates to a system for treating pH. The system comprises one of the dry powder compositions disclosed herein and a dry powder inhaler (DPI), which may be a single-dose or multi-dose inhaler. In another embodiment, the DPI is a predicted amount or device-measured amount.

[0047] Another aspect of the invention relates to a method for treating PH (e.g., PAH or PH-ILD) in an adult patient in need, the method comprising administering a dry powder composition once daily by inhalation to the patient's lungs during an administration period, the dry powder composition comprising about 80 μg to about 675 μg of a compound of formula (I):

[0048]

[0049] Its stereoisomers or its pharmaceutically acceptable salts,

[0050] Where R 1 It is tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl.

[0051] During the administration period, the patient possesses at least one of the following characteristics:

[0052] (a) The maximum plasma concentration of treprostacyclin (C0.05) in the range of approximately 80% to 125% of the range of approximately 17 pg / mL to approximately 1150 pg / mL. max );or

[0053] (b) Plasma concentration curves (AUC) ranging from approximately 80% to approximately 125% of the range of approximately 475 pg*h / mL to approximately 8000 pg*h / mL. 0-inf The treprostacyclin region below. In another embodiment, R 1 It is a hexadecyl group, for example, a straight-chain hexadecyl group.

[0054] In another embodiment, the composition comprises a dose of the compound of formula (I) selected from the group consisting of 80 μg, 160 μg, 240 μg, 320 μg, 400 μg, 480 μg, and 640 μg. The dose may be, for example, present in a dry powder capsule or multiple capsules.

[0055] In another aspect, the present invention relates to a dry powder composition comprising about 80 μg to about 675 μg of a compound of formula (I):

[0056]

[0057] Its stereoisomer or a pharmaceutically acceptable salt thereof. In this respect, the dry powder composition provides at least one of the following properties:

[0058] (a) The maximum treprostacyclin plasma concentration (C) in the range of approximately 80% to approximately 125% of the maximum treprostacyclin plasma concentration (C) in the range of approximately 17 pg / mL to approximately 1150 pg / mL. max );or

[0059] (b) Plasma concentration curves (AUC) ranging from approximately 80% to approximately 125% of the range of approximately 475 pg*h / mL to approximately 8000 pg*h / mL. 0-inf The area under )

[0060] In another embodiment, the composition comprises a dose of the compound of formula (I) selected from the group consisting of 80 μg, 160 μg, 240 μg, 320 μg, 400 μg, 480 μg, and 640 μg. The dose may be, for example, present in a dry powder capsule or multiple capsules.

[0061] In some embodiments, the dry powder composition described herein and used in the methods described herein comprises about 1 wt% to about 5 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein the remainder is one or more pharmaceutically acceptable excipients suitable for use in a dry powder inhaler. In some embodiments, one or more pharmaceutically acceptable excipients suitable for use in a dry powder inhaler include sugars, amino acids, and optionally distearate-phosphoryl ethanolamine-polyethylene glycol 2000 (DPSE-PEG2000). In some embodiments of the dry powder composition or method described herein, the dry powder composition comprises about 25 wt% to about 61 wt% leucine, wherein the remainder is one or more sugars. In some embodiments, one or more sugars are selected from trehalose and mannitol. In some embodiments of the dry powder composition or method described herein, the dry powder composition does not contain distearate-phosphoryl ethanolamine-polyethylene glycol 2000 (DPSE-PEG2000). Attached Figure Description

[0062] Figure 1This is a graph showing the concentration of treprostacyclin palmitate (TP) in the lungs after inhalation of TPIP-A or TPIP-B.

[0063] Figure 2 This is a graph showing the concentration of TRE in plasma after inhalation of TPIP-A or TPIP-B.

[0064] Figure 3 A graph showing the concentration of treprostacyclin palmitate (TP) equivalents in the lungs after inhalation of TPIP-A or TPIP-B.

[0065] Figure 4 This is a graph showing the concentration of TRE in plasma after inhalation of TPIP-A or TPIP-B.

[0066] Figure 5 This is a graph showing the concentration of TP in BAL cell fractions after inhalation of TPIP-A or TPIP-B.

[0067] Figure 6 This is a graph showing the concentration of TRE in BAL cell fractions after inhalation of TPIP-A or TPIP-B.

[0068] Figure 7 This is a graph showing the concentration of TP equivalents in BAL cell fractions after inhalation of TPIP-A or TPIP-B.

[0069] Figure 8 This is a graph showing the concentration of TP in BAL fluid after inhalation of TPIP-A or TPIP-B.

[0070] Figure 9 This is a graph showing the concentration of TRE in BAL fluid after inhalation of TPIP-A or TPIP-B.

[0071] Figure 10 This is a graph showing the concentration of TP equivalent in BAL fluid after inhalation of TPIP-A or TPIP-B.

[0072] Figure 11 This is a graph showing the ΔRVPP response to hypoxia challenge in rats exposed to 6 μg / kg of inhaled TPIP-B.

[0073] Figure 12 This is a graph showing the ΔRVPP response to hypoxia challenge in rats exposed to inhaled TPIP-B at 23 μg / kg.

[0074] Figure 13 This is a graph showing the ΔRVPP response to hypoxia challenge in rats exposed to inhaled TPIP-B at a dose of 57 μg / kg.

[0075] Figure 14 This is a graph showing the ΔRVPP response to hypoxia challenge in rats exposed to inhaled TPIP-B at 138 μg / kg.

[0076] Figure 15 This is a graph showing the TRE concentration in plasma after inhalation of TPIP-B.

[0077] Figure 16 This is a graph showing the TP concentration in the lungs after inhaling TPIP-B.

[0078] Figure 17 This is a graph showing the TRE concentration in the lungs after inhaling TPIP-B.

[0079] Figure 18 This is a graph showing the concentration of TP equivalent in the lungs after inhalation of TPIP-B.

[0080] Figure 19 This is a schematic diagram of a study design for testing the pharmacokinetic (PK) characteristics of single and multiple daily doses of TPIP-B in healthy adults. D: Day; PK: Pharmacokinetics; QD: Once daily; Scn: Screening; TPIP: Treprostacyclin palmitate inhalation powder.

[0081] Figure 20A This is a graph showing the PK results of TPIP-A in healthy adults (single dose).

[0082] Figure 20B This is a graph showing the PK findings of TPIP-A in healthy adults (multi-dose).

[0083] Figure 21 The top shows an example of a dosing titration schedule for compounds of formula (I) or (II). Figure 21 The bottom shows according to Figure 21 The titration schedule at the top of the table specifies the capsule dosage used. Detailed Implementation

[0084] Throughout this disclosure, the term “about” may be used in conjunction with numerical values ​​and / or ranges. The term “about” should be understood to mean those values ​​that are close to the listed values. For example, “about 40 [units]” may mean within ±25% (e.g., 30 to 50) of 40, within ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, or any other value or range of values ​​in or below these values.

[0085] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, wherein the non-toxic base or acid comprises an inorganic or organic base and an inorganic or organic acid. The properties of the salt are not critical, the condition being that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or from organic acids. Exemplary pharmaceutical salts are disclosed in the following literature: *Handbook of Pharmaceutical Salts: Properties, Selection and Use*, edited by Stahl, PH and Wermuth, CG; Verlag Helvetica Chimica Acta / Wiley-VCH: Zurich, 2002, the contents of which are incorporated herein by reference in their entirety. Specific, non-limiting examples of inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclic carboxylic acids and sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylsulfamic acid, alginic acid, 3-hydroxybutyric acid, galactobionic acid, or galacturonic acid. Suitable pharmaceutically acceptable salts of the free acid-containing compounds disclosed herein include, but are not limited to, metal salts and organic salts. Exemplary metal salts include, but are not limited to, suitable alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Exemplary organic salts can be made from primary amines, secondary amines, tertiary amines, and quaternary ammonium salts, such as tromethamine, diethylamine, tetra-N-methylammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine.

[0086] As used herein, the term "stereoisomer" refers to two molecules having the same molecular formula and a sequence of bound atoms but with different three-dimensional orientations of their atoms in space. A preferred stereoisomer according to the invention is a diastereomer. In one embodiment, the stereoisomer is a diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the stereoisomer is a diastereomer of a compound of formula (I). In yet another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of a compound of formula (I). In yet another embodiment, the stereoisomer is a diastereomer of a compound of formula (II). In even another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of a compound of formula (II).

[0087] Throughout this specification, a specific number of numerical ranges are provided. It should be understood that these ranges include all subranges within them. Therefore, the range "50-80" encompasses all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range can be endpoints of the ranges it covers (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0088] Throughout this specification, numerical ranges are described as covering “about 80% to about 125%” or “about 80-125%” of the range of values. It should be understood that these include 80% of the lowest endpoint of the range to 125% of the highest endpoint of the range and all values ​​therein.

[0089] Term "C" max "This refers to the maximum (or peak) serum concentration of treprostacyclin measured after administration of a compound of formula (I) or (II) or its stereoisomers or pharmaceutically acceptable salts thereof to the lungs of a subject via the dry powder composition described herein. Additionally, C can be measured after a single administration of a compound of formula (I) or (II) described herein, its stereoisomers or pharmaceutically acceptable salts thereof." max Alternatively, treprostacyclin C can be measured under steady-state conditions. max Unless otherwise stated, C max This refers to the mean treprostacyclin C measured after a single administration in a subject population (e.g., a population of patients with PH). max .

[0090] The term "AUC" refers to the region under the plasma concentration-time curve of treprostacyclin, measured from time 0 to a point after administration to the lungs of the subject, calculated using a combination of linear and logarithmic trapezoidal methods (linear ascending / logarithmic descending methods). In some embodiments, AUC can be measured from time 0 to 24 hours after administration.0-24 ”), or it can be extrapolated from time 0 to infinity (“AUC”). 0-inf The AUC is measured. Alternatively, the AUC of treprostacyclin can be measured either after a single administration or at steady-state values. Unless otherwise stated, AUC refers to the mean AUC measured after a single administration in a subject population (e.g., a population of patients with PH).

[0091] The term "plasma trough concentration" refers to the plasma concentration of treprostacyclin prior to administration of a subsequent dose of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. For example, treprostacyclin plasma trough concentration may be measured 2 hours, 1 hour, or 30 minutes after administration of a subsequent dose. Plasma trough concentration may be measured immediately after a single administration or at steady state. Unless otherwise stated, plasma trough level refers to the mean treprostacyclin trough level measured in a subject population (e.g., a population of patients with PH).

[0092] The term "adult" refers to a human subject, such as a human patient who is at least 18 years of age or older. In some embodiments, an adult is defined as 18-100 years of age, for example, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57. Ages 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, including all values ​​and ranges in between.

[0093] In one aspect of the invention, a dry powder composition of a treprost prodrug is provided. The dry powder composition comprises:

[0094] (a) A compound of formula (I) or a pharmaceutically acceptable salt thereof present in about 0.5 wt% to about 5 wt% of the total weight of the dry powder composition:

[0095]

[0096] Where R 1 It is tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl;

[0097] (b) Leucine, approximately 10 wt% to approximately 61 wt%, with the remainder being...

[0098] (c) Sugars selected from the group consisting of trehalose and mannitol. The total weight of (a), (b), and (c) is 100 wt%.

[0099] In another embodiment, the composition comprises about 25 wt% to about 61 wt% of leucine. In even another embodiment, the composition comprises about 25 wt% to about 45 wt% of leucine. In yet another embodiment, the composition comprises about 45 wt% to about 61 wt% of leucine.

[0100] In some embodiments, the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof is present in about 0.4 wt%, about 0.5 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.5 wt%, about 1.7 wt%, about 2.0 wt%, about 2.3 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 4 wt%, about 3.5 wt%, or about 5 wt% of the total weight of the dry powder composition.

[0101] The compound of formula (I) and its pharmaceutically acceptable salt are treprostacyclin prodrugs as disclosed in International Application Publication WO 2015 / 061720, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, leucine is present in about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or about 60 wt% of the total weight of the dry powder composition.

[0102] In one embodiment of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, R 1 It is tetradecyl. In another embodiment, R 1 It is a straight-chain tetradecyl group.

[0103] In another embodiment of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, R 1 It is a pentadecyl group. In another embodiment, R... 1 It is a straight-chain pentadecyl group.

[0104] In another embodiment of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, R 1 It is a heptadecanyl group. In another embodiment, R... 1 It is a straight-chain heptadecanyl group.

[0105] In another embodiment of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, R1 It is octadecyl. In another embodiment, R 1 It is a straight-chain octadecyl group.

[0106] In another embodiment of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, R 1 It is a hexadecyl group. In another embodiment, R... 1 It is a straight-chain hexadecyl group, that is, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is a compound of formula (II):

[0107]

[0108] Its stereoisomer or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is the compound of formula (II). R 1 Compound (I) of formula (I) being a straight-chain hexadecyl group is also referred to herein as C16TR or its international non-proprietary name, treprostacyclin palmitate. In this application, C16TR and treprostacyclin palmitate are used interchangeably. Similarly, compound (II) is equivalent to compound (I), wherein R... 1 It is a straight-chain hexadecyl group.

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

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

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

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

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

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

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

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

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

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

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

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

[0121]

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

[0123]

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

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

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

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

[0128] In another embodiment, the dry powder composition comprises: (a) about 1.5 wt% of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof; (b) about 29.6 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0129] In another embodiment, the dry powder composition comprises: (a) about 3 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0130] In another embodiment, the dry powder composition comprises: (a) about 3 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29 wt% of leucine; and the remainder is (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

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

[0132] In another embodiment, the dry powder composition comprises: (a) about 1 wt% of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; (b) about 29.6 wt% of leucine; and the remainder being (c) mannitol. In another embodiment, R 1 It is a straight-chain hexadecyl group in compound (I).

[0133] In some embodiments, the dry powder composition does not contain distearate phosphoethanolamine-polyethylene glycol 2000 (DPSE-PEG2000).

[0134] In one embodiment, the dry powder composition comprises about 80 μg to about 700 μg of a compound of formula (I) or (II), for example, about 80 μg, about 100 μg, about 110 μg, about 112.5 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, etc. g, approximately 210 μg, approximately 220 μg, approximately 225 μg, approximately 230 μg, approximately 240 μg, approximately 250 μg, approximately 260 μg, approximately 270 μg, approximately 280 μg, approximately 290 μg, approximately 300 μg, approximately 310 μg, approximately 320 μg, approximately 330 μg, approximately 340 μg, approximately 350 μg, approximately 360 μg, approximately 370 μg, approximately 380 μg Approximately 390 μg, approximately 400 μg, approximately 410 μg, approximately 420 μg, approximately 430 μg, approximately 440 μg, approximately 450 μg, approximately 460 μg, approximately 470 μg, approximately 480 μg, approximately 490 μg, approximately 500 μg, approximately 510 μg, approximately 520 μg, approximately 530 μg, approximately 540 μg, approximately 550 μg, approximately 560 μg, approximately 570 μg About 580 μg, about 590 μg, about 600 μg, about 610 μg, about 620 μg, about 630 μg, about 640 μg, about 650 μg, about 660 μg, about 670 μg, about 675 μg, about 680 μg, about 690 μg, or about 700 μg of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, including all values ​​and ranges therein. In one embodiment, the dry powder composition comprises about 80 μg to about 640 μg of a compound of formula (I) or (II). In one embodiment, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of a compound of formula (I). In one embodiment, the composition may be contained in one dry powder capsule or multiple (two or more) dry powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of formula (I) is distributed among the capsules. In one embodiment, the capsules are HPMC capsules of size #3.

[0135] Examples of TPIP compositions with different unit strengths are provided in Table C below. It should be understood that the unit strength of the components provided herein can be calculated based on the weight percentage of the component and the desired dosage.

[0136] For example, for an 80 μg dose of TP, each component is multiplied by 80 to obtain the unit strength of each component.

[0137]

[0138] In one embodiment, the dry powder composition comprises about 80 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0139] In one embodiment, the dry powder composition comprises about 160 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0140] In another embodiment, the dry powder composition comprises about 240 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In yet another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0141] In one embodiment, the dry powder composition comprises about 320 μg of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0142] In another embodiment, the dry powder composition comprises about 400 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0143] In another embodiment, the dry powder composition comprises about 480 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In yet another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0144] In one embodiment, the dry powder composition comprises about 640 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, R 1 It is a hexadecyl group. In even other embodiments, R 1 It is a straight-chain hexadecyl group.

[0145] In a preferred embodiment of the dry powder composition provided herein, the leucine is L-leucine.

[0146] On the other hand, this disclosure provides a dry powder composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, which provides specific pharmacokinetic characteristics after once-daily administration. Advantageously, this is similar to the current treprostacyclin inhalation solution. Compared to other drugs, its pharmacokinetic characteristics have a lower C-value. max And a longer half-life.

[0147] In one embodiment, a dry powder composition exhibiting one of the pharmacokinetic characteristics described herein is the composition described in U.S. Patent Application Publication No. 2020 / 0338005, which is incorporated herein by reference in its entirety for all purposes.

[0148] In another embodiment, the dry powder composition exhibiting one of the pharmacokinetic characteristics described herein comprises: (a) about 1 wt% to about 5 wt% of a compound of formula (I) or (II) by weight of the total dry powder composition; (b) about 25 wt% to about 61 wt% of leucine; and the remainder being (c) a sugar selected from trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%.

[0149] As discussed in Example 5, the pharmacokinetic (PK) characteristics of compounds of formula (I) or (II), their stereoisomers, or pharmaceutically acceptable salts thereof are linear in the dose range of 112.5 μg to 675 μg. Based on this data, a person skilled in the art can determine the pharmacokinetic parameters for doses outside the range or for doses within the range not specifically tested in Example 5. For example, to find the pharmacokinetic parameters at a given dose, Cmax and AUC can be plotted against specific doses (112.5 μg, 225 μg, 450 μg, and / or 675 μg). The scatter plot can be fitted to a straight line, y = mx + b, where m is the slope of the line, b is the y-intercept, and the value of the unknown pharmacokinetic parameter (y) can be calculated by interpolating the dose x. Additionally, when R... 1 When the compound is hexadecyl (i.e., compound (II)), the dosage range of 112.5 μg to 675 μg is based on the molecular weight of compound (I). The equivalent doses of other treprostacyclin prodrugs (when R...) 1 (When it is tetradecyl, pentadecyl, heptadecanyl, or octadecyl) the molecular weight of the treprostacycline prodrug of interest can be used to calculate. For example, when R... 1 When it is tetradecyl, it is equivalent to 112.5 μg of compound II (R). 1 The dosage of compound (I) of formula (hexadecyl) can be determined by multiplying 112.5 μg by the molecular weight of compound (II) (614.95 μg / mol) and when R 1The calculation is based on the ratio of the molecular weight (586.9 μg / mol) of the compound of formula (I) when it is tetradecyl.

[0150] In the embodiments, the dry powder composition of this disclosure is formulated to be administered once daily to the lungs of a subject by means of an inhalation dose ranging from about 80 μg to about 675 μg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and provides at least one of the following properties:

[0151] (a) Maximum plasma concentrations of treprostacyclin in the range of approximately 14 pg / mL to approximately 1430 pg / mL (C max );or

[0152] (b) Treprostacyclin region under plasma concentration curves (AUC) ranging from approximately 500 pg*h / mL to approximately 10000 pg*h / mL.

[0153] In another embodiment, the composition comprises about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 μg, about 480 μg, about 640 μg, or about 675 μg of a compound of formula (I). In another embodiment, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of a compound of formula (I). In another embodiment, R... 1 The compound is hexadecyl, for example, a linear hexadecyl. In one embodiment, the composition may be present in one or more (two or more) dry powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of formula (I) is dispensed between the capsules.

[0154] In the embodiments, the dry powder composition of this disclosure is formulated for once-daily administration to the lungs of a subject (e.g., a patient) via an inhalation dose ranging from about 80 μg to about 640 μg of a compound of formula (II) or a pharmaceutically acceptable salt thereof, and provides at least one of the following properties:

[0155] (a) Maximum plasma concentrations of treprostacyclin in the range of approximately 14 pg / mL to approximately 1430 pg / mL (C max );or

[0156] (b) Treprostacyclin region under plasma concentration curves (AUC) ranging from approximately 380 pg*h / mL to approximately 10000 pg*h / mL.

[0157] In another embodiment, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of a compound of formula (II). In one embodiment, the composition may be present in one or more dry powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of formula (II) is dispensed between the capsules.

[0158] In one embodiment, the dry powder composition is formulated to be administered once daily to the lungs of a subject (e.g., a patient) via an inhalation dose ranging from about 112.5 μg to about 675 μg of a compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and provides at least one of the following properties:

[0159] (a) Maximum plasma concentrations of treprostacyclin in the range of approximately 17 pg / mL to approximately 1370 pg / mL (C max );or

[0160] (b) Treprostacyclin region under plasma concentration curves (AUC) ranging from approximately 700 pg*h / mL to approximately 7800 pg*h / mL.

[0161] In another embodiment, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of a compound of formula (II). In one embodiment, the composition may be present in one or more dry powder capsules. When present in multiple capsules, one of the aforementioned doses of the compound of formula (II) is dispensed between the capsules.

[0162] In the examples, the dry powder composition having one of the pharmacokinetic characteristics described herein comprises about 80 μg to about 675 μg of a compound of formula (I), for example about 80 μg to about 640 μg or about 112.5 μg to about 675 μg. In one embodiment, a dry powder composition having one of the pK characteristics described herein includes about 80 μg, about 100 μg, about 110 μg, about 112.5 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg, about 225 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, about 310 μg, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 39 ... 0 μg, approximately 400 μg, approximately 410 μg, approximately 420 μg, approximately 430 μg, approximately 440 μg, approximately 450 μg, approximately 460 μg, approximately 470 μg, approximately 480 μg, approximately 490 μg, approximately 500 μg, approximately 510 μg, approximately 520 μg, approximately 530 μg, approximately 540 μg, approximately 550 μg, approximately 560 μg, approximately 570 μg Approximately 580 μg, approximately 590 μg, approximately 600 μg, approximately 610 μg, approximately 620 μg, approximately 630 μg, approximately 640 μg, approximately 650 μg, approximately 660 μg, approximately 670 μg, approximately 675 μg, approximately 680 μg, approximately 690 μg, or approximately 700 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, including all values ​​and ranges thereof. In further examples, R 1 It is a hexadecyl group, for example, a straight-chain hexadecyl group.

[0163] In some embodiments, following once-daily administration of a dry powder composition comprising about 80 μg to about 675 μg (e.g., about 80 μg to about 640 μg or about 112.5 μg to about 675 μg) of a compound of formula (I), its stereoisomers (or an equivalent dose of a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II))), the dry powder composition or its method of use provides a maximum treprostacyclin plasma concentration (C0) in the range of about 10 pg / mL to about 2000 pg / mL. maxFor example, approximately 10 pg / mL, approximately 15 pg / mL, approximately 20 pg / mL, approximately 25 pg / mL, approximately 30 pg / mL, approximately 35 pg / mL, approximately 40 pg / mL, approximately 45 pg / mL, approximately 50 pg / mL, approximately 55 pg / mL, approximately 60 pg / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately... 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL Approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL, approximately 580 pg / mL, approximately 590 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL, approximately 750 pg / mL, approximately 800 pg / mL, approximately 850 pg / mL, approximately 900 pg / mL, approximately 950 pg / mL, approximately 1000 pg / mL, approximately 1050 pg / mL, approximately 1100 pg / mL, approximately 1150 pg / mL, approximately 1200 pg / mL, approximately 1250 pg / mL, approximately 1300 pg / mL, approximately 1350 pg / mL, approximately 1400 pg / mL, approximately 1450 pg / mL, approximately 1500 pg / mL, approximately 1550 pg / mL, approximately 1600 pg / mL, approximately 1650 pg / mL, approximately 1700 pg / mLApproximately 1750 pg / mL, approximately 1800 pg / mL, approximately 1850 pg / mL, approximately 1900 pg / mL, or approximately 2000 pg / mL, including all values ​​and ranges therein.

[0164] In some embodiments, following a once-daily administration of about 80 μg to about 675 μg (e.g., about 80 μg to about 640 μg or about 112.5 μg to about 675 μg) of a compound of formula (II), the dry powder composition or method of this disclosure provides a region 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, and so on. g*h / mL, approximately 1300 pg*h / mL, approximately 1400 pg*h / mL, approximately 1500 pg*h / mL, approximately 1600 pg*h / mL, approximately 1700 pg*h / mL, approximately 1800 pg*h / mL, approximately 1900 pg*h / mL, approximately 2000 pg*h / mL, approximately 2100 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 ng*h / mL, approximately 2800 ng*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, approximately 4400 pg*h / mL, approximately 4500 pg*h / mL, approximately 4600 pg*h / mL, approximately 4700 pg*h / mL, approximately 4800 pg*h / mL, approximately 4900 pg*h / mL, approximately 5000 pg*h / mL Approximately 5100 pg*hr / mL, approximately 5200 pg*hr / mL, approximately 5300 pg*hr / mL, approximately 5400 pg*hr / mL, approximately 5500 pg*hr / mL, approximately 5600 pg*hr / mL, approximately 5700 pg*hr / mL, approximately 5800 pg*hr / mL, approximately 5900 pg*hr / mL, approximately 6000 pg*hr / mL, approximately 6100 pg*hr / mL, approximately 6200 pg*hr / mL, approximately 6300 pg*hr / mL, approximately 6400 pg*hr / mL, approximately 6500 pg*hr / mL, approximately 6600 pg*hr / mL, approximately 6700 pg*hr / mL.Approximately 6800 pg*hr / mL, approximately 6900 pg*hr / mL, approximately 7000 pg*hr / mL, approximately 7100 pg*hr / mL, approximately 7200 pg*hr / mL, approximately 7300 pg*hr / mL, approximately 7400 pg*hr / mL, approximately 7500 pg*hr / mL, approximately 7600 pg*hr / mL, approximately 7700 pg*hr / mL, approximately 7800 pg*hr / mL, approximately 7 900 pg*hr / mL, approximately 8000 pg*hr / mL, approximately 8100 pg*hr / mL, approximately 8200 pg*hr / mL, approximately 8300 pg*hr / mL, approximately 8400 pg*hr / mL, approximately 8500 pg*hr / mL, approximately 8600 pg*hr / mL, approximately 8700 pg*hr / mL, approximately 8800 pg*hr / mL, approximately 8900 pg*hr / mL, approximately 900 0 pg*hr / mL, approximately 9100 pg*hr / mL, approximately 9200 pg*hr / mL, approximately 9300 pg*hr / mL, approximately 9400 pg*hr / mL, approximately 9500 pg*hr / mL, approximately 9600 pg*hr / mL, approximately 9700 pg*hr / mL, approximately 9800 pg*hr / mL, approximately 9900 pg*hr / mL, approximately 10000 pg*hr / mL, approximately 1010 0 pg*hr / mL, approximately 10200 pg*hr / mL, approximately 10300 pg*hr / mL, approximately 10400 pg*hr / mL, approximately 10500 pg*hr / mL, approximately 10600 pg*hr / mL, approximately 10700 pg*hr / mL, approximately 10800 pg*hr / mL, approximately 10900 pg*hr / mL, or approximately 11000 pg*hr / mL, including all values ​​and ranges therein.

[0165] In some embodiments, the dry powder composition or method of this disclosure achieves treprostol plasma trough concentrations during the administration period of the dry powder composition. In some embodiments, the plasma trough level is sufficient to provide a sustained therapeutic response during the administration period. In some embodiments, the dry powder composition comprises about 80 μg to about 675 μg of a compound of formula (I) or a stereoisomer thereof (e.g., wherein R...). 1The powder composition is hexadecyl (e.g., linear hexadecyl), and after once-daily administration, the dry powder composition provides or the subject (e.g., the patient) has the following treprostacyclin plasma trough concentrations: at least about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL. / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, including all values ​​and ranges therein. In some embodiments, the dry powder composition comprises about 80 μg to about 640 μg of a compound of formula (II), and the treprostacyclin plasma trough concentration is in the range of about 3 pg / mL to about 125 pg / mL, for example, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL. 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 dry powder composition comprises about 80 μg to about 640 μg of a compound of formula (II), and the treprostacyclin plasma trough concentration is in the range of about 10 pg / mL to about 100 pg / mL.

[0166] In some embodiments, following once-daily administration of a dry powder composition comprising about 80 μg to about 675 μg of a compound of formula (II) or a stereoisomer thereof (or an equivalent dose of a pharmaceutically acceptable salt thereof, or a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof), the dry powder composition provides or the subject (e.g., a patient) with at least one of the following properties:

[0167] (a) The maximum treprostacyclin plasma concentration (C) within the range of approximately 80% to approximately 125% of approximately 17 pg / mL to approximately 1150 pg / mL. maxFor example, approximately 13 pg / mL, approximately 14 pg / mL, approximately 15 pg / mL, approximately 20 pg / mL, approximately 25 pg / mL, approximately 30 pg / mL, approximately 35 pg / mL, approximately 40 pg / mL, approximately 45 pg / mL, approximately 50 pg / mL, approximately 55 pg / mL, approximately 60 pg / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 16 0 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 40 0 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL, approximately 580 pg / mL, approximately 590 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 64 0 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL, approximately 750 pg / mL, approximately 800 pg / mL, approximately 850 pg / mL, approximately 900 pg / mL, approximately 950 pg / mL, approximately 1000 pg / mL, approximately 1050 pg / mL, approximately 1100 pg / mL, approximately 1150 pg / mL, approximately 1200 pg / mL, approximately 1250 pg / mL, approximately 1300 pg / mL, approximately 1350 pg / mL, approximately 1400 pg / mL, or approximately 1430 pg / mL, including all values ​​and ranges therein; or

[0168] (b) Plasma concentration curves (AUC) ranging from 80% to 125% of the range of approximately 475 pg*h / mL to approximately 8000 pg*h / mL. 0-infThe treprostacyclin range below, for example, approximately 370 pg*h / mL, approximately 400 pg*h / mL, approximately 450 pg*h / mL, approximately 500 pg*h / mL, approximately 550 pg*h / mL, approximately 600 pg*h / mL, approximately 650 pg*h / mL, approximately 700 pg*h / mL, approximately 800 pg*h / mL, approximately 900 pg*h / mL, approximately 1000 pg*h / mL, approximately 1100 pg*h / mL, approximately 1200 pg*h / mL, approximately 1300 pg*h / mL, approximately 1400 pg*h / mL, approximately 1500 pg*h / mL, approximately 1600 pg*h / mL, approximately 1700 pg*h / mL, approximately 1800 pg*h / mL. Approximately 1900 pg*h / mL, approximately 2000 pg*h / mL, approximately 2100 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 ng*h / mL, approximately 2800 ng*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3 800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, approximately 4400 pg*h / mL, approximately 4500 pg*h / mL, approximately 4600 pg*h / mL, approximately 4700 pg*h / mL, approximately 4800 pg*h / mL, approximately 4900 pg*h / mL, approximately 5000 pg*h / mL, approximately 5100 pg*hr / mL, approximately 5200 pg*hr / mL, approximately 5300 pg*hr / mL, approximately 5400 pg*hr / mL, approximately 5500 pg*hr / mL, approximately 5600 pg*hr / mL Approximately 5700 pg*hr / mL, approximately 5800 pg*hr / mL, approximately 5900 pg*hr / mL, approximately 6000 pg*hr / mL, approximately 6100 pg*hr / mL, approximately 6200 pg*hr / mL, approximately 6300 pg*hr / mL, approximately 6400 pg*hr / mL, approximately 6500 pg*hr / mL, approximately 6600 pg*hr / mL, approximately 6700 pg*hr / mL, approximately 6800 pg*hr / mL, approximately 6900 pg*hr / mL, approximately 7000 pg*hr / mL, approximately 7100 pg*hr / mL, approximately 7200 pg*hr / mL, approximately 7300 pg*hr / mL, approximately 7400 pg*hr / mLApproximately 7500 pg*hr / mL, approximately 7600 pg*hr / mL, approximately 7700 pg*hr / mL, approximately 7800 pg*hr / mL, approximately 7900 pg*hr / mL, approximately 8000 pg*hr / mL, approximately 8100 pg*hr / mL, approximately 8200 pg*hr / mL, approximately 8300 pg*hr / mL, approximately 8400 pg*hr / mL, approximately 8500 pg*hr / mL, approximately 8600 pg*hr / mL, approximately 8700 pg*hr / mL, approximately 8800 pg*hr / mL The values ​​and ranges are included: approximately 8900 pg*hr / mL, approximately 9000 pg*hr / mL, approximately 9100 pg*hr / mL, approximately 9200 pg*hr / mL, approximately 9300 pg*hr / mL, approximately 9400 pg*hr / mL, approximately 9500 pg*hr / mL, approximately 9600 pg*hr / mL, approximately 9700 pg*hr / mL, approximately 9800 pg*hr / mL, approximately 9900 pg*hr / mL, or approximately 10000 pg*hr / mL.

[0169] In some embodiments, the dry powder composition comprises about 80 μg of a compound of formula (II), administered once daily, and provides treprostacyclin C in the range of about 14 pg / mL to about 155 pg / mL. max For example, approximately 14 pg / mL, approximately 15 pg / mL, approximately 20 pg / mL, approximately 25 pg / mL, approximately 30 pg / mL, approximately 35 pg / mL, approximately 40 pg / mL, approximately 45 pg / mL, approximately 50 pg / mL, approximately 55 pg / mL, approximately 60 pg / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately... 90 pg / mL, 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 μg of the compound of formula (II) or its stereoisomer (or an equivalent dose of a pharmaceutically acceptable salt thereof, or the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt thereof) is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 17 pg / mL to about 125 pg / mL. maxIn some embodiments, about 80 μg of the compound of formula (II) or its stereoisomer (or an equivalent dose of a pharmaceutically acceptable salt thereof, or the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof) is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 35 pg / mL to about 105 pg / mL. max .

[0170] In some embodiments, the dry powder composition comprises about 112.5 μg of a compound of formula (II) or a stereoisomer thereof (or an equivalent dose of a pharmaceutically acceptable salt thereof, or a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof), and provides about 80% to about 125% of treprostacyclin C at about 78.4 (72.9) pg / mL. max (CV%).

[0171] In some embodiments, the dry powder composition comprises about 160 μg of a compound of formula (II), administered once daily, and provides treprostacyclin C in the range of about 30 pg / mL to about 335 pg / mL. maxFor example, approximately 30 pg / mL, approximately 35 pg / mL, approximately 40 pg / mL, approximately 45 pg / mL, approximately 50 pg / mL, approximately 55 pg / mL, approximately 60 pg / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 105 pg / mL, approximately 110 pg / mL, approximately 11 5 pg / mL, approximately 120 pg / mL, approximately 125 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 145 pg / mL, approximately 150 pg / mL, approximately 155 pg / mL, approximately 160 pg / mL, approximately 165 pg / mL, approximately 170 pg / mL, approximately 175 pg / mL, approximately 180 pg / mL, approximately 1850 pg / mL, approximately 190 pg / mL, approximately 195 pg / mL g / mL, approximately 200 pg / mL, approximately 205 pg / mL, approximately 210 pg / mL, approximately 215 pg / mL, approximately 220 pg / mL, approximately 225 pg / mL, approximately 230 pg / mL, approximately 235 pg / mL, approximately 240 pg / mL, approximately 245 pg / mL, approximately 250 pg / mL, approximately 255 pg / mL, approximately 260 pg / mL, approximately 265 pg / mL, approximately 270 pg / mL, approximately 275 pg / mL L, 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 μg of the compound of formula (II), its stereoisomer (or an equivalent dose of its pharmaceutically acceptable salt, or the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt) is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 35 pg / mL to about 270 pg / mL. max In some embodiments, about 160 μg of the compound of formula (II) or its stereoisomer (or an equivalent dose of a pharmaceutically acceptable salt thereof, or the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof) is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 76 pg / mL to about 230 pg / mL. max .

[0172] In some embodiments, the dry powder composition comprises about 225 μg of a compound of formula (II), administered once daily, and provides about 80% to about 125% of treprostacyclin C at about 287 (46.6) pg / mL. max In some embodiments, the dry powder composition comprises about 225 μg of a compound of formula (II) or a stereoisomer thereof (or an equivalent dose of a pharmaceutically acceptable salt thereof, or a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof), and provides a steady-state treprostacyclin C in the range of about 80% to about 125% at about 193 (32.9) pg / mL. max In some embodiments, the dry powder composition comprises about 225 μg of a compound of formula (II), administered once daily, and provides a steady-state treprostacyclin C concentration ranging from about 80% to about 125% at about 228 (46.4) pg / mL. max (CV%).

[0173] In some embodiments, the dry powder composition comprises about 240 μg of a compound of formula (II), administered once daily, and provides treprostacyclin C in the range of about 45 pg / mL to about 520 pg / mL. maxFor example, approximately 45 pg / mL, approximately 50 pg / mL, approximately 60 pg / mL, approximately 70 pg / mL, approximately 80 pg / mL, approximately 90 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 2 90 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, or approximately 520 pg / mL, including all values ​​and ranges therein. In some embodiments, about 240 μg of the compound of formula (II) or its stereoisomer (or an equivalent dose of a pharmaceutically acceptable salt thereof, or the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof) is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 55 pg / mL to about 415 pg / mL. max In some embodiments, about 240 μg of the compound of formula (II) or its stereoisomer (or an equivalent dose of a pharmaceutically acceptable salt thereof, or the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof) is administered once daily, providing about 80%-125% treprostacyclin C in the range of about 115 pg / mL to about 355 pg / mL. max .

[0174] In some embodiments, the dry powder composition comprises about 320 μg of a compound of formula (II), administered once daily, and provides treprostacyclin C in the range of about 60 pg / mL to about 700 pg / mL. maxFor example, approximately 60 pg / mL, approximately 70 pg / mL, approximately 80 pg / mL, approximately 90 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL. Approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, 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 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 80 pg / mL to about 560 pg / mL. max In some embodiments, about 320 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 160 pg / mL to about 480 pg / mL. max .

[0175] In some embodiments, the dry powder composition comprises about 400 μg of a compound of formula (II), administered once daily, and provides treprostacyclin C in the range of about 80 pg / mL to about 885 pg / mL. maxFor example, approximately 80 pg / mL, approximately 90 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL Approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL Approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL, approximately 580 pg / mL, approximately 590 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL and 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 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 100 pg / mL to about 705 pg / mL. maxIn some embodiments, about 400 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 200 pg / mL to about 605 pg / mL. max .

[0176] In some embodiments, the dry powder composition comprises about 450 μg of a compound of formula (II) or a stereoisomer thereof (or an equivalent dose of a pharmaceutically acceptable salt thereof, or a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof), and provides about 80% to about 125% of treprostacyclin C at about 387 (38.6) pg / mL. max .

[0177] In some embodiments, the dry powder composition comprises about 480 μg of a compound of formula (II), administered once daily, and provides treprostacyclin C in the range of about 95 pg / mL to about 1065 pg / mL. maxFor example, approximately 95 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL. pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL, approximately 580 pg / mL, approximately 590 pg / mL, approximately 600 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL, approximately 710 pg / mL, approximately 720 pg / mL, approximately 730 pg / mL, approximately 740 pg / mL, approximately 750 pg / mL, approximately 760 pg / mL, approximately 770 pg / mL, approximately 780 pg / mL, approximately 790 pg / mL, approximately 800 pg / mL L, approximately 810 pg / mL, approximately 820 pg / mL, approximately 830 pg / mL, approximately 840 pg / mL, approximately 850 pg / mL, approximately 860 pg / mL, approximately 870 pg / mL, approximately 880 pg / mL, approximately 890 pg / mL, approximately 900 pg / mL, approximately 910 pg / mL, approximately 920 pg / mL, approximately 930 pg / mL, approximately 940 pg / mL, approximately 950 pg / mL, approximately 960 pg / mL, approximately 970 pg / mL, approximately 980 pg / mL, approximately 1000 pg / mL, approximately 1010 pg / mL, approximately 1020 pg / mL, approximately 1030 pg / mL, approximately 1040 pg / mL, approximately 1050 pg / mL,Approximately 1060 pg / mL or approximately 1065 pg / mL, including all values ​​and ranges therein. In some embodiments, approximately 480 μg of the compound of formula (II) is administered once daily, providing approximately 80%-125% treprostacyclin C at a concentration of approximately 120 pg / mL to approximately 855 pg / mL. max In some embodiments, about 480 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 240 pg / mL to about 730 pg / mL. max .

[0178] In some embodiments, the dry powder composition comprises about 640 μg of a compound of formula (II), administered once daily, and provides treprostacyclin C in the range of about 130 pg / mL to about 1430 pg / mL. maxFor example, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, approximately 340 pg / mL, approximately 350 pg / mL. pg / mL, approximately 360 pg / mL, approximately 370 pg / mL, approximately 380 pg / mL, approximately 390 pg / mL, approximately 400 pg / mL, approximately 410 pg / mL, approximately 420 pg / mL, approximately 430 pg / mL, approximately 440 pg / mL, approximately 450 pg / mL, approximately 460 pg / mL, approximately 470 pg / mL, approximately 480 pg / mL, approximately 490 pg / mL, approximately 500 pg / mL, approximately 510 pg / mL, approximately 520 pg / mL, approximately 530 pg / mL, approximately 540 pg / mL, approximately 550 pg / mL, approximately 560 pg / mL, approximately 570 pg / mL, approximately 580 pg / mL, approximately 590 pg / mL, approximately 60 0 pg / mL, approximately 610 pg / mL, approximately 620 pg / mL, approximately 630 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL, approximately 710 pg / mL, approximately 720 pg / mL, approximately 730 pg / mL, approximately 740 pg / mL, approximately 750 pg / mL, approximately 760 pg / mL, approximately 770 pg / mL, approximately 780 pg / mL, approximately 790 pg / mL, approximately 800 pg / mL, approximately 810 pg / mL, approximately 820 pg / mL, approximately 830 pg / mL, approximately 840 pg / mL, approximately... 850 pg / mL, approximately 860 pg / mL, approximately 870 pg / mL, approximately 880 pg / mL, approximately 890 pg / mL, approximately 900 pg / mL, approximately 910 pg / mL, approximately 920 pg / mL, approximately 930 pg / mL, approximately 940 pg / mL, approximately 950 pg / mL, approximately 960 pg / mL, approximately 970 pg / mL, approximately 980 pg / mL, approximately 1000 pg / mL, approximately 1010 pg / mL, approximately 1020 pg / mL, approximately 1030 pg / mL, approximately 1040 pg / mL, approximately 1050 pg / mL, approximately 1060 pg / mL, approximately 1070 pg / mL, approximately 1080 pg / mL, approximately 1090 pg / mLApproximately 1100 pg / mL, approximately 1110 pg / mL, approximately 1120 pg / mL, approximately 1130 pg / mL, approximately 1140 pg / mL, approximately 1150 pg / mL, approximately 1160 pg / mL, approximately 1170 pg / mL, approximately 1180 pg / mL, approximately 1190 pg / mL, approximately 1200 pg / mL, approximately 1210 pg / mL, approximately 1220 pg / mL, approximately 1230 pg / mL, approximately 1240 pg / mL, approximately 1250 pg / mL, approximately 1260 pg / mL, approximately 1270 pg / mL g / 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, about 1410 pg / mL, about 1420 pg / mL, or about 1430 pg / mL, including all values ​​and ranges therein. In some embodiments, about 640 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 160 pg / mL to about 1140 pg / mL. max In some embodiments, about 640 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of treprostacyclin C in the range of about 325 pg / mL to about 980 pg / mL. max .

[0179] In some embodiments, the dry powder composition comprises about 675 μg of a compound of formula (II) and provides about 80% to about 125% of treprostacyclin C at about 717 (52.8) pg / mL. max .

[0180] In some embodiments, the dry powder composition comprises about 80 μg of a compound of formula (II) and provides treprostacyclin AUC in the range of about 375 pg*h / mL to about 1800 pg*h / mL after administration. 0-infFor example, 375 pg*h / mL, 400 pg*h / mL, 500 pg*h / mL, 600 pg*h / mL, approximately 700 pg*h / mL, approximately 800 pg*h / mL, approximately 900 pg*h / mL, approximately 1000 pg*h / mL, approximately 1100 pg*h / mL, approximately 1200 pg*h / mL, approximately 1300 pg*h / mL, approximately 1400 pg*h / mL, approximately 1500 pg*h / mL, approximately 1600 pg*h / mL, approximately 1700 pg*h / mL, or approximately 1800 pg*h / mL, including all values ​​and ranges therein. In some embodiments, about 80 μg of the compound of formula (II) is administered once daily, providing about 80%-125% of the treprostacyclin AUC in the range of about 475 pg*h / mL to about 1430 pg*h / mL. 0-inf In some embodiments, the dry powder composition comprises about 80 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC at about 660 pg*h / mL to about 1240 pg*h / mL after administration. 0-inf .

[0181] In some embodiments, the dry powder composition comprises about 112.5 μg of a compound of formula (II) and provides treprostacyclin AUC ranging from about 80% to about 125% of about 1090 (91.8) pg*h / mL. 0-inf .

[0182] In some embodiments, the dry powder composition comprises about 160 μg of a compound of formula (II) and provides treprostacyclin AUC in the range of about 630 pg*h / mL to about 3000 pg*h / mL after administration. 0-infFor example, 630 pg*h / mL, approximately 700 pg*h / mL, approximately 800 pg*h / mL, approximately 900 pg*h / mL, approximately 1000 pg*h / mL, approximately 1100 pg*h / mL, approximately 1200 pg*h / mL, approximately 1300 pg*h / mL, approximately 1400 pg*h / mL, approximately 1500 pg*h / mL, approximately 1600 pg*h / mL, approximately 1700 pg*h / mL, approximately 1800 pg*h / mL, Approximately 1900 pg*h / mL, approximately 2000 pg*h / mL, approximately 2100 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 pg*h / mL, approximately 2800 pg*h / mL, approximately 2900 pg*h / mL, or approximately 3000 pg*h / mL, including all values ​​and ranges therein. In some embodiments, the dry powder composition comprises approximately 160 μg of a compound of formula (II) and provides approximately 80%–125% of the treprostacyclin AUC in the range of approximately 785 pg*h / mL to approximately 2370 pg*h / mL after administration. 0-inf In some embodiments, the dry powder composition comprises about 160 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC in the range of about 1100 pg*h / mL to about 2050 pg*h / mL after administration. 0-inf .

[0183] In some embodiments, the dry powder composition comprises about 225 μg of a compound of formula (II) and provides an AUC ranging from about 80% to about 125% of about 2130 (30.0) ng*h / mL after application. 0-inf In some embodiments, the dry powder composition comprises about 225 μg of a compound of formula (II) and provides a steady-state treprostacyclin AUC ranging from about 80% to about 125% of about 1680 (28.7) ng*h / mL. 0-24 (CV%). In some embodiments, the dry powder composition comprises about 225 μg of a compound of formula (II) or a stereoisomer thereof (or an equivalent dose of a pharmaceutically acceptable salt thereof, or a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof), and provides a steady-state treprostacyclin AUC ranging from about 80% to about 125% at about 1790 (39.6) ng*h / mL. 0-24 (CV%).

[0184] In some embodiments, the dry powder composition comprises about 450 μg of a compound of formula (II) and provides, upon application, about 80% to about 125% of treprostacyclin AUC at about 4040 (27.4) pg*h / mL.0-inf .

[0185] In some embodiments, the dry powder composition comprises about 240 μg of a compound of formula (II) and provides treprostacyclin AUC in the range of about 880 pg*h / mL to about 4130 pg*h / mL after administration. 0-infFor example, approximately 800 pg*h / mL, approximately 900 pg*h / mL, approximately 950 pg*h / mL, approximately 1000 pg*h / mL, approximately 1050 pg*h / mL, approximately 1100 pg*h / mL, approximately 1150 pg*h / mL, approximately 1200 pg*h / mL, approximately 1250 pg*h / mL, approximately 1300 pg*h / mL, approximately 1350 pg*h / mL, approximately 1400 pg*h / mL, approximately 1450 pg*h / mL, approximately 1500 pg*h / mL, approximately 1550 pg*h / mL, approximately 1600 pg*h / mL, approximately 1 650 pg*h / mL, approximately 1700 pg*h / mL, approximately 1750 pg*h / mL, approximately 1800 pg*h / mL, approximately 1850 pg*h / mL, approximately 1950 pg*h / mL, approximately 2000 pg*h / mL, approximately 2050 pg*h / mL, approximately 2100 pg*h / mL, approximately 2150 pg*h / mL, approximately 2200 pg*h / mL, approximately 2250 pg*h / mL, approximately 2300 pg*h / mL, approximately 2350 pg*h / mL, approximately 2400 pg*h / mL, approximately 2450 pg*h / mL, approximately 2500 pg*h / mL pg*h / mL, approximately 2550 pg*h / mL, approximately 2600 pg*h / mL, approximately 2650 pg*h / mL, approximately 2700 pg*h / mL, approximately 2750 pg*h / mL, approximately 2800 pg*h / mL, approximately 2850 pg*h / mL, approximately 2950 pg*h / mL, approximately 3000 pg*h / mL, approximately 3050 pg*h / mL, approximately 3100 pg*h / mL, approximately 3150 pg*h / mL, approximately 3200 pg*h / mL, approximately 3250 pg*h / mL, approximately 3300 pg*h / mL, approximately 3350 pg*h / mL The values ​​and ranges are: approximately 3400 pg*h / mL, approximately 3450 pg*h / mL, approximately 3500 pg*h / mL, approximately 3550 pg*h / mL, approximately 3600 pg*h / mL, approximately 3650 pg*h / mL, approximately 3700 pg*h / mL, approximately 3750 pg*h / mL, approximately 3800 pg*h / mL, approximately 3850 pg*h / mL, approximately 3950 pg*h / mL, approximately 4000 pg*h / mL, approximately 4050 pg*h / mL, approximately 4100 pg*h / mL, and approximately 4130 pg*h / mL. In some embodiments, the dry powder composition comprises about 240 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC in the range of about 1100 pg*h / mL to about 3305 pg*h / mL after administration. 0-infIn some embodiments, the dry powder composition comprises about 240 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC in the range of about 1540 pg*h / mL to about 2865 pg*h / mL after administration. 0-inf .

[0186] In some embodiments, the dry powder composition comprises about 320 μg of a compound of formula (II) and provides treprostacyclin AUC in the range of about 1130 pg*h / mL to about 5310 pg*h / mL after administration. 0-inf For example, approximately 1130 pg*h / mL, approximately 1200 pg*h / mL, approximately 1300 pg*h / mL, approximately 1400 pg*h / mL, approximately 1450 pg*h / mL, approximately 1500 pg*h / mL, approximately 1550 pg*h / mL, approximately 1600 pg*h / mL, approximately 1700 pg*h / mL, approximately 1800 pg*h / mL, approximately 1900 pg*h / mL, approximately 2000 pg*h / mL. / mL, approximately 2100 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 pg*h / mL, approximately 2800 pg*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, approximately 4400 pg*h / mL L, approximately 4500 pg*h / mL, approximately 4600 pg*h / mL, approximately 4700 pg*h / mL, approximately 4800 pg*h / mL, approximately 4900 pg*h / mL, approximately 5000 pg*h / mL, approximately 5100 pg*h / mL, approximately 5200 pg*h / mL, approximately 5300 pg*h / mL, approximately 5300 pg*h / mL, or approximately 5310 pg*h / mL, encompassing all values ​​and ranges therein. In some embodiments, the dry powder composition comprises approximately 320 μg of a compound of formula (II) and provides approximately 80%–125% of treprostacyclin AUC in the range of approximately 1400 pg*h / mL to approximately 4250 pg*h / mL after administration. 0-infIn some embodiments, about 320 μg of the compound of formula (II) or its stereoisomer (or an equivalent dose of a pharmaceutically acceptable salt thereof, or the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof) is administered once daily, providing about 80%-125% of the treprostacyclin AUC in the range of about 1975 pg*h / mL to about 3680 pg*h / mL. 0-inf .

[0187] In some embodiments, the dry powder composition comprises about 400 μg of a compound of formula (II) and provides treprostacyclin AUC of about 1380 pg*h / mL to about 6480 pg*h / mL after administration. 0-infFor example, approximately 1380 pg*h / mL, approximately 1400 pg*h / mL, approximately 1450 pg*h / mL, approximately 1500 pg*h / mL, approximately 1550 pg*h / mL, approximately 1600 pg*h / mL, approximately 1700 pg*h / mL, approximately 1800 pg*h / mL, approximately 1900 pg*h / mL, approximately 2000 pg*h / mL, approximately 2100 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL. / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 pg*h / mL, approximately 2800 pg*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, approximately 4400 pg*h / mL, approximately 4500 pg*h / mL, approximately 4600 pg*h / mL, approximately 4700 pg*h / mL, approximately 4800 pg*h / mL, approximately 4900 pg*h / mL, approximately 5000 pg*h / mL, approximately 5100 pg*h / mL, approximately 5200 pg*h / mL L, approximately 5300 pg*h / mL, approximately 5400 pg*h / mL, approximately 5500 pg*h / mL, approximately 5600 pg*h / mL, approximately 5700 pg*h / mL, approximately 5800 pg*h / mL, approximately 5900 pg*h / mL, approximately 6000 pg*h / mL, approximately 6100 pg*h / mL, approximately 6200 pg*h / mL, approximately 6300 pg*h / mL, approximately 6400 pg*h / mL, or approximately 6480 pg*h / mL, including all values ​​and ranges therein. In some embodiments, the dry powder composition comprises approximately 400 μg of a compound of formula (II) and provides approximately 80%–125% of treprostacyclin AUC in the range of approximately 1725 pg*h / mL to approximately 5180 pg*h / mL after application. 0-inf In some embodiments, the dry powder composition comprises about 400 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC in the range of about 2415 pg*h / mL to about 4490 pg*h / mL after administration. 0-inf .

[0188] In some embodiments, the dry powder composition comprises about 480 μg of a compound of formula (II) and provides treprostacyclin AUC in the range of about 1630 pg*h / mL to about 7650 pg*h / mL after administration. 0-inf For example, approximately 1630 pg*h / mL, approximately 1700 pg*h / mL, approximately 1800 pg*h / mL, approximately 1900 pg*h / mL, approximately 2000 pg*h / mL, approximately 2100 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 pg*h / mL, approximately 2800 pg*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 31 00 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, approximately 4400 pg*h / mL, approximately 4500 pg*h / mL, approximately 4600 pg*h / mL mL, approximately 4700 pg*h / mL, approximately 4800 pg*h / mL, approximately 4900 pg*h / mL, approximately 5000 pg*h / mL, approximately 5100 pg*h / mL, approximately 5200 pg*h / mL, approximately 5300 pg*h / mL, approximately 5400 pg*h / mL, approximately 5500 pg*h / mL, approximately 5600 pg*h / mL, approximately 5700 pg*h / mL, approximately 5800 pg*h / mL, approximately 5900 pg*h / mL, approximately 6000 pg*h / mL, approximately 6100 pg*h / mL, approximately 620 0 pg*h / mL, approximately 6300 pg*h / mL, approximately 6400 pg*h / mL, approximately 6500 pg*h / mL, approximately 6600 pg*h / mL, approximately 6700 pg*h / mL, approximately 6800 pg*h / mL, approximately 6900 pg*h / mL, approximately 7000 pg*h / mL, approximately 7100 pg*h / mL, approximately 7200 pg*h / mL, approximately 7300 pg*h / mL, approximately 7400 pg*h / mL, approximately 7500 pg*h / mL, or approximately 7650 pg*h / mL, including all values ​​and ranges therein. In some embodiments, the dry powder composition comprises about 480 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC in the range of about 2040 pg*h / mL to about 6120 pg*h / mL after administration. 0-infIn some embodiments, the dry powder composition comprises about 480 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC in the range of about 2855 pg*h / mL to about 5310 pg*h / mL after administration. 0-inf .

[0189] In some embodiments, the dry powder composition comprises about 640 μg of a compound of formula (II) and provides treprostacyclin AUC in the range of about 2130 pg*h / mL to about 10000 pg*h / mL after administration. 0-infFor example, approximately 2130 pg*h / mL, approximately 2200 pg*h / mL, approximately 2300 pg*h / mL, approximately 2400 pg*h / mL, approximately 2500 pg*h / mL, approximately 2600 pg*h / mL, approximately 2700 pg*h / mL, approximately 2800 pg*h / mL, approximately 2900 pg*h / mL, approximately 3000 pg*h / mL, approximately 3100 pg*h / mL, approximately 3200 pg*h / mL, approximately 3300 pg*h / mL, approximately 3400 pg*h / mL, approximately 3500 pg*h / mL, approximately 3600 pg*h / mL, approximately 3700 pg*h / mL, approximately 3800 pg*h / mL, approximately 3900 pg*h / mL. mL, approximately 4000 pg*h / mL, approximately 4100 pg*h / mL, approximately 4200 pg*h / mL, approximately 4300 pg*h / mL, approximately 4400 pg*h / mL, approximately 4500 pg*h / mL, approximately 4600 pg*h / mL, approximately 4700 pg*h / mL, approximately 4800 pg*h / mL, approximately 4900 pg*h / mL, approximately 5000 pg*h / mL, approximately 5100 pg*h / mL, approximately 5200 pg*h / mL, approximately 5300 pg*h / mL, approximately 5400 pg*h / mL, approximately 5500 pg*h / mL, approximately 5600 pg*h / mL, approximately 5700 pg*h / mL, approximately 5800 pg*h / mL L, approximately 5900 pg*h / mL, approximately 6000 pg*h / mL, approximately 6100 pg*h / mL, approximately 6200 pg*h / mL, approximately 6300 pg*h / mL, approximately 6400 pg*h / mL, approximately 6500 pg*h / mL, approximately 6600 pg*h / mL, approximately 6700 pg*h / mL, approximately 6800 pg*h / mL, approximately 6900 pg*h / mL, approximately 7000 pg*h / mL, approximately 7100 pg*h / mL, approximately 7200 pg*h / mL, approximately 7300 pg*h / mL, approximately 7400 pg*h / mL, approximately 7500 pg*h / mL, approximately 7600 pg*h / mL, approximately 7700 pg*h / mL Approximately 7800 pg*h / mL, approximately 8000 pg*h / mL, approximately 8100 pg*h / mL, approximately 8200 pg*h / mL, approximately 8300 pg*h / mL, approximately 8400 pg*h / mL, approximately 8500 pg*h / mL, approximately 8600 pg*h / mL, approximately 8700 pg*h / mL, approximately 8800 pg*h / mL, approximately 8900 pg*h / mL, approximately 9000 pg*h / mL, approximately 9100 pg*h / mL, approximately 9200 pg*h / mL, approximately 9300 pg*h / mL, approximately 9350 pg*h / mL, approximately 9400 pg*h / mL, approximately 9450 pg*h / mL, approximately 9500 pg*h / mLApproximately 9600 pg*h / mL, approximately 9700 pg*h / mL, approximately 9800 pg*h / mL, approximately 9900 pg*h / mL, or approximately 10000 pg*h / mL, including all values ​​and ranges therein. In some embodiments, the dry powder composition comprises approximately 640 μg of a compound of formula (II) and provides approximately 80%-125% of the treprostacyclin AUC in the range of approximately 2650 pg*h / mL to approximately 8000 pg*h / mL after administration. 0-inf In some embodiments, the dry powder composition comprises about 640 μg of a compound of formula (II) and provides about 80%-125% of treprostacyclin AUC in the range of about 3730 to about 6935 pg*h / mL after administration. 0-inf .

[0190] In some embodiments, the dry powder composition comprises about 675 μg of a compound of formula (II) or a stereoisomer thereof (or an equivalent dose of a pharmaceutically acceptable salt thereof, or a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof), and provides about 80% to about 125% of treprostacyclin AUC at about 5480 (13.8) pg*h / mL. 0-24 In another embodiment, the compound is the compound of formula (II).

[0191] In some embodiments, the dry powder composition comprises about 80 μg to about 675 μg of a compound of formula (II), and the dry powder composition provides or, after once daily administration, a subject (e.g., a patient) with a plasma trough concentration of treprostacyclin ranging from about 3 pg / mL to about 150 mg / mL, such as about 4 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, or about 55 pg / mL. g / mL, approximately 60 pg / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 100 pg / mL, approximately 105 pg / mL, approximately 110 pg / mL, approximately 115 pg / mL, approximately 120 pg / mL, approximately 125 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 145 pg / mL, or approximately 150 pg / mL, including all values ​​and ranges therein.

[0192] In some embodiments, the dry powder composition comprises about 80 μg of a compound of formula (II), and the dry powder composition provides, or, after once daily administration to a subject (e.g., a patient), a treprostacyclin plasma trough concentration in the range of about 3 pg / mL to about 25 mg / mL, for example, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, or about 25 pg / mL, encompassing all values ​​and ranges therein. In another embodiment, the treprostacyclin plasma trough concentration is in the range of about 6 pg / mL to about 18 mg / mL.

[0193] In some embodiments, the dry powder composition comprises about 112.5 μg of a compound of formula (II), and the dry powder composition provides or, after once daily administration to a subject (e.g., a patient), a plasma trough concentration of treprostacyclin ranging from about 4 pg / mL to about 30 mg / mL, such as 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.

[0194] In some embodiments, the dry powder composition comprises about 160 μg of a compound of formula (II), and the dry powder composition provides, or, after once daily administration to a subject (e.g., a patient), a treprostacyclin plasma trough concentration in the range of about 5 pg / mL to about 35 mg / mL, such as 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, encompassing all values ​​and ranges therein. In other embodiments, the treprostacyclin plasma trough concentration is in the range of about 10 pg / mL to about 30 mg / mL or 15 pg / mL to about 25 pg / mL.

[0195] In some embodiments, the dry powder composition comprises about 225 μg of a compound of formula (II), and the dry powder composition provides or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration ranging from about 15 pg / mL to about 45 mg / mL, such as about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, or about 45 pg / mL, including all values ​​and ranges therein.

[0196] In some embodiments, the dry powder composition comprises about 240 μg of a compound of formula (II), and the dry powder composition provides, or, after once daily administration to a subject (e.g., a patient), a treprostacyclin plasma trough concentration in the range of about 7 pg / mL to about 50 mg / mL, such as about 7 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, or about 50 pg / mL, including all values ​​and ranges therein. In some embodiments, the treprostacyclin plasma trough concentration is in the range of about 15 pg / mL to about 50 mg / mL or 20 pg / mL to about 45 pg / mL.

[0197] In some embodiments, the dry powder composition comprises about 320 μg of a compound of formula (II), and the dry powder composition provides, or, after once daily administration to a subject (e.g., a patient), a treprostacyclin plasma trough concentration in the range of about 9 pg / mL to about 65 mg / mL, such as about 9 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, or about 65 pg / mL, encompassing all values ​​and ranges therein. In some embodiments, the treprostacyclin plasma trough concentration is in the range of about 15 pg / mL to about 50 mg / mL or 20 pg / mL to about 45 pg / mL.

[0198] In some embodiments, the dry powder composition comprises about 400 μg of a compound of formula (II), and the dry powder composition provides, or, after once daily administration to a subject (e.g., a patient), a treprostacyclin plasma trough concentration in the range of about 10 pg / mL to about 80 mg / mL, such as about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, or about 80 pg / mL, including all values ​​and ranges therein. In some embodiments, the treprostacyclin plasma trough concentration is in the range of about 35 pg / mL to about 70 mg / mL or 40 pg / mL to about 65 pg / mL.

[0199] In some embodiments, the dry powder composition comprises about 480 μg of a compound of formula (II), and the dry powder composition provides or, after once daily administration to a subject (e.g., a patient), a plasma trough concentration of treprostacyclin ranging from about 13 pg / mL to about 95 mg / mL, such as about 13 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, including all values ​​and ranges therein. In some embodiments, the plasma trough concentration of treprostacyclin is in the range of about 25 pg / mL to about 75 mg / mL or 30 pg / mL to about 70 pg / mL.

[0200] In some embodiments, the dry powder composition comprises about 640 μg of a compound of formula (II), and the dry powder composition provides or, after once daily administration, a subject (e.g., a patient) with a treprostacyclin plasma trough concentration in the range of about 15 pg / mL to about 125 mg / mL, such as about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 5 pg / mL, or about 5 mg / mL. 0 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, or about 125 pg / mL, including all values ​​and ranges therein. In some embodiments, the trough plasma concentration of treprostacyclin is in the range of about 35 pg / mL to about 100 mg / mL or 50 pg / mL to about 90 pg / mL.

[0201] In some embodiments, the dry powder composition comprises about 450 μg of a compound of formula (II), and the dry powder composition provides or, after once daily administration to a subject (e.g., a patient), a plasma trough concentration of treprostacyclin ranging from about 30 pg / mL to about 75 mg / mL, such as about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, and about 75 pg / mL, including all values ​​and ranges therein.

[0202] In some embodiments, the dry powder composition comprises about 675 μg of a compound of formula (II), and the dry powder composition provides or, after once daily administration to a subject (e.g., a patient), a plasma trough concentration of treprostacyclin ranging from about 50 pg / mL to about 100 mg / mL, such as about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL, about 80 pg / mL, about 85 pg / mL, about 90 pg / mL, about 95 pg / mL, about 100 pg / mL, and about 100 pg / mL, including all values ​​and ranges therein.

[0203] Aerosolized Composition

[0204] In some embodiments, the dry powder composition described herein is aerosolized via DPI to provide an aerosolized composition. The aerosolized composition is administered to a patient requiring treatment for PH. In another embodiment, the aerosolized composition is administered to a patient requiring treatment for pulmonary fibrosis (e.g., PH-ILD, where ILD is pulmonary fibrosis). The aerosolized composition can be characterized by certain parameters known to those skilled in the art, such as mass median aerodynamic diameter (MMAD) and fine particulate fraction (FPF).

[0205] The mass median aerodynamic diameter (MMAD) is the aerodynamic diameter value associated with 50% of the mass of a given aerosol being smaller than the median aerodynamic diameter (MAD) and with 50% of the mass being larger than the MAD. MMAD can be determined by impactor measurement, such as an Anderson Cascade Impactor (ACT) or a Next Generation Impactor (NGI). In some embodiments, the aerosolized dry powder composition comprises particles with MMADs of about 1 μm to about 10 μm, about 1 μm to about 7 μm, about 1 μm to about 5 μm, or about 1 μm to about 4 μm, or about 1.5 μm to about 3.5 μm, or about 2 μm to about 3 μm, as measured by NGI. In one embodiment, a dry powder composition exhibiting one of the MMAD characteristics provided above comprises mannitol. In another embodiment, a dry powder composition exhibiting the MMAD characteristics provided above comprises trehalose.

[0206] "Fine particle fraction" or "FPF" refers to the fraction of aerosols with a diameter of less than 5 μm, as measured by cascade impaction. FPF is typically expressed as a percentage. FPF has been shown to correlate with the fraction of powder deposited in the lungs of a subject (e.g., a patient). In some embodiments, the dry powder composition is in aerosol form comprising particles with an FPF of at least 20%, at least 30%, at least 40%, at least 50%, about 30% to about 60%, about 35% to about 55%, or about 40% to about 50%, as measured by NGI. In one embodiment, the aerosolized dry powder composition comprises particles with an FPF of about 40% to about 70%, about 30% to about 60%, or about 50% to about 60%, as measured by NGI. In one embodiment, a dry powder composition exhibiting one of the FPF characteristics provided above comprises mannitol. In another embodiment, a dry powder composition exhibiting the FPF characteristics provided above comprises trehalose.

[0207] The dry powder compositions disclosed herein can be produced from liquid compositions using lyophilization or spray drying techniques. When using lyophilization, the lyophilized composition can be milled to obtain a finely granulated dry powder containing particles within the desired size range described above. When using spray drying, the process is performed under conditions that produce a finely granulated dry powder containing particles within the desired size range described above. Exemplary methods for preparing pharmaceutical compositions in dry powder form 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 its entirety. 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 its entirety.

[0208] In some embodiments, the dry powder compositions of this disclosure are prepared by the following process: A stock solution of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is prepared using an organic solvent such as an alcohol (e.g., 1-propanol). An aqueous stock solution of a sugar (e.g., mannitol or trehalose) and leucine is also prepared. Subsequently, the desired amount of the above stock solution is added to a mixture of water and an organic solvent to form a spray-drying feed solution. In the spray-drying feed solution, the volume ratio of water to organic solvent can be from about 3:2 to about 1:1.

[0209] Spray drying is initiated by starting the drying gas flow and heating the drying gas to a desired inlet temperature, 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, from about 55°C to about 65°C, the liquid slide inlet is configured to allow blank solvent to enter the spray dryer via nitrogen atomization, allowing the system to cool and stabilize. The product filter pulse is initiated, and the product filter purge flow is set to, for example, 10 to 20 scfh. After the system stabilizes, the liquid slide inlet is switched to the feed solution prepared above, and the process continues until the feed solution is depleted. When the feed solution is depleted, the liquid slide inlet is switched back to blank solvent, allowing it to spray for about 5 to about 20 minutes. At this time, the powder collects at the bottom of the product filter. After spraying blank solvent for about 5 to about 20 minutes, the system is shut down by closing the liquid line, atomizing gas, drying gas heater, drying gas inlet, and finally the exhaust pipe.

[0210] The dry powder composition of this disclosure is delivered to the lungs of a subject (e.g., a patient) by inhalation using a dry powder inhaler (DPI). In one embodiment, the dry powder inhaler is a single-dose dry powder inhaler. Propellant-free devices, i.e., DPIs, utilize the subject's (e.g., a patient's) inhalation to deliver dry powder to the subject's (e.g., a patient's) lungs. The unit dose of dry powder composition used in a DPI device is typically a dry powder blister pack of a hard capsule. Exemplary DPI devices suitable for delivering the dry powder composition of this 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 incorporated herein by reference in its entirety.

[0211] The inhaler (Alkermes) comprises a small respiratory activation system that delivers porous powder from a capsule. The porous particles have an aerodynamic diameter of 1-5 μm. See International Patent Application Publications WO 99 / 66903 and WO 00 / 10541, the disclosure of each of which is incorporated herein by reference in its entirety.

[0212] Aerolizer TM Novartis is a single-dose dry powder inhaler. In this device, the dry powder medication is stored in a capsule and released by penetrating the capsule wall with a Teflon-coated steel needle. See U.S. Patent Nos. 6,488,027 and 3,991,761, the disclosure of each of which is incorporated herein by reference in its entirety.

[0213] Bang Olufsen offers a respiratory-actuated inhaler using blister packs with up to sixty doses. The dose is obtained only during inhalation via a novel trigger mechanism. The device is equipped with a dose counter, which can be removed after all doses have been used. See EP 1522325, the disclosure of which is incorporated herein by reference in its entirety.

[0214] Innovata Publications, Inc. (Innovata) is a large-capacity, multi-dose device for respiratory activation. See U.S. Patent 5,437,270, the disclosure of which is incorporated herein by reference in its entirety.

[0215] DirectHaler TM (Direct-Haler A / S) is a single-dose, pre-filled, disposable DPI device made of polypropylene. See U.S. Patent No. 5,797,392, the disclosure of which is incorporated herein by reference in its entirety.

[0216] Diskus TM (GlaxoSmithKline) is a disposable, small DPI device that contains up to 60 doses in a double-foil blister pack for moisture protection. See GB2242134, the disclosure of which is incorporated herein by reference in its entirety.

[0217] Eclipse TM Aventis is a reusable, respirator-operated capsule device capable of delivering up to 20 mg of dry powder composition. The powder is inhaled from the capsule into a vortex chamber where a rotating ball aids in powder disintegration as the subject (e.g., a patient) inhales. See U.S. Patent 6,230,707 and WO 9,503,846, the disclosure of each of which is incorporated herein by reference in its entirety.

[0218] It is a respiratory-activated plastic dry powder inhaler and is suitable for use with the dry powder compositions provided herein.

[0219] Hovione is a capsule-based, refillable, reusable passive dry powder inhaler that holds up to 14 capsules. The inhaler itself is moisture-proof. See U.S. Patent 5,673,686, the disclosure of which is incorporated herein by reference in its entirety.

[0220] (Vectura) is a passive disposable DPI containing a blister strip. See GB2407042, the disclosure of which is incorporated herein by reference in its entirety.

[0221] (Boehringer Ingelheim GmbH) is a single-dose DPI device. It can deliver up to 30 mg of dry powder composition in a capsule. See International Patent Application Publication No. WO04 / 024156, the disclosure of which is incorporated herein by reference in its entirety.

[0222] MicroDose DPI (MicroDose Technologies) is a small electronic DPI device. It uses a piezoelectric vibrator (ultrasonic frequency) to break down drug powder in an aluminum blister pack (single or multiple doses). See U.S. Patent No. 6,026,809, the disclosure of which is incorporated herein by reference in its entirety.

[0223] Nektar Dry Powder (Nektar) is a palm-sized and easy-to-use device. It provides convenient drug delivery from standard capsules and lung deposition regardless of flow rate.

[0224] Nektar Pulmonary (Nektar) efficiently removes powder from the packaging, pulverizes particles, and generates an aerosol cloud suitable for deep lung delivery. This enables the delivery of aerosolized particles from the device to deep into the lungs during the breathing of a subject (e.g., a patient), thereby reducing loss in the throat and upper respiratory tract. Compressed gas is used to aerosolize the powder. See AU4090599 and U.S. Patent No. 5,740,794, the disclosure of each of which is incorporated herein by reference in its entirety.

[0225] NEXT DPI TM This is a device characterized by multi-dose functionality, moisture protection, and dose counting. The device may only be used when the appropriate inspiratory flow rate is achieved, regardless of orientation (inversion) and dosage. See EP 1196146, U.S. Patent No. 6,528,096, WO0178693, and WO0053158, the disclosure of each of which is incorporated herein by reference in its entirety.

[0226] It is a plastic dry powder inhaler based on capsule-based respiratory activation.

[0227] Oriel TM DPI is an active DPI that utilizes piezoelectric film and non-linear vibration to aerosolize powder formulations. See International Patent Application Publication No. WO 01 / 68169, the disclosure of which is incorporated herein by reference in its entirety.

[0228] In one embodiment, the DPI is a capsule-based DPI. In another embodiment, the capsule-based DPI is manufactured by Plastiape. In yet another embodiment, the capsule-based DPI is the RS01 single-dose dry powder inhaler developed by Plastiape, which features a compact size and a simple and effective perforation system, and is suitable for both gelatin and HMPC capsules.

[0229] Pressair TM It is a respiratory-activated plastic dry powder inhaler.

[0230] The inhaler (Chiesi) is a respiratory-actuated, multi-dose (100-dose) dry powder inhaler. The dry powder is stored in a transparent and clearly labeled reservoir to indicate when the 100th dose has been delivered. See U.S. Patent No. 5,351,683, the disclosure of which is incorporated herein by reference in its entirety.

[0231] (GlaxoSmithKline) is a single-use device utilizing capsules. See U.S. Patent Nos. 5,673,686 and 5,881,721, the disclosure of each of which is incorporated herein by reference in its entirety.

[0232] Rexam DPI (Rexam Pharma) is a single-dose, reusable device designed for use with a capsule. See U.S. Patent No. 5,651,359 and EP 0707862, the disclosure of each of which is incorporated herein by reference in its entirety.

[0233] S2 (Innovata Public Company Limited) is a reusable or single-dose DPI for delivering high concentrations of dry powder compositions. Its dispersion mechanism achieves good drug delivery to the lungs of a subject (e.g., a patient) with minimal effort. S2 is easy to use and features a passive engine, thus requiring no battery or power source. See AU3320101, the disclosure of which is incorporated herein by reference in its entirety.

[0234] DPI (SkyePharma) is a multi-dose device containing up to 300 individual doses in a single-use or replaceable cartridge. The device is powered by respiration and does not require coordination between breathing and actuation. See U.S. Patent Nos. 6,182,655 and WO97 / 20589, the disclosure of each of which is incorporated herein by reference in its entirety.

[0235] The DPI (Laboratory International) is a multi-dose (up to 200) DPI device. It is respiratory-actuated and flow rate independent. The device includes a unique fluid-balanced drug reservoir coupled to a volumetric dosing system for consistent administration. See U.S. Patent No. 6,132,394, the disclosure of which is incorporated herein by reference in its entirety.

[0236] As described in U.S. Patent No. 5,983,893 (by AstraZeneca), the entire disclosure of which is incorporated herein by reference. This DPI device is an inspiratory flow-driven, multi-dose dry powder inhaler having a multi-dose reservoir providing up to 200 doses of the dry powder composition, with a dose range from a few micrograms to 0.5 mg.

[0237] Schering-Plough's products are multi-dose devices with dose counting capabilities and are capable of 14-200 actuations. The dry powder composition is packaged in a cartridge containing a desiccant. See U.S. Patent No. 5,829,434, the disclosure of which is incorporated herein by reference in its entirety.

[0238] (Aventis) combines accurate dosing with excellent dispersibility. It is an easy-to-use, disassembled, pocket-sized device with a digital dose counter, dose acquisition indicator, and locking mechanism. The device is capable of delivering up to 20 mg of dry powder composition. The disclosures of each of the documents described in U.S. Patent Nos. 5,678,538 and WO2004026380 are incorporated herein by reference in their entirety.

[0239] Xcelovair TM (Meridica / Pfizer) Contains 60 pre-selective, airtight, sealed doses ranging from 5 to 20 mg. The device provides moisture protection under accelerated conditions at 40°C / 75% RH. The dispersion system maximizes fine particle fractionation, delivering up to 50% fine particle mass.

[0240] On the other hand, a system is provided comprising (i) one of the dry powder compositions described herein and (ii) a dry powder inhaler (DPI) for administering the dry powder composition. The DPI comprises (a) a reservoir containing the dry powder composition disclosed herein, and (b) means for delivering the dry powder composition into the lungs of a subject by inhalation. In one embodiment, the reservoir comprises the dry powder composition of the invention in a capsule or blister pack. The capsule shell may be made of gelatin, a cellulose derivative, starch, a starch derivative, chitosan, or a synthetic plastic. The DPI may be a single-dose or multi-dose inhaler. Additionally, the DPI may be a pre-measured amount or a device-measured amount. In one embodiment, the dry powder inhaler is a single-dose dry powder inhaler.

[0241] In one embodiment, the system is used to treat pulmonary hypertension (e.g., Group 1 or Group 3 PH), portal pulmonary hypertension, or pulmonary fibrosis, as described in further detail below. The system comprises a dry powder composition disclosed herein, i.e., a dry powder composition comprising a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, and a DPI. In one embodiment, the dry powder composition comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In another embodiment, the dry powder composition comprises a compound of formula (I) or (II). The dry powder inhaler may be the dry powder inhaler described above, may be a single-dose or multi-dose inhaler, and / or may be a pre-measured or device-measured inhaler. In one embodiment, the dry powder inhaler is a single-dose dry powder inhaler.

[0242] The term "treatment" includes: (1) preventing or delaying the onset of clinical symptoms of a state, condition, or symptom developing in a patient who may have or be susceptible to the state, condition, or symptom but has not yet experienced or exhibited clinical or subclinical symptoms of the state, condition, or symptom; (2) suppressing the state, condition, or symptom (e.g., preventing, alleviating, or delaying the development of the disease or the recurrence of at least one clinical or subclinical symptom thereof under maintenance treatment); and / or (3) alleviating symptoms (e.g., causing at least one symptom of the state, condition, or symptom thereof to subside). In one embodiment, "treatment" means suppressing a state, condition, or symptom (e.g., preventing, alleviating, or delaying the development of the disease or the recurrence of at least one clinical or subclinical symptom thereof under maintenance treatment). In another embodiment, "treatment" means alleviating symptoms (e.g., by causing at least one symptom of the state, condition, or symptom thereof to subside). The benefit to the treated patient is statistically significant compared to the condition or symptoms of the same patient before treatment, or compared to the condition or symptoms of an untreated control patient, or the benefit is at least perceptible to the patient or physician.

[0243] "Effective amount" means the amount of the dry powder composition of this disclosure sufficient to produce the desired therapeutic response. "Effective amount" is the amount of compound of formula (I) or (II) administered in a single dose.

[0244] In one aspect of the invention, a method for treating pulmonary hypertension (PH) in a patient of need is provided. The method comprises administering an effective amount of one of the dry powder compositions disclosed herein once daily to the patient's lungs via a dry powder inhaler (DPI) during an administration period. The dry powder composition comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The administration comprises (i) aerosolizing the dry powder composition via a DPI to provide an aerosolized dry powder composition, and (ii) administering the aerosolized dry powder composition to the patient's lungs by inhalation via the DPI.

[0245] The World Health Organization (WHO) has classified pulmonary hypertension (PH) into five groups. Group 1 PH includes pulmonary arterial hypertension (PAH), idiopathic pulmonary arterial hypertension (IPAH), familial pulmonary arterial hypertension (FPAH), and pulmonary arterial hypertension associated with other diseases (APAH). For example, pulmonary arterial hypertension associated with collagen vascular disease (e.g., sclerosis), congenital shunting between systemic and pulmonary circulation, portal hypertension, and / or HIV infection is included in Group 1 PH. Group 2 PH includes pulmonary hypertension associated with left heart disease such as atrial or ventricular disease or valvular disease (e.g., mitral stenosis). WHO's Group 3 pulmonary hypertension is characterized by pulmonary hypertension associated with lung diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and / or hypoxemia. Group 4 pulmonary hypertension is pulmonary hypertension caused by chronic thrombotic and / or embolic diseases. Group 4 PH is also known as chronic thrombotic pulmonary hypertension. Patients with Group 4 PH experience blocked or narrowed blood vessels due to blood clots. Group 5 PH is the “Other” category and includes PH caused by blood disorders (e.g., polycythemia vera, spontaneous thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis), and / or metabolic disorders (e.g., thyroid disease, glycogen storage disease).

[0246] The methods described in this article can be used to treat PH patients in groups 1, 2, 3, 4 or 5 as defined by the WHO.

[0247] In one embodiment of the method, the pulmonary hypertension being treated is chronic thrombotic pulmonary hypertension.

[0248] In a preferred embodiment, pulmonary hypertension is a Group 1 PH as characterized by the WHO. In another embodiment, the method provided herein is a method for treating pulmonary arterial hypertension (PAH). In yet another embodiment, PAH is a Class I, Class II, Class III, or Class IV PAH as characterized by the New York Heart Association (NYHA).

[0249] In one embodiment, the PAH is a Class I PAH as characterized by NYHA.

[0250] In another embodiment, the PAH is a Class II PAH as characterized by NYHA.

[0251] In yet another embodiment, the PAH is a Class III PAH as characterized by NYHA.

[0252] In yet another embodiment, the PAH is a Class IV PAH as characterized by NYHA.

[0253] In one embodiment, pulmonary hypertension (PH) is portal pulmonary hypertension (PPH). PPH is defined by the coexistence of portal hypertension and pulmonary hypertension. The diagnosis of portal pulmonary hypertension is based on hemodynamic criteria: (1) portal hypertension and / or liver disease (clinical diagnosis—ascites / varicose veins / splenomegaly), (2) mean pulmonary artery pressure at rest >25 mmHg, and (3) pulmonary vascular resistance >240 dynes s / cm. 5 (4) Pulmonary artery obstruction pressure <15 mmHg or transpulmonary gradient >12 mmHg. PPH is a serious complication of liver disease and is present in 0.25% to 4% of patients with cirrhosis. It is estimated that 4-6% of patients who have undergone liver transplantation have comorbid PPH.

[0254] In a preferred embodiment, pulmonary hypertension is Group 3 PH as characterized by the WHO. In another embodiment, the method provided herein is a method for treating PH associated with interstitial lung disease (PH-ILD).

[0255] In the methods for treating PH-ILD provided herein, the ILD may comprise one or more lung diseases. In one embodiment, one or more lung diseases include: idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia, nonspecific interstitial pneumonia, allergic pneumonia, acute interstitial pneumonia, interstitial pneumonia (e.g., idiopathic interstitial pneumonia), connective tissue disease, sarcoidosis, or asbestosis. In one embodiment, the ILD is connective tissue disease-associated interstitial lung disease (CTD-ILD). In another embodiment, the ILD is sarcoidosis. In yet another embodiment, the ILD is IPF. In still another embodiment, the ILD is idiopathic interstitial pneumonia (IIP).

[0256] In one embodiment for treating PH-ILD as described herein, the ILD comprises pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF). Pulmonary fibrosis is a respiratory disease in which scarring forms in the lung tissue, leading to severe breathing problems. Scarring (i.e., the accumulation of excessive fibrous connective tissue) causes thickening of the lung walls and reduces the oxygen supply to the blood. Therefore, patients with pulmonary fibrosis suffer from persistent shortness of breath. In some patients, the specific cause of the disease can be diagnosed, but in others, the possible cause may not be determined; this condition is referred to as IPF.

[0257] In any given case, the length of the administration period can depend on the nature and severity of the PH being treated, as well as the patient's tolerance and response to the therapy. The treatment methods provided herein are offered as chronic therapies, and therefore, patients receive treatment as long as the therapy is safe and effective. Thus, in one embodiment, the administration period continues until the patient's death. In another embodiment, the administration period is the length of time for which the treatment is effective.

[0258] In one embodiment, if a patient experiences an adverse reaction to the therapy, a reduced dose is administered during the administration period. Similarly, if a patient shows good tolerance to the lower dose, it can be titrated to a higher dose. In one embodiment, uptipping occurs only after the patient has shown tolerance to the lower dose for two or more days, such as two, three, four, five, six, or seven days.

[0259] In some embodiments, the application period is approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 1 year, approximately 2 years, approximately 3 years, approximately 4 years, approximately 5 years, approximately 6 years, approximately 7 years, approximately 8 years, approximately 9 years, approximately 10 years, approximately 15 years, approximately 20 years, or approximately 30 years.

[0260] In another embodiment, the application period of the method provided herein is at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years, or at least about 20 years. In another embodiment, the application period is from about 30 days to about 2 years. In another embodiment, the application period is from about 6 months to about 3 years, or 6 months to about 4 years, or about 6 months to about 5 years, or about 6 months to about 6 years, or about 6 months to about 7 years, or about 6 months to about 8 years, or about 1 year to about 10 years, or about 2 years to about 10 years, or about 6 months to about 20 years, or about 5 years to about 20 years, or about 10 years to about 30 years.

[0261] In one embodiment, the application period is at least about one year.

[0262] In one embodiment, the application period is at least about 5 years.

[0263] In one embodiment, the application period is from about 1 year to about 15 years. In another embodiment, the application period is from about 5 years to about 15 years. In yet another embodiment, the application period is from about 10 years to about 20 years. In yet another embodiment, the application period is from about 1 year to about 20 years.

[0264] In one embodiment of the disclosed method, the dry powder composition is administered to the patient once daily in a single dosing cycle during the administration period. In another embodiment, the dry powder composition is administered to the patient twice daily (i.e., in two separate dosing cycles). In one embodiment, administration is performed with food. In one embodiment, each dosing cycle includes 1 to 5 inhalations (aspirations) from a DPI, such as 1 inhalation (1 aspiration), 2 inhalations (2 aspirations), 3 inhalations (3 aspirations), 4 inhalations (4 aspirations), or 5 inhalations (5 aspirations). As used herein, a “dosing cycle” refers to 1 to 5 inhalations (aspirations) from a DPI as needed to administer about 80 μg to about 700 μg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof. In one embodiment, the DPI is small and can be carried by the patient. In one embodiment, the DPI is a single-dose DPI.

[0265] In one embodiment, more than one DPI capsule comprising the composition may be used to achieve a specific dosage. For example, two 320 μg DPI capsules may be used for a 640 μg dosage. Each capsule may be administered by one or two inhalations.

[0266] An effective amount of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof may comprise a fixed dose of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the fixed dose is present in one or more DPI capsules. In one embodiment, the fixed dose is a dose titrated from a previous dose (up or down). In another embodiment, the fixed dose is the same dose as or substantially the same dose as the previous dose. In one embodiment, the effective amount is the amount of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof administered during each dosing cycle. In some embodiments, "administered" refers to the amount of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof administered in a single dosing cycle in a capsule or in multiple capsules of a DPI. In some embodiments, the fixed dose ranges from about 80 μg to about 700 μg of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, for example, about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 μg, about 480 μg, about 640 μg, or about 675 μg of a compound of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof. For example, if the dry powder composition is administered once daily in a single dosing cycle, the effective amount can be considered as the amount of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof administered during a single dosing cycle in the capsule or multiple capsules. For example, in one embodiment, one or more capsules may be formulated with a dry powder composition, wherein the total dose of the one or more capsules is about 80 μg, about 112.5 μg, about 160 μg, about 225 μg, about 240 μg, about 320 μg, about 400 μg, about 450 μg, about 480 μg, about 640 μg, or 675 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and each of the aforementioned doses may be an effective amount and may also be referred to as an amount administered once daily during a single administration during the administration period. As another example, in one embodiment, the capsules comprise a dry powder composition comprising about 320 μg of a compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and for the purposes of this disclosure, the amount administered is 640 μg, even if 640 μg is administered by taking two or more aspirations from two capsules. Similarly, in this example, the amount applied is 640 μg, even if the remaining amount of the compound of formula (II), its stereoisomer or its pharmaceutically acceptable salt remains in the DPI (e.g., if about 5%, 10%, 20%, 30%, 40% or 50% remains in the DPI).

[0267] The term "administered" in a single dosing procedure also covers situations where the DPI is refiled or reloaded one or more times (e.g., by changing the capsule) to achieve the desired effective dose. In such cases, "administered" refers to the total dose in the capsule administered during the dosing procedure. For example, to administer a dose of 240 μg of a compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, an 80 μg capsule and a 160 μg capsule may be used. The DPI may be filed with the first 80 μg capsule, and after emptying the cartridge in one or more aspirations, the 160 μg capsule may be loaded into the DPI and emptyed in one or more aspirations. Both capsules are used in the same dosing procedure, and therefore the dose administered is 240 μg.

[0268] In another embodiment, the effective dose comprises an escalating dose over the administration period. In yet another embodiment, the effective dose is based on upward titration, which is based on the patient's highest tolerated dose. In one embodiment, 80 μg is initially administered to the patient. If this dose is well tolerated, the dose is titrated upward until the patient's highest tolerated dose is reached. During the titration period, the patient maintains the same dose for a minimum cumulative number of days, such as 2, 3, or 4 days, before titrating to the next higher dose. For examples of dose titration, see, for instance... Figure 21 If the patient is not tolerated by the dose, the dose can be reduced to the previous dose level.

[0269] During the titration period, the dose for each patient can be titrated up to that patient's highest tolerable dose. As an example, in one embodiment, a patient begins the method of the invention with a single 80 μg DPI capsule once daily. If this dose is well tolerated, the dose is titrated up until the patient's highest tolerable dose is reached. During the titration period, the patient maintains the study drug for a minimum cumulative number of days before starting the next higher dose (e.g., 2 days at 80 μg, 160 μg, or 240 μg, 3 days at 320 μg, or 4 days at 400 μg or 480 μg). The titration of the study drug may occur more slowly than in the examples above, but not more quickly. Figure 21 An exemplary embodiment of dose titration for a patient requiring treatment is provided. If the patient is not tolerated by the dose, the dose can be reduced to the previous dose level.

[0270] In some embodiments, patients treated by the disclosed method exhibit one or more of the following treatment responses during the administration period compared to before the administration period: (1) a decrease in pulmonary vascular resistance index (PVRI), (2) a decrease in mean pulmonary artery pressure, (3) an increase in hypoxemia score, (4) a decrease in oxygenation index, (5) improved right ventricular function, and (6) improved exercise capacity (e.g., as measured by a six-minute walk test).

[0271] The 6-minute walk test (6MWT) is an empirically proven method for measuring exercise capacity and assessing lung function, and is performed according to the American Thoracic Society (ATS) guidelines. See the American Thoracic Society ATS statement: Guidelines for the Six-Minute Walk Test, *American Journal of Respiratory and Critical Care Medicine*, 2002; 166(1):111-17, which is incorporated herein by reference in its entirety for all purposes. In one embodiment, the 6MWT is performed at approximately the same time of day as the day preceding the administration period. In another embodiment, the same equipment is used to perform the 6MWT. In yet another embodiment, the same person administers the 6MWT.

[0272] In one embodiment, compared to before the application period, the patient's walking distance during the 6MWT increased 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 application period. In another embodiment, compared to before the application period, the patient's walking distance during the 6MWT increased by about 5 meters to about 60 meters, about 5 meters to about 50 meters, about 10 meters to about 50 meters, about 15 meters to about 50 meters, or about 20 meters to about 40 meters during the application period. In yet another embodiment, compared to before the application period, the patient's walking distance during the 6MWT increased by at least about 30 meters during the application period.

[0273] In one embodiment, compared to before the application period, the distance walked by the patient in 6MWT during the application period increased by approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, or approximately 90%. In another embodiment, compared to before the application period, the distance walked by the patient in 6MWT during the application period increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In another embodiment, compared to before the application period, the distance walked by the patient in 6MWT during the application period increased by about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0274] In one embodiment of the treatment of PH, the treatment included improving the patient's quality of life during the administration period compared to the patient's quality of life before the administration period. In one embodiment, quality of life was measured using the Cambridge Hypertension Outcomes Review (CAMPHOR) questionnaire. McCabe et al. (2013). Chest 2013;144(2):522-30, the cited literature is incorporated herein by reference in its entirety for all purposes. The CAMPHOR questionnaire is a pulmonary hypertension-specific measure of health-related quality of life (QOL), consisting of 3 parts and evaluating a total of 65 items (25 related to symptoms, 15 related to activity, and 25 related to QOL). The CAMPHOR score is negatively weighted, therefore, a higher score indicates poorer QOL and greater functional limitations. Symptom and QOL items are each scored out of 25, and activity items have 3 possible responses (0-2 points) out of 30. Each CAMPHOR assessment takes an average of 10 minutes. In one embodiment of the treatment of PH, the treatment includes reducing the patient's CAMPHOR questionnaire score during the administration period compared to the CAMPHOR questionnaire score prior to the administration period. In one embodiment, the reduction is from 1 to about 10, from 1 to about 9, from 1 to about 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.

[0275] In one embodiment of a method for treating PH, the method includes increasing the patient's resting SpO2 during the application period compared to the patient's resting peripheral capillary oxygen saturation (SpO2) as assessed by pulse oximetry prior to the application period.

[0276] Oxygen saturation is an indicator of how much hemoglobin in the blood binds to oxygen and is typically provided as a percentage of oxyhemoglobin to total hemoglobin. SpO2 is an indicator of oxygen saturation in peripheral capillaries. Exemplary methods for measuring SpO2 include, but are not limited to, pulse oximetry using a pulse oximeter. In one embodiment of the method for treating PH provided herein, the method includes increasing the patient's resting SpO2 by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% during the application period compared to before the application period. In another embodiment, the method for treating PH includes increasing the patient's resting SpO2 by about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50% during the application period, compared to before the application period.

[0277] In one embodiment, the method for treating PH provided herein includes improving a patient's lung function during the administration period compared to the patient's lung function before the administration period. In one embodiment, the improvement in lung function is measured by a vital capacity test.

[0278] In one embodiment, improving a patient's lung function includes increasing the patient's forced vital capacity (FVC) during the application period compared to corresponding values ​​before the application period, increasing the patient's percentage of predicted forced vital capacity (ppFVC), increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's percentage of predicted forced expiratory volume in one second (ppFEV1), and increasing the patient's forced expiratory flow rate by 25% to 75% of FVC (FEF). (25-75％) This can increase a patient's total vital capacity (TLC) or increase a patient's pulmonary carbon monoxide diffusion capacity (DLCO).

[0279] In one embodiment, for example, via FVC, ppFVC, FEV1, ppFEV1, FEF ( 25-75％) Lung function assessments performed using TLC or DLCO measurements involve comparing a patient’s lung function prior to the administration period (e.g., before treatment) with the mean of measurements taken at time points during the administration period or during the administration period.

[0280] As provided herein, in one embodiment, a method for treating PH includes improving a patient's lung function during the application period compared to a corresponding value prior to the application period, wherein lung function is measured by a vital capacity measurement. A vital capacity measurement is a physiological test that measures how much air an individual inhales or exhales. The primary signal measured in a vital capacity measurement can be volume or flow rate. For the methods described herein, vital capacity measurements (e.g., FEV1, FVC, FEF) are used. (25-75％) Pulmonary function tests (PFT) performed on TLC were performed according to American Thoracic Society (ATS) / European Respiratory Society (ERS) standards, for example, as described by Miller et al. (Miller et al., “Standardization of Spirometry”, *Eur. Respir. J.* 26:319-38 (2005), which are incorporated herein by reference in their entirety for all purposes. DLCO can be measured using the techniques described in the following literature: Modi P, Castella M, “Diffusing Capacity Of The Lungs For Carbon Monoxide”, [Updated March 24, 2021] in: StatPearls [Internet] *Treasure Island*. Island (FL): StatPearls; January 2021. Available at: www.ncbi.nlm.nih.gov / books / NBK556149 / ; Graham et al., “2017 ERS / ATS standards for single-breath carbon monoxide uptake in the lung”, European Journal of Respiratory Medicine 49:1600016 (2017); Each of the references cited herein is incorporated herein by reference in its entirety for all purposes.

[0281] In one embodiment, the spirometer is capable of accumulating volume over a period of 15 seconds or more, for example, ≥20 seconds, ≥25 seconds, ≥30 seconds, or ≥35 seconds. In one embodiment, the spirometer can measure a volume of ≥8 L (BTPS) with an accuracy of at least 3% of the reading or ±0.050 L, whichever is greater, wherein the flow rate is between 0 and 14 L·s. -1之间 In one embodiment, the spirometer measures 14 L·s -1 The total resistance to airflow is <1.5 cmH2O·L. -1 ·s -1 (0.15kPa?L) -1 ·s -1 In one embodiment, the total resistance of the spirometer is measured using any tubing, valves, pre-filters, etc., that can be inserted between the patient and the spirometer. Regarding devices exhibiting resistance variations due to water vapor condensation, in one embodiment, the accuracy requirement of the spirometer is met by performing up to eight consecutive FVC operations over a 10-minute time period under BTPS (body temperature, water vapor saturated ambient pressure) without inhaling from the instrument.

[0282] Regarding the forced exhalation procedure described herein, in one embodiment, the range and accuracy recommendations set forth in Table 6 of Miller et al. are satisfied (Miller et al., “Standardization of vital capacity measurement”, European Journal of Respiration 26:319-38 (2005), which is incorporated herein by reference in its entirety for all purposes).

[0283] In one embodiment, improved lung function includes an improvement in the patient's forced vital capacity (FVC) during the administration period compared to the FVC prior to the administration period; that is, the maximum amount of air that can be exhaled with maximum effort from a maximal inhalation. FVC is expressed in liters at body temperature and ambient pressure at water vapor saturation (BTPS). In another embodiment, the improvement in lung function is a predicted improvement in percentage forced vital capacity (ppFVC).

[0284] Forced vital capacity (FVC) represents the amount of air exhaled during a forced exhalation, beginning at a full inspiratory position and ending at a full expiratory position, and is a measure of therapeutic efficacy. FVC can be expressed as a percentage of the predicted FVC (i.e., ppFVC) obtained from a normal population based on the patient's age, height, sex, and sometimes weight and race. In one embodiment of a method for treating PH, improving the patient's lung function includes increasing the patient's FVC or ppFVC during the administration period compared to the patient's corresponding FVC or ppFVC prior to the administration period. In one embodiment, the increase in FVC or ppFVC is an increase of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In another embodiment, the increase in FVC or ppFVC is an increase of about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%. In one embodiment, the increase in FVC or ppFVC is an increase in FVC or ppFVC prior to the use of a bronchodilator. In another embodiment, the increase in FVC or ppFVC is an increase in FVC or ppFVC following the use of a bronchodilator.

[0285] In one embodiment, the patient's ppFVC was 80% or less before the application period. In another embodiment, the patient's ppFVC was 70% or less before the application period. In yet another embodiment, the patient's ppFVC was 60% or less before the application period. In yet another embodiment, the patient's ppFVC was 50% or less before the application period. In yet another embodiment, the patient's ppFVC was 30% to 80%, 40% to 70%, or 50% to 60% before the application period.

[0286] The FVC procedure can be performed according to a procedure known to those skilled in the art. In short, the three distinct phases of the FVC procedure are (1) maximal inspiration; (2) “expulsive” exhalation; and (3) sustained complete exhalation until the end of the test (EOT). The procedure can be performed using either a closed-circuit or open-circuit method. In either case, the patient takes a rapid, complete inhalation, pausing for less than one second at total vital capacity (TLC). The patient then exhales maximally until no air can be expelled while maintaining an upright posture. Exhalation begins with “expulsion” of air from the lungs, followed by a forceful, complete exhalation. The patient is enthusiastically instructed to continue the procedure at least three times.

[0287] FEV1 is the amount of air exhaled within a specific time (usually 1 second, FEV1) at the start of a forced vital capacity test (Quanjer et al. (1993). European Journal of Respiration 6, Supplement 16, pp. 5-40, which is incorporated herein by reference for all purposes). FEV1 can also be expressed as a percentage of the predicted FEV1 obtained from the normal population based on the patient's sex, height, and age, and sometimes race and weight (i.e., ppFEV1).

[0288] In one embodiment, improving a patient's lung function includes increasing the patient's FEV1 or ppFEV1 during the administration period compared to the patient's corresponding FEV1 or ppFEV1 before the administration period. In one embodiment, the increase in FEV1 or ppFEV1 is an increase of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%. In another embodiment, the increase in FEV1 or ppFEV1 is an increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In another embodiment, the increase in FEV1 or ppFEV1 includes an increase of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In another embodiment, the increase in FEV1 or ppFEV1 is an increase of about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0289] In one embodiment, increasing FEV1 or ppFEV1 means increasing FEV1 or ppFEV1 before the use of a bronchodilator. In another embodiment, increasing FEV1 or ppFEV1 means increasing FEV1 or ppFEV1 after the use of a bronchodilator.

[0290] In one embodiment, the patient's ppFEV1 was 80% or less before the application period. In another embodiment, the patient's ppFEV1 was 70% or less before the application period. In yet another embodiment, the patient's ppFEV1 was 60% or less before the application period. In yet another embodiment, the patient's ppFEV1 was 50% or less before the application period. In yet another embodiment, the patient's ppFEV1 was 30% to 80%, 40% to 70%, or 50% to 60% before the application period.

[0291] In another embodiment, improving a patient's lung function includes increasing the patient's FEV1 by approximately 25 mL to approximately 500 mL, approximately 25 mL to approximately 400 mL, approximately 25 mL to approximately 300 mL, approximately 25 mL to approximately 250 mL, approximately 25 mL to approximately 200 mL, or approximately 50 mL to approximately 200 mL during the administration period, compared to the patient's FEV1 before the administration period. In one embodiment, increasing FEV1 is increasing the FEV1 before the use of the bronchodilator. In another embodiment, increasing FEV1 is increasing the FEV1 after the use of the bronchodilator.

[0292] In one embodiment, improving a patient's lung function includes improving mean forced expiratory flow (FEF) by 25% to 75% of the patient's FVC prior to the administration period. (25-75％) Compared to (also known as maximum intermediate expiratory flow), this increases the patient's FEF during the administration period. (25-75％) FEF (25-75％) The measurement depends on the validity of the FVC measurement and the degree of expiratory effort. FEF (25-75％) The index is taken from the maximum exhalation of the sum of FEV1 and FVC.

[0293] In one embodiment, the patient's FEF is increased during the administration period. (25-75％) This includes increasing the patient's FEF by at least approximately 1%, at least approximately 5%, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, or at least approximately 50%. In another embodiment, increasing the patient's FEF during the administration period. (25-75％) This includes increasing by about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%. In one embodiment, FEF is increased. (25-75％) FEF before the use of bronchodilators (25-75％) In another embodiment, FEF is added. (25-75％) FEF is the result of increased use of bronchodilators. (25-75％) .

[0294] Total vital capacity (TLC) is the sum of vital capacity and residual volume, representing the total amount of air that the lungs can hold. TLC is divided into four quantities, including tidal volume (V). T Inspiratory reserve (IRV) is the maximum amount of air that can be inhaled or exhaled during normal, quiet breathing. Expiratory reserve (ERV) is the maximum amount of air that can be exhaled after a normal, quiet exhalation. Residual volume (RV) is the amount of air remaining in the lungs after a maximal exhalation. Vital capacity (VC) is the maximum amount of air that can be exhaled after a maximal inhalation; VC = IRV + V T +ERV. In one embodiment, improving a patient's lung function includes increasing the patient's total vital capacity (TLC) during the administration period compared to the patient's TLC before the administration period. In one embodiment, the increase is at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In another embodiment, the increase is about 1% to about 50%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0295] Lung carbon monoxide diffusing capacity (DLCO), also known as transfer factor, is a measure of the lungs' ability to divert gas from inhaled air into the bloodstream. Carbon monoxide (CO) has a high affinity for hemoglobin and follows the same pathway as oxygen to ultimately bind to hemoglobin. Inhaled CO is used for this test due to its high affinity for hemoglobin (200 to 250 times that of oxygen). Since anemia can reduce DLCO, DLCO can be adjusted for hemoglobin levels. Several other factors, such as carboxyhemoglobin and FiO2, may also need to be adjusted for. See Modi P, Castella M, “Lung carbon monoxide diffusing capacity” [Updated March 24, 2021] in: StatPearls [Internet] Treasure Island (FL): StatPearls Publishing; January 2021, the cited literature is incorporated herein by reference in its entirety for all purposes. In another embodiment, improving a patient's lung function includes increasing the patient's DLCO during the administration period compared to the patient's DLCO% before the administration period. In one embodiment, adjusting DLCO for hemoglobin levels, i.e., improving a patient's lung function, includes increasing the patient's DLCO for hemoglobin adjustment during the administration period compared to the patient's DLCO adjusted for hemoglobin before the administration period. In another embodiment, improving a patient's lung function includes increasing the predicted DLCO% for the patient during the administration period compared to the predicted DLCO% for the patient before the administration period. The predicted normal DLCO value can be calculated according to the equation established by Crapo et al. in *American Review of Respiratory Diseases* 123(2):185-9 (1981) or by the equation established by Miller et al. in *American Review of Respiratory Diseases* 127(3):270-7 (1983), each of which is incorporated herein by reference in its entirety for all purposes. In another embodiment, the predicted DLCO% for hemoglobin adjustment is...

[0296] In one embodiment, improving lung function includes increasing a patient's DLCO or predicted DLCO% by at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In another embodiment, improving lung function includes increasing a patient's DLCO or predicted DLCO% by about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%. In yet another embodiment, the patient's DLCO or predicted DLCO is adjusted for hemoglobin.

[0297] In one embodiment, prior to the administration period, the patient's predicted DLCO% was 80% or less, 70% or less, 60% or less, or 50% or less. In another embodiment, the patient's predicted DLCO% was adjusted for hemoglobin. In yet another embodiment, prior to the administration period, the patient's predicted DLCO% was 30% to 80%, 40% to 70%, or 50% to 60%. In yet another embodiment, the patient's predicted DLCO was adjusted for hemoglobin.

[0298] In one embodiment of the method for treating PH provided herein, the method includes increasing the duration of clinical deterioration compared to untreated PH patients or PH patients not treated with compounds of formula (I) or (II), wherein the clinical deterioration is a deterioration selected from the group consisting of: death, hospitalization for respiratory indications (e.g., dyspnea and / or worsening lung function indicated by reduced FVC, DLCO, and / or SpO2), a 10% or greater reduction in the percentage of FVC predicted by ppFVC of the patient relative to two consecutive administration periods 4–14 weeks apart, lung transplantation, and a 15% or greater reduction in the distance walked in the 6-minute walk test (6MWT) of the patient relative to two consecutive administration periods at least 24 hours apart.

[0299] In one embodiment, the duration of clinical deterioration is increased by about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks. In another embodiment, the duration of clinical deterioration is increased by at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks. In another embodiment, the duration of clinical deterioration is increased by about 20 days to about 100 days, about 30 days to about 100 days, about 20 days to about 75 days, about 20 days to about 50 days, or about 20 days to about 40 days. In yet another embodiment, the duration of clinical deterioration is increased by at least 1 month, for example, about 1 month to about 6 months, about 1 month to about 4 months, or about 1 month to about 3 months.

[0300] In one embodiment, the method for treating PH provided herein includes increasing the patient's lung lobe volume and / or airway volume as assessed by computed tomography (CT) during the administration period, compared to the patient's lung lobe volume and / or airway volume prior to the administration period. The CT scan can be performed via a chest CT scan during the respiratory cycle to generate CT images in functional residual capacity (FRC) and / or total vital capacity (TLC). In one embodiment, lung lobe volume is the volume of the lung lobe structures of the patient's respiratory system in TLC or FRC, and airway volume is the volume of the airway structures of the patient's respiratory system in TLC or FRC.

[0301] In one embodiment, increasing the patient's lung lobe volume and / or airway volume includes an increase of at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In another embodiment, the patient's lung lobe volume and / or airway volume increases by about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0302] Other embodiments

[0303] Example 1. A dry powder composition comprising:

[0304] (a) About 0.1 wt% to about 5 wt% of compound (I):

[0305]

[0306] Or its enantiomer, diastereomer, or pharmaceutically acceptable salt, wherein R 1 Tetradecyl, pentadecyl, hexadecyl, heptadecanyl, or octadecyl,

[0307] (b) Leucine, approximately 10 wt% to approximately 50 wt%, and

[0308] The remaining portion consists of sugars selected from the group composed of trehalose and mannitol, (c)

[0309] The total weight of (a), (b), and (c) is 100 wt%.

[0310] Example 2. The dry powder composition according to Example 1, wherein (a) is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0311] Example 3. The dry powder composition according to Example 1 or 2, wherein (a) is a compound of formula (I).

[0312] Example 4. The dry powder composition according to any one of Examples 1 to 3, wherein R 1 It is a tetradecyl group.

[0313] Example 5. The dry powder composition according to Example 4, wherein R 1 It is a straight-chain tetradecyl group.

[0314] Example 6. The dry powder composition according to any one of Examples 1 to 3, wherein R 1 It is a pentadecyl group.

[0315] Example 7. The dry powder composition according to Example 6, wherein R 1 It is a straight-chain pentadecyl group.

[0316] Example 8. A dry powder composition according to any one of Examples 1 to 3, wherein R 1 It is a heptadecanyl group.

[0317] Example 9. The dry powder composition according to Example 8, wherein R 1 It is a straight-chain heptadecanyl group.

[0318] Example 10. A dry powder composition according to any one of Examples 1 to 3, wherein R 1 It is an octadecyl group.

[0319] Example 11. The dry powder composition according to Example 10, wherein R 1 It is a straight-chain octadecyl group.

[0320] Example 12. The dry powder composition according to any one of Examples 1 to 3, wherein R 1 It is a hexadecyl group.

[0321] Example 13. The dry powder composition according to Example 12, wherein R 1 It is a straight-chain hexadecyl group.

[0322] Example 14. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomers, diastereomers or pharmaceutically acceptable salts are present in about 0.1 wt% to about 4.5 wt% of the total weight of the dry powder composition.

[0323] Example 15. The dry powder composition according to Example 14, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.1 wt% to about 4.5 wt% of the total weight of the dry powder composition.

[0324] Example 16. A dry powder composition according to Example 14 or 15, wherein the compound of formula (I) is present in about 0.1 wt% to about 4.5 wt% of the total weight of the dry powder composition.

[0325] Example 17. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 0.1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0326] Example 18. The dry powder composition according to Example 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0327] Example 19. A dry powder composition according to Example 17 or 18, wherein the compound of formula (I) is present in about 0.1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0328] Example 20. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomers, diastereomers or pharmaceutically acceptable salts are present in about 0.1 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0329] Example 21. The dry powder composition according to Example 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.1 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0330] Example 22. A dry powder composition according to Example 20 or 21, wherein the compound of formula (I) is present in about 0.1 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0331] Example 23. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomers, diastereomers or pharmaceutically acceptable salts are present in about 0.1 wt% to about 3 wt% of the total weight of the dry powder composition.

[0332] Example 24. The dry powder composition according to Example 23, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.1 wt% to about 3 wt% of the total weight of the dry powder composition.

[0333] Example 25. A dry powder composition according to Example 23 or 24, wherein the compound of formula (I) is present in about 0.1 wt% to about 3 wt% of the total weight of the dry powder composition.

[0334] Example 26. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 0.5 wt% to about 3.5 wt% or about 0.8 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0335] Example 27. The dry powder composition according to Example 26, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.5 wt% to about 3.5 wt% or about 0.8 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0336] Example 28. A dry powder composition according to Example 26 or 27, wherein the compound of formula (I) is present in about 0.5 wt% to about 3.5 wt% or about 0.8 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0337] Example 29. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomers, diastereomers or pharmaceutically acceptable salts are present in about 1 wt% to about 2 wt% of the total weight of the dry powder composition.

[0338] Example 30. The dry powder composition according to Example 29, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 2 wt% of the total weight of the dry powder composition.

[0339] Example 31. A dry powder composition according to Example 29 or 30, wherein the compound of formula (I) is present in about 1 wt% to about 2 wt% of the total weight of the dry powder composition.

[0340] Example 32. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomers, diastereomers or pharmaceutically acceptable salts are present in about 1.2 wt% to about 1.8 wt% of the total weight of the dry powder composition.

[0341] Example 33. The dry powder composition according to Example 32, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 1.2% to about 1.8 wt% of the total weight of the dry powder composition.

[0342] Example 34. A dry powder composition according to Example 32 or 33, wherein the compound of formula (I) is present at about 1.2 wt% to about 1.8 wt% of the total weight of the dry powder composition.

[0343] Example 35. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0344] Example 36. The dry powder composition according to Example 35, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0345] Example 37. A dry powder composition according to Example 35 or 36, wherein the compound of formula (I) is present at about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0346] Example 38. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomers, diastereomers or pharmaceutically acceptable salts are present in about 1.4 wt% to about 1.6 wt% of the total weight of the dry powder composition.

[0347] Example 39. The dry powder composition according to Example 38, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 1.4 wt% to about 1.6 wt% of the total weight of the dry powder composition.

[0348] Example 40. A dry powder composition according to Example 38 or 39, wherein the compound of formula (I) is present at about 1.4 wt% to about 1.6 wt% of the total weight of the dry powder composition.

[0349] Example 41. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 1 wt% of the total weight of the dry powder composition.

[0350] Example 42. The dry powder composition according to Example 41, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 1 wt% of the total weight of the dry powder composition.

[0351] Example 43. A dry powder composition according to Example 41 or 42, wherein the compound of formula (I) is present at about 1 wt% of the total weight of the dry powder composition.

[0352] Example 44. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 1.5 wt% of the total weight of the dry powder composition.

[0353] Example 45. The dry powder composition according to Example 44, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 1.5 wt% of the total weight of the dry powder composition.

[0354] Example 46. The dry powder composition according to Example 44 or 45, wherein the compound of formula (I) is present at about 1.5 wt% of the total weight of the dry powder composition.

[0355] Example 47. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 0.5 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0356] Example 48. The dry powder composition according to Example 47, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.5 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0357] Example 49. A dry powder composition according to Example 47 or 48, wherein the compound of formula (I) is present in about 0.5 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0358] Example 50. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 0.7 wt% to about 1.3 wt% of the total weight of the dry powder composition.

[0359] Example 51. The dry powder composition according to Example 50, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.7 wt% to about 1.3 wt% of the total weight of the dry powder composition.

[0360] Example 52. A dry powder composition according to Example 50 or 51, wherein the compound of formula (I) is present in about 0.7 wt% to about 1.3 wt% of the total weight of the dry powder composition.

[0361] Example 53. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 0.8 wt% to about 1.2 wt% of the total weight of the dry powder composition.

[0362] Example 54. The dry powder composition according to Example 53, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.8 wt% to about 1.2 wt% of the total weight of the dry powder composition.

[0363] Example 55. A dry powder composition according to Example 53 or 54, wherein the compound of formula (I) is present in about 0.8 wt% to about 1.2 wt% of the total weight of the dry powder composition.

[0364] Example 56. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomers, diastereomers or pharmaceutically acceptable salts are present in about 0.9 wt% to about 1.1 wt% of the total weight of the dry powder composition.

[0365] Example 57. The dry powder composition according to claim 56, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 0.9 wt% to about 1.1 wt% of the total weight of the dry powder composition.

[0366] Example 58. A dry powder composition according to Example 56 or 57, wherein the compound of formula (I) is present in about 0.9 wt% to about 1.1 wt% of the total weight of the dry powder composition.

[0367] Example 59. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 1.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0368] Example 60. The dry powder composition according to claim 59, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 1.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0369] Example 61. The dry powder composition according to claim 59 or 60, wherein the compound of formula (I) is present in about 1.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0370] Example 62. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present at about 2.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0371] Example 63. The dry powder composition according to Example 62, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 2.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0372] Example 64. A dry powder composition according to Example 62 or 63, wherein the compound of formula (I) is present at about 2.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0373] Example 65. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present at about 2.7 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0374] Example 66. The dry powder composition according to claim 65, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 2.7 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0375] Example 67. A dry powder composition according to Example 65 or 66, wherein the compound of formula (I) is present at about 2.7 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0376] Example 68. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present at about 2.8 wt% to about 3.2 wt% of the total weight of the dry powder composition.

[0377] Example 69. The dry powder composition according to Example 68, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 2.8 wt% to about 3.2 wt% of the total weight of the dry powder composition.

[0378] Example 70. A dry powder composition according to Example 68 or 69, wherein the compound of formula (I) is present at about 2.8 wt% to about 3.2 wt% of the total weight of the dry powder composition.

[0379] Example 71. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present at about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0380] Example 72. The dry powder composition according to Example 71, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0381] Example 73. A dry powder composition according to Example 71 or 72, wherein the compound of formula (I) is present in about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0382] Example 74. A dry powder composition according to any one of Examples 1 to 13, wherein the compound of formula (I) or its enantiomer, diastereomer or pharmaceutically acceptable salt is present in about 3 wt% of the total weight of the dry powder composition.

[0383] Example 75. The dry powder composition according to Example 74, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in about 3 wt% of the total weight of the dry powder composition.

[0384] Example 76. The dry powder composition according to Example 74 or 75, wherein the compound of formula (I) is present at about 3 wt% of the total weight of the dry powder composition.

[0385] Example 77. A dry powder composition according to any one of Examples 1 to 76, wherein the leucine is present at about 12 wt% to about 42 wt% of the total weight of the dry powder composition.

[0386] Example 78. The dry powder composition according to Example 77, wherein the leucine is present at about 15 wt% to about 40 wt% of the total weight of the dry powder composition.

[0387] Example 79. The dry powder composition according to Example 78, wherein the leucine is present at about 18 wt% to about 33 wt% of the total weight of the dry powder composition.

[0388] Example 80. The dry powder composition according to Example 79, wherein the leucine is present at about 20 wt% to about 33 wt% of the total weight of the dry powder composition.

[0389] Example 81. The dry powder composition according to Example 80, wherein the leucine is present at about 25 wt% to about 33 wt% of the total weight of the dry powder composition.

[0390] Example 82. The dry powder composition according to Example 81, wherein the leucine is present at about 27 wt% to about 33 wt% of the total weight of the dry powder composition.

[0391] Example 83. The dry powder composition according to Example 82, wherein the leucine is present at about 27 wt% to about 31 wt% of the total weight of the dry powder composition.

[0392] Example 84. The dry powder composition according to Example 83, wherein the leucine is present at about 27 wt% to about 30 wt% of the total weight of the dry powder composition.

[0393] Example 85. The dry powder composition according to Example 84, wherein the leucine is present at about 28 wt% to about 30 wt% of the total weight of the dry powder composition.

[0394] Example 86. The dry powder composition according to Example 80, wherein the leucine is present at about 20 wt% of the total weight of the dry powder composition.

[0395] Example 87. The dry powder composition according to Example 80, wherein the leucine is present at about 30 wt% of the total weight of the dry powder composition.

[0396] Example 88. A dry powder composition according to any one of Examples 1 to 87, wherein the sugar is trehalose.

[0397] Example 89. A dry powder composition according to any one of Examples 1 to 87, wherein the sugar is mannitol.

[0398] Example 90. A dry powder composition according to any one of Examples 1 to 13, comprising: (a) about 1.5 wt% of a compound of formula (I) or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof; (b) about 29.3 wt% of leucine; and the remainder being (c) mannitol.

[0399] Example 91. The dry powder composition according to Example 90, comprising: (a) about 1.5 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) about 29.3 wt% of leucine; and the remainder being (c) mannitol.

[0400] Example 92. The dry powder composition according to Example 90 or 91 comprises: (a) about 1.5 wt% of the compound of formula (I); (b) about 29.3 wt% of leucine; and the remainder is (c) mannitol.

[0401] Example 93. A dry powder composition according to any one of Examples 1 to 13, comprising: (a) about 1 wt% of a compound of formula (I) or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof; (b) about 29.3 wt% of leucine; and the remainder being (c) mannitol.

[0402] Example 94. The dry powder composition according to Example 93 comprises: (a) about 1 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) about 29.3 wt% of leucine; and the remainder being (c) mannitol.

[0403] Example 95. The dry powder composition according to Example 93 or 94 comprises: (a) about 1 wt% of the compound of formula (I); (b) about 29.3 wt% of leucine; and the remainder is (c) mannitol.

[0404] Example

[0405] The invention is further illustrated by reference to the following examples. However, it should be noted that these examples, like the embodiments described above, are illustrative and should not be construed as limiting the scope of the invention in any way.

[0406] The following examples involve two different treprostacyclin palmitate inhaled powder (TPIP) formulations (TPIP-A and TPIP-B). Tables D and E summarize the compositions of TPIP-A and TPIP-B as weight ratios, the target weight percentages calculated based on the weight ratios, and the actual weight percentages of the components from typical batches of each formulation, respectively.

[0407]

[0408]

[0409] Example 1: Preparation, characterization, and packaging of inhalable treprostacycline palmitate dry powder formulation

[0410] This example describes the manufacturing and packaging of TPIP-B via spray drying. It also describes the characterization of TPIP-B, which is manufactured in parallel with TPIP-A, in terms of moisture content, residual solvent, particle morphology, particle size distribution, and thermal properties using scanning electron microscopy (SEM).

[0411] 1. Spray drying manufacturing of TPIP-B

[0412] Spray-dried TPIP-B was manufactured using a BLD-200 spray dryer with a drying gas flow rate capacity of 200 kg / h. Specifically, the spray solution was prepared according to the composition shown in Table 1.

[0413]

[0414]

[0415] The final spray-dried TPIP-B composition is shown in Table 2.

[0416]

[0417] The manufacturing process of spray-dried TPIP-B is outlined in Table 3.

[0418]

[0419] 2. Analytical characterization and stability study of TPIP-B

[0420] TPIP-B and TPIP-A were manufactured, packaged in high-density polyethylene bottles, sealed in low-density polyethylene bags with desiccant, then sealed in foil bags, and stored at 2–8°C. Initial analytical characterization and stability studies were then performed. Initial analytical characterization included moisture content, residual solvent, particle morphology, particle size distribution, and thermal properties obtained using SEM. The methods used for the above analytical characterization are described in U.S. Application No. 16 / 860,428, the disclosure of which is incorporated herein by reference in its entirety. The physical stability of the two spray-dried powder formulations was evaluated using SEM based on changes in thermal properties, moisture content, particle size distribution, and particle morphology relative to an initial time point under storage conditions of 25°C / 60% RH and 40°C / 75% RH for 1 month, 3 months, and 6 months.

[0421] Table 4 provides an overview of the initial characterization results for TPIP-B and TPIP-A, demonstrating that TPIP-B and TPIP-A have similar measurement characteristics.

[0422]

[0423] Tables 5A, 5B, and 5C show the stability study results at 1 month, 3 months, and 6 months, respectively. The results indicate that TPIP-B and TPIP-A have similar stability curves.

[0424]

[0425]

[0426]

[0427] 3. Powder packaging

[0428] Approximately 7.5 mg of spray-dried TPIP-B was loaded into #3 size hydroxypropyl methylcellulose (HPMC) DPI grade capsules using Xcelodose 600S. Three sets of capsules were prepared, packaged in high-density polyethylene bottles, sealed in low-density polyethylene bags with desiccant, and then sealed in foil bags for 2-8 days. ℃ The capsules were then stored. The fine particle dose (FPD) and MMAD obtained by NGI were then determined from the stored dry powder formulation. The FPD and MMAD results are shown in Table 6. Additionally, the amount of treprostacyclin palmitate in each capsule was determined to be 114.3 mcg.

[0429]

[0430] Example 2: Pharmacokinetic evaluation of TPIP-B and TPIP-A in Spratly-Dowley rats

[0431] Materials and methods

[0432] A. Types

[0433] These PK studies were conducted using male Sprague-Dowley rats weighing between 300 and 350 g. The exact weight of the rats was recorded on the day of the experiment.

[0434] B. Qualification and randomization of the test system

[0435] 1. Animals must arrive at the site at least 3 days before the planned experiment.

[0436] 2. Identify the animal upon arrival according to CCAC guidelines.

[0437] 3. Record all animal care and facility maintenance, and keep the records at the testing facility.

[0438] 4. Before the experiment, the research leader, who keeps a record of the ID number of each animal, randomly assigns animals.

[0439] C. Drug administration and dosage selection

[0440] 170 mg of TPIP-B or TPIP-A was loaded into a Vilnius aerosol generator (VAG), which was connected to a 12-port rodent nasal-only inhalation system (CH Technologies, Westwood, NJ, USA) at the bottom of the tower. The nasal-only airflow was set to 7 L / min. Material from the VAG was delivered at an output voltage of 1.0 V, and the nebulizer was shut off when all material had been aerosolized, which took approximately 40 minutes. The actual aerosolization duration for each exposure was recorded. A glass fiber filter was placed on one of the exposure ports and connected to a vacuum source at a vacuum flow of 0.5 L / min for 5 minutes (starting 5 minutes after aerosolization began and ending at 10 minutes). A Mercer-type cascade impactor was placed on one of the exposure ports and connected to a vacuum source at a vacuum flow of 0.5 L / min for 5 minutes. Following administration of the test product (i.e., TPIP-B or TPIP-A), animals were euthanized at time points to collect various biological samples (bronchial lavage fluid, lungs, spleen, liver, kidneys, heart, stomach, and plasma) (Tables 7 and 8). Between experiments, the tower, nasal restriction tubes only, and all connecting tubing were cleaned with aqueous solutions of 0.5% sodium dodecyl sulfate (SDS), tap water, and distilled water. Powder in the VAG cups was removed, and all parts of the VAG system were cleaned with air.

[0441] D. Sample Analysis

[0442] Powders collected from the nasal inhalation tower (via filters) and Mercer cascade impactors were analyzed. Concentrations of treprostacyclin palmitate (TP) and treprostacyclin (TRE) in the lungs, liver, heart, kidneys, spleen, stomach, BALC, BALF, and plasma were analyzed by LC-MS / MS. TP and TRE values ​​reported below the level of quantitation (BLQ) were each assigned a zero value.

[0443] E. Research Design and Experimental Procedures

[0444] 1. Research Design

[0445] Thirty-six (36) rats were exposed to TPIP-A and thirty-six (36) rats were exposed to TPIP-B. Rats were acclimatized to the nasal cone cavity by placing them in the cavity once daily for three consecutive days, with increasing durations each time (starting at 5 minutes, increasing to 15 minutes, and ending at 20 minutes). On the day of administration, nine rats from the first cohort were placed inside the nasal cone confinement cavity, which was connected to a 12-port nasal inhalation-only cavity. The test product was delivered via VAG at a flow rate of 7 L / min, and the actual dose duration was recorded. A glass fiber filter was placed on one of the exposed ports and connected to a vacuum source at a vacuum flow rate of 0.5 L / min for 5 minutes (starting 5 minutes after aerosolization began and ending at 10 minutes). A Mercer-type cascade impactor was placed on one of the exposed ports and connected to a vacuum source at a vacuum flow rate of 0.5 L / min for 5 minutes. After sampling, the impactor was removed, and aerosols were collected at each stage with 4 mL (4 times 1 mL) of 75% IPA. Collection was performed in cohorts 2 and 4 using a Mercer cascade impactor. This experiment was conducted twice, with nine rats in each cohort. On the second day, cohorts 3 and 4 were exposed to the test product. At the end of compound exposure, blood and tissue samples were obtained according to the schedule listed in Table 7. IPD necropsy times were recorded. For each time point, rats experiencing the final time point were anesthetized with 2% isoflurane via pure oxygen inhalation. Rats were weighed. Approximately 3.0 mL of blood was obtained via cardiac puncture. K2-EDTA tubes were centrifuged at 3,000 rpm at 4°C for 10 minutes. Approximately 0.5 mL of plasma was aliquoted into three 1 mL tubes and labeled with study number, animal identifier, dose group, and time point. Plasma samples were flash-frozen and cryopreserved (-80°C) prior to drug concentration analysis. Bloodletting was performed on animals by cutting the abdominal aorta. To collect BAL fluid from cohorts 3 and 4, the trachea was dissected and a 14G InSyte catheter was inserted into the lung, just above the thoracic inlet, ensuring it was positioned above the carina. Rinse the lungs with a syringe containing 2 mL of sterile PBS. Gently massage the chest four times by applying inward pressure to the rib cages, then aspirate the BAL fluid back into the syringe. Repeat the rinsing with another 2 mL of sterile PBS and transfer to the same Eppendorf tube. Centrifuge the BALF fluid, remove the supernatant, and store at -80°C. Discard the last drop of BALF (remove as much as possible). Preserve the cell clumps, flash-freeze, and store at -80°C. Collect and clean the lungs, spleen, kidneys, heart, and liver lobes to remove excess tissue, and dissect the stomach and empty the solid contents. Weigh all organs, place them in 5.0 mL Eppendorf tubes, flash-freeze, and store at -80°C for subsequent analysis of lung drug concentrations.

[0446]

[0447] F. Drug dosing calculation based on filtered data

[0448] Total delivery dose and pulmonary delivery dose were calculated using equations described by Alexander DJ et al. in the following literature: Recommendations from the Association of Inhalation Toxicologists (AIT) Working Group on Standard Delivery Dose Calculations and Expressions for Nonclinical Aerosol Inhalation Toxicology Studies of Drugs, Inhalation Toxicology (Inhal. Tox.) 20:p1179-1189, 2008. These equations are derived from the concentration of TP in the nasal inhalation tower (filter results), minute respiratory rate, duration of exposure, deposition fraction, and body weight.

[0449]

[0450] in,

[0451] C = Concentration in inhaled air (μg / L)

[0452] RMV = respiratory volume per minute (liters / minute), where RMV is calculated using the following formula: RMV (liters / minute) = 0.608 × BW (kg) 0.852 .

[0453] D = Exposure duration (minutes)

[0454] DF = Deposition fraction, assumed to be 100% for calculating total delivered dose and assumed to be 10% for calculating lung dose.

[0455] BW = body weight (kg)

[0456] G. TP dose as input to the PK solver

[0457] The absolute dose of TP (ng) = TP exposure dose (μg / kg) × BW (kg) × 1000 ng / μg, where BW = the average body weight of rats in the experiment. This TP dose was used as input for PK analysis performed by the PK Solver (Zhang Y, Huo M, Zhou J, and Xie S. "PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel" [Comp. Methods Prog. Biomed.] 99: pp. 306-314, 2010).

[0458] H. Calculation of lung TPeq concentration

[0459] Lung TPeq (ng / g) = TP + TRE (614.95 / 390.52), where: molecular weight TRE = 390.52 g / mol and molecular weight TP = 614.95 g / mol

[0460] I. Method

[0461] 1. Male Sprague-Dowley rats weighing between 300 and 350 g at the start of administration were required to arrive at the site at least three days prior to the day of administration. During the experiment, the animals were housed by two people.

[0462] 2. Rats were acclimatized to the nasal conus by placing them in the nasal conus once a day for three consecutive days, with the duration of each session increasing (starting from 5 minutes, increasing to 15 minutes, and ending at 30 minutes).

[0463] 3. Nine (9) rats were introduced into the nasal cone cavity prior to the start of administration. 170 mg of the test product was loaded into the VAG and delivered until no powder left the cavity. A 1.0 volt VAG setting was used with an airflow of 7 liters / minute. The exact duration of drug exposure was measured.

[0464] 4. Connect the filter to one of the nasal inhalation ports and begin sampling 5 minutes after administration and continue for 5 minutes. The vacuum flow rate for filter sampling is 0.5 L / min. Place the Mercer cascade impactor on one of the exposed ports and connect it to a vacuum source at a vacuum flow rate of 0.5 L / min for 5 minutes. The Mercer cascade impactor is a seven-stage aerosol sampler. During operation, aerosol is aspirated through a series of successively smaller jet openings and impacts the collection surface (impact plate). After passing through each jet, particles must turn to the right to follow the airflow. Larger particles cannot make this turn and impact the collection surface. Each subsequent stage of the impactor is designed to continuously provide higher jet velocities, resulting in progressively smaller average particle sizes collected. The filter collects the smallest particles that successfully bypass all the collection plates after the final stage. Before sampling each stage of the impactor, apply glycerin to promote particle recovery. After sampling, disassemble the impactor and collect the aerosol at each stage with 2 mL of 75% IPA and place it in a 4 mL vial. If the 75% IPA solution does not clarify, or if visible material remains on the stage, repeat the rinsing process with an additional 2 mL of 75% IPA; the washing procedure may be repeated up to three times. Collect only on the first cohort using a Mercer cascade impactor.

[0465] 5. Following exposure to the test article, collect blood and other biological samples at the appropriate time points according to Table 8. IPD collection of blood and lungs should be performed 0.5 hours after test article exposure. Weigh any dry powder remaining in the cavities after delivery.

[0466] 6. Repeat the exposure procedures described in steps 3 and 4 for animals in cohorts 2, 3, and 4. For cohorts 3 and 4, BAL fluid was collected prior to lung collection. Each cohort contained 9 animals. The exposure dates differed for cohorts 1-2 and 3-4.

[0467] 7. For rats experiencing the final time point, anesthetize them with 2% isoflurane via pure oxygen inhalation, and obtain approximately 3.0 mL of blood sample via cardiac puncture. Centrifuge the K2-EDTA tubes at 3,000 rpm at 4°C for 10 minutes.

[0468] 8. Aliquot the plasma into 1 mL tubes (3 tubes for the final time point) and label them with study number, animal identifier, dose group, and time point. Flash-freeze the plasma samples and freeze-store them (at approximately -80°C) for drug concentration analysis.

[0469] 9. Remove the lungs from the chest, clean to remove excess tissue, weigh, flash-freeze, and store at -80°C for subsequent lung drug concentration analysis. Process all other tissues in a similar manner.

[0470] 10. To collect BAL fluid, dissociate the trachea and insert a 14G InSyte catheter into the lung, just above the thoracic inlet, ensuring it is positioned above the carina. Flush the lung with a syringe containing 2 mL of sterile PBS. Gently massage the chest four times by applying inward pressure to the costal cage, then aspirate the BAL fluid back into the syringe. Transfer the BAL fluid to a 5 mL Eppendorf tube and keep it on ice at 2–4°C before centrifugation. Repeat the flushing with another 2 mL of sterile PBS and transfer to the same Eppendorf tube. Centrifuge the BALF liquid at 400 g for 10 minutes at 4°C. Remove the supernatant and store at -80°C. Discard the last drop of BALF (remove as much as possible). Preserve the cell clumps, flash freeze, and store at -80°C.

[0471]

[0472]

[0473] result

[0474] A. Definition of Pharmacokinetic Modeling

[0475]

[0476] B. Drug Dosage Calculation

[0477]

[0478] Lung concentrations of C.TP, TRE, and TPeq

[0479]

[0480]

[0481] Plasma concentrations of D.TP, TRE, and TPeq

[0482]

[0483]

[0484]

[0485] Bronchoalveolar lavage cell concentrations of E.TP, TRE, and TPeq

[0486]

[0487]

[0488]

[0489] Bronchoalveolar lavage fluid concentrations of F.TP, TRE, and TPeq

[0490]

[0491]

[0492]

[0493] Other tissue concentrations of G.TP, TRE, and TPeq

[0494]

[0495] In this study, the plasma, tissue, and BAL (fluid and cellular) pharmacokinetics of two different formulations, TPIP-A and TPIP-B, were evaluated. Exposure to both TPIP-A and TPIP-B was well-tolerated at each dose and did not result in any deaths. The total delivered inhaled doses of TPIP-B and TPIP-A were 100.5 and 85.5 μg / kg body weight, respectively (Table 9). Cohorts 1-2 exposed to TPIP-B and TPIP-A... maxThe corresponding lung TPeq concentrations at 0.5 hours were 2768 and 2264 ng / g lung tissue, respectively (Table 10). Lung TPeq levels in cohorts 3-4 exposed to TPIP-B and TPIP-A were 1217 and 1084 ng / g lower, respectively, than their comparison cohorts 1-2, because BAL extraction was performed on cohorts 3-4 (Table 10).

[0496] Within 24 hours, for cohorts 1-2, the highest concentrations (Cmax) of TP, TRE, and TPeq in the lungs were observed 0.5 hours after exposure to TPIP-B and TPIP-A (Table 11). Furthermore, a single exponential decrease in lung drug concentrations was observed within this 24-hour period (Table 9 and 11). Figure 1-3 For cohorts 3-4 and TPIP-B, the TPeq curves in the lungs differed slightly because Cmax occurred 3 hours post-exposure, and TRE Cmax also occurred 3 hours post-exposure to TPIP-A (Table 11). This difference can be explained by BAL performed on these rats. Generally, TPIP-B and TPIP-A have similar pharmacokinetic characteristics.

[0497] Plasma concentrations of TREs following inhalation of TPIP-A and TPIP-B peaked at 0.5 hours post-exposure and decreased exponentially over 24 hours (Table 12). Plasma TP concentrations were very low at 0.5 hours (Table 13).

[0498] The pharmacokinetic characteristics of TPIP-A and TPIP-B were also evaluated by bronchoalveolar lavage (BAL). TP, TRE, and TPeq concentrations were analyzed in cells and in the fluid collected from BAL after cell removal. For both formulations, the highest concentrations were found in cells and fluid at 0.5 h, except in cohorts 3–4 exposed to TPIP, where TRE Cmax was observed at 3 h post-dose (Tables 15 and 17). Figure 5-10 ).

[0499] In summary, the pharmacokinetic (PK) characteristics of inhaled TPIP-A and TPIP-B exhibited similar drug characteristics, with peak TPeq concentrations in the lungs and TRE concentrations in plasma observed at 30 minutes, followed by a single exponential decrease in drug levels over 24 hours. Some exceptions were observed in cohorts 1-2 and 3-4 exposed to TPIP-B. For cohorts 1-2, plasma TRE concentrations increased slightly at 6 hours, and for cohorts 3-4, TPeq concentrations in the lungs increased slightly at 3 hours.

[0500] Example 3: Efficacy of different doses of TPIP-B in hypoxic challenge telemetry rats

[0501] Materials and methods

[0502] A. Types

[0503] At the start of the study, male Sprague-Dowley rats weighing 300 to 500 g at the time of implantation with a dual pressure telemetry implantation device (TRM-54-PP) were used. The exact weight of the rats was recorded on the day of the experiment.

[0504] B. Qualification and randomization of the test system

[0505] 1. Animals must arrive at the site at least 3 days before the planned experiment.

[0506] 2. Identify the animal upon arrival according to CCAC guidelines.

[0507] 3. Record all animal care and facility maintenance, and keep the records at the testing facility.

[0508] 4. Before the experiment, the research leader, who keeps a record of the ID number of each animal, randomly assigns animals.

[0509] C. Drug administration and dosage selection

[0510] TPIP-B was administered using a Vilnius aerosol generator (VAG). The VAG was connected to a 12-port rodent nasal-only inhalation system (CH Technologies, Westwood, NJ, USA) at the bottom of the tower. An airflow connected to the bottom and exiting from the top of the nasal-only inhalation chamber was introduced into the VAG at a flow rate of 7 liters per minute. TPIP-B was placed in the VAG chamber at doses of 25 mg, 50 mg, 90 mg, and 170 mg to aerosolize the material at VAG voltages of 0.125, 0.25, 0.5, and 1.0 volts (V), respectively. The nebulizer was shut off when all material had been aerosolized and no drug flowed from the VAG chamber or remained at the nasal-only inhalation outlet port. The time to complete aerosolization of the material was measured. The nasal-only inhalation tower, tubing, and other materials used in the dry powder process were cleaned by sequentially running aqueous solutions of 0.5% sodium dodecyl sulfate (SDS), tap water, and distilled water. After use, use air blowing from a fume hood equipped with a HEPA filter to remove any remaining powder inside the aerosol generator. After thoroughly cleaning the tower and VAG, proceed to the next experiment.

[0511] D. Sample Analysis

[0512] Filters collected from the nasal inhalation tower alone were used to analyze C16TR by high-performance liquid chromatography (HPLC) and charged aerosol detector (CAD). The concentrations of C16TR and TRE in lung and plasma samples were also analyzed using LC-MS / MS. C16TR and TRE values ​​reported below the level of quantitation (BLQ) were each assigned a zero value.

[0513] E. Acquisition System

[0514] A networked personal computer running Microsoft Windows Office 2016 was used for data acquisition. For systemic arterial blood pressure (SAP) and RVPP, data were acquired at a frequency of 500 Hz using a Powerlab acquisition system (AD instrument) and the software used was Labchart. All records were stored on a server for further analysis. Data were recorded every minute, and results were presented during normoxic-hypoxic-noroxic periods. To avoid misinterpreting artifacts caused by animal movement or probe positioning relative to the ventricular wall, 3 to 4 typical pulses in RVPP and SAP were manually selected. Normal right ventricular pressure has an almost square waveform and no spikes. A good signal (noroxic-hypoxic-noroxic) was obtained in the last minute of the 10-minute duration of each of the three steps. Each of these values ​​was retranscribed in an Excel file listing data for individual rats at each time point before drug exposure (baseline data) and at different times after drug exposure.

[0515] F. Research Design and Experimental Procedures

[0516] 1. Research Design

[0517] These studies used a total of seven (7) telemetry-implanted male Sprague-Dawley rats. For each dose, three (3) telemetry rats were used for efficacy assessment, and seven (7) PK rats were dedicated to PK assays. In each experiment, a filter was connected to the remaining 1 port in the nasal cavity only to sample the inhaled drug content. Hypoxia challenge in telemetry rats and blood and tissue collection in PK rats are shown in Tables 19 and 20. In PK rats, blood samples were collected from the jugular vein, and at the endpoint, blood was collected by cardiac puncture, and the lungs were harvested, cleaned from the surrounding tissue, and weighed. Plasma and lungs were stored at -80°C and filtered at 4°C. All telemetry rats were acclimatized to the hypoxia exposure chamber, and rats dedicated to inhalation studies (telemetry rats and PK rats) were acclimatized to a nasal-only inhalation tower once daily for 3 consecutive days, with each additional inhalation lasting 5 minutes and 20 minutes at the end of the acclimatization period.

[0518]

[0519]

[0520] 2. Telemetry of normoxic / hypoxic challenges in rats

[0521] Each rat was housed in an 8×16×8 inch cage placed atop a telemetry receiver (smart disc). A custom-made cover was placed on top of the cage, which contained an air inlet port, an exhaust port for venting air, and an oxygen probe (Vernier, Beaverton, Oregon, USA) for continuous measurement of oxygen concentration inside the cage. Individual mixing chambers were pre-filled with a hypoxic (10% O2 / 90% N2) gas mixture obtained by combining 100% N2 and ambient air to stabilize the oxygen level at 10% O2. The hypoxic gas mixture was delivered to four separate chambers containing the telemetry rats at a flow rate of approximately 35 liters per minute. Cardiovascular data were collected for 10 minutes while the rats were exposed to room air. The 3-way stopcock was then switched, directing the hypoxic gas from the mixing chamber to the cages containing the rats. The hypoxic air then flowed through the inlet port to replace the normoxic air in the rat cages. Equilibration took approximately 2 minutes for the rats to be fully exposed to the 10% O2 / 90% N2 gas mixture. Cardiovascular parameters were continuously recorded during the 10-minute exposure to hypoxic gas. At the end of the 10-minute hypoxic challenge, the inflow of hypoxic air from the mixing chamber was shut off, and the sealed lid was opened to allow the rats to return to breathing normoxic gas. Cardiovascular parameters were continuously recorded during the 10-minute recovery period after hypoxic exposure. After collecting data on normoxic / hypoxic / normoxic exposure, the rats were returned to their enclosures. All rats were given free access to food and water after the drug and hypoxic exposures.

[0522] 3. Inhalation of TPIP-B

[0523] Using a nasal cone chamber connected to a 12-port nasal inhalation-only chamber (CH Technologies), three telemetry rats and seven PK rats were exposed to inhaled TPIP-B at voltages of 0.125, 0.25, 0.5, and 1.0 V. Airflow was circulated through the nasal cavity only using an inflow airflow rate of 7 L / min. A glass fiber filter was connected to one of the exposure ports during the study duration. Airflow sampling was performed using a vacuum source established at 0.5 L / min for 5 minutes, starting 5 minutes after aerosolization began and ending at 10 minutes. Air circulated through the nasal inhalation tower into the bottom and out through a port at the top of the tower.

[0524] G. Method

[0525] 1. For these studies, a total of seven (7) male Sprague-Dowley rats with dual-pressure telemetry implants were used. For these experiments, three telemetry rats were used at 0.125, 0.25, 0.5 V, and 1 V. Additionally, a cohort of seven rats was used for pharmacokinetic determination in each study. A filter was connected to the remaining port in each study.

[0526] 2. Twenty-four hours prior to exposure of telemetry rats to the test product, they were exposed to a normoxic / hypoxic / normoxic challenge, during which cardiopulmonary responses to RVPP and SAP were continuously measured. The procedure was repeated at three different times, performed at 1, 6, and 12 hours of the day, and the mean response at these three determined times was used to represent the baseline pre-drug response to hypoxia.

[0527] 3. After obtaining a baseline hypoxic response, exposure to the test product was performed. Rats were exposed to TPIP-B until no powder residue remained in the VAG cup. Cardiovascular responses to normoxic / hypoxic / return to normoxic challenges were performed as planned in Table 21. Blood and lung samples were drawn from PK-specific rats at the times indicated in Table 20.

[0528] 4. Analyze the filter.

[0529] 5. For blood collection, 0.5 mL of blood was obtained from the jugular vein of a conscious rat and deposited in a 0.5 mL K2-EDTA tube. The K2-EDTA tube was centrifuged at 900 g for 10 minutes at 4 °C.

[0530] 6. Divide the plasma into 1 mL tubes, freeze quickly, and store at approximately -80°C before analysis.

[0531] 7. Rats at the end of the time point were anesthetized with 2% isoflurane via pure oxygen inhalation, and approximately 3.0 mL of blood was obtained via cardiac puncture. K2-EDTA tubes were centrifuged at 900 x g for 10 minutes at 4°C.

[0532] 8. Divide the plasma into three 1 mL tubes and store at approximately -80°C prior to drug concentration analysis.

[0533] 9. Collect the right and left lungs, weigh them, and flash-freeze them at -80°C for subsequent lung drug concentration analysis.

[0534] result

[0535] A. Inhalation of TPIP-B

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548] In this study, the efficacy of different doses of DSPE-PEG-free TPIP (TPIP-B) was evaluated. Experiments were conducted in rats equipped with telemetry probes implanted in the right ventricle and descending aorta to measure increases in RVPP and changes in SAP induced by exposure to acute hypoxia. TPIP-B exposure was well tolerated and did not lead to any death.

[0549] All doses of TPIP-B inhibited the ΔRVPP response to hypoxia over 24 hours. At the highest dose of 138 μg / kg, statistically significant (p<0.05) inhibition was observed over 24 hours, with inhibitory effects ranging from 40% to 70%, except at 12 hours. Slightly lower doses of TPIP-B at 57 μg / kg increased over time, reaching a maximum effect (71% inhibition) at 24 hours. The lowest doses of 23 and 6 μg / kg showed similar pharmacodynamic effects, with maximum activity (approximately 65% ​​inhibition) at 1 hour and decreasing to 57% and 40%, respectively, at 24 hours.

[0550] With increasing TPIP-B dosage, dose-related increases were observed in the concentrations of treprostacyclin palmitate equivalent (C16TReq) in the lungs and in TRE concentrations in plasma. At 0.5 hours, C16TReq concentrations in the lungs were high, and within 24 hours, these concentrations decreased by 94-97% for each TPIP-B dose. Plasma TRE concentrations were highest at 0.5 hours among all TPIP-B doses, exhibiting a single exponential decrease over 12 hours and a decrease of 89-92% within 24 hours.

[0551] In summary, efficacy studies in hypoxia-challenged telemetry rats demonstrated that the highest dose of TPIP-B (138 μg / kg) significantly inhibited the increase in RVPP induced by hypoxia challenge over 24 hours. Lower doses of TPIP-B were less effective, exhibiting activity over 24 hours, but not significantly at any time point.

[0552] Example 4: TPIP-B assessment of cough and ventilation in guinea pigs

[0553] In this case study, the effects of TPIP-B on cough, ventilation changes, and expiratory interval changes were evaluated in conscious male guinea pigs. Expiratory interval is a dimensionless indicator of the changes in respiratory pattern typically observed during bronchoconstriction (see ChongBTY et al. (1998. Measurement of bronchoconstriction using whole-body plethysmograph: comparison of freely moving versus restrained guinea pigs, J. Pharmacol. Toxicol. Methods) 39, 163-168 and Lomask M (2006. Further exploration of the expiratory interval parameter, Exp. and Toxicol. Pathol.) 57, 13-20).

[0554] A. method

[0555] 1. Experiments were conducted in male Hartley guinea pigs (230–430 g). After a 3-day acclimatization period, the guinea pigs were placed in a whole-body plethysmometer to measure ventilation (tidal volume, respiratory rate, and minute volume), expiratory interval, and cough using established techniques. Cough measurements were recorded via the plethysmometer, showing a large inspiration followed by a large expiration, and confirmed by manual observation, video recording, and cough sounds. Ventilation, expiratory interval, and cough data were measured during a baseline 15-minute period prior to exposure to the dry powder aerosol.

[0556] 2. In this study, the test product was administered by a Vilnius aerosol generator (VAG) (CH Technologies, Westwood, NJ) at a specific voltage output and microparticle range to aerosolize a specific amount of dry powder, followed by observation for 120 minutes after the aerosolized compound was applied. Approximately 110 mg of TPIP-B placebo was administered at a setting of 1 volt at 2500 mg / m². 3 Aerosolize in the microparticle range until the powder is completely consumed (Table 29). Then administer TPIP-B at approximately 110 mg or 200 mg under similar conditions. To reduce exposure time, an output of 0.3 volts at 25 g / m³ was also used. 3A 200 mg dose was administered in the microparticle range. To standardize the duration of exposure to the test article, additional experiments were performed in which excess TPIP-B (ranging from approximately 200 mg to 450 mg) was administered at 25 g / m³ at increasing VAG outputs of 0.15 V, 0.3 V, and 0.5 V. 3 The microparticles were aerosolized for 15 minutes. Finally, to compare TPIP-A and TPIP-B, the aerosols were set at 0.15 volts and 0.5 volts at 25 g / m³. 3 The microparticle range delivers approximately 250 mg to 400 mg of TPIP-A over 15 minutes (Table 29).

[0557] 3. Air for aerosol delivery in all experiments was supplied by an air compressor unit with a total inflow of 5.5 L / min of humidified air (30% RH) (4.5 L / min for aerosol dispersion, combined with 1 L / min of humidified air) to facilitate aerosol delivery to the plethysmometer and minimize electrostatic adhesion issues. Ventilation, expiratory intervals, and coughing were measured before, during, and after exposure to the test article. An 8 L / min vacuum was established at the bottom of the plethysmometer, allowing air and aerosols to enter at the top and exit at the bottom of the system. A separate 0.5 L / min vacuum source was also connected to a glass fiber filter assembly, which was attached to a port in the plethysmometer to sample aerosol concentrations in TPIP-B placebo (containing 70 wt% mannitol and 30 wt% leucine), TPIP-B, and TPIP-A aerosols. Except for TPIP-B placebo, filtered samples used for TPIP-B and TPIP-A were analyzed using HPLC and CAD against TP (C16TR) analyte content to determine TP aerosol concentrations. Filter sampling was maintained for the entire study duration; i.e., 135 minutes, but the TP aerosol concentration in the plethysmometer was calculated using either the filter exposure time or the drug delivery duration (at the start of the study, the drug was delivered for the full duration until depletion; in subsequent studies, the drug delivery time was adjusted to 15 minutes).

[0558] 4. When the deposition factor (DF) is 100%, the total TP dose delivered by guinea pig nasal inhalation is calculated using the following equation:

[0559]

[0560] 5. At the end of the study, the guinea pigs were euthanized and blood (plasma) and lung samples were collected to measure TP (C16TR) and TRE concentrations using LC-MS / MS in these samples.

[0561] result

[0562] Exposure to TPIP-B placebo, TPIP-B, and TPIP-A was well tolerated and did not result in any deaths. In the first series of experiments where the test article was aerosolized until all material disappeared, aerosolization of 100–115 mg of TPIP-B placebo for 32–45 minutes did not induce coughing in all four guinea pigs studied. Aerosolization of 89–105 mg of TPIP-B for 23–32 minutes (mean total inhaled dose = 5.7 μg / kg body weight) did not induce coughing in two guinea pigs studied, and increasing the aerosolized dose to 184–201 mg of TPIP-B (mean total inhaled dose = 69.1 μg / kg body weight, exposure time range 62–74 minutes) induced coughing in one out of three guinea pigs. However, aerosolizing 197 mg TPIP-B (mean total inhaled delivery dose = 69.2 μg / kg body weight) for 19 minutes did not induce coughing in the guinea pig studied.

[0563] In the second group of experiments, where an excess of the test product was aerosolized over a fixed time of 15 minutes, aerosolization of 102–111 mg TPIP-B (mean total inhaled dose = 17.7 μg / kg body weight) induced coughing in 1 out of 5 guinea pigs. Increasing the aerosolized dose to 115–139 mg TPIP-B (mean total inhaled dose = 43.2 μg / kg body weight) did not induce coughing in the 2 guinea pigs studied. However, further increasing the aerosolized dose to 211–457 mg TPIP-B (mean total inhaled dose = 153.2 μg / kg body weight) induced coughing in 3 out of 4 guinea pigs (Table 29).

[0564] In summary, the results of this study indicate that coughing is observed at the threshold inhalation dose of TPIP-B at 17.7 μg / kg. For comparison, aerosolizing 90–98 mg of TPIP-A for 15 minutes (mean total inhaled dose = 8.3 μg / kg body weight) did not produce coughing in the two guinea pigs studied, and increasing the aerosolized dose to 322 mg of TPIP-A (mean total inhaled dose = 185.4 μg / kg body weight) did not produce coughing in the one guinea pig studied. However, based on previous research, coughing was observed at the threshold inhalation dose of TPIP at 12.8 μg / kg.

[0565] Compared to values ​​obtained by exposure to a placebo of TPIP-B, administration of TPIP-B produced a 1 to 2-fold increase in expiratory interval. Based on prior experience that values ​​typically observed during challenge periods in the presence of bronchodilators such as capsaicin or citrate are in the range of 1,000% and higher, the expiratory interval parameter values ​​suggest that TPIP-B is unlikely to induce bronchoconstriction, and there were no consistent changes in ventilation at inhaled doses of TPIP-B.

[0566] Lung TPeq concentrations increase with the dose of inhaled medication (Table 29).

[0567]

[0568]

[0569] This study investigated the effects of TPIP-B on cough and ventilation in guinea pigs, a species that exhibits coughing upon exposure to inhaled TRE administered via nebulization. The results showed that coughing occurred concurrently with TPIP-B and was observed at a threshold delivery dose of 17.7 μg TP / kg body weight (equivalent to 11.2 μg TRE / kg body weight), approximately nine times higher than the threshold dose of 1.2 μg TRE / kg body weight that induces cough in guinea pigs. The cough threshold of TPIP-B was similar to that of TPIP-A at 12.8 μg TP / kg body weight (equivalent to 8.1 μg TRE / kg body weight).

[0570] TRE dosage is derived from the equation:

[0571] TRE (equivalent) dose = TP dose × 390.52 / 614.94

[0572] (where 614.94 and 390.52 are the molecular weights of TP and TRE, respectively).

[0573] Following exposure to TPIP-B at the cough threshold inhaled dose, the first cough episode occurred at 34 minutes, which was later than the time of coughs occurring within the first 10 minutes of exposure with a nebulized TRE. Cough response represents the response observed with treprostacyclin exposure and occurred in separate cough episodes (as seen in the TPIP-A study), rather than in isolated coughs.

[0574] In summary, TPIP-B induced cough at a delivery dose of 17.7 μg TP / kg body weight (equivalent to 11.2 μg TRE / kg body weight), which is 9 times higher than the delivery dose of nebulized TREs that induced cough in guinea pigs. There were no significant changes in cough and ventilation responses between TPIP-B and TPIP-A.

[0575] Example 5: Evaluation of the safety, tolerability, and pharmacokinetics of single- and multiple-dose daily administration of TPIP-B in healthy adults. Conquest

[0576] design

[0577] To evaluate the pharmacokinetic (PK) characteristics of TPIP-B in healthy adults, TPIP-B was formulated as a dry powder composition and administered by inhalation in single-dose or multi-dose studies, such as... Figure 19 As shown. The following single doses were tested: 112.5 μg; 225 μg; 450 μg; and 675 μg. The multi-dose groups were structured as follows: 225 μg; and an upward titration of 112.5 μg administered on days 1–4, followed by an increase in dose to 225 μg on day 5.

[0578] All doses were administered using a single-actuated capsule of 112.5 μg. Blood samples for pharmacokinetic (PK) assessment in the single-dose groups were collected within 15 minutes before administration and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 24 (day 2), 36 (day 2), 48 (day 3), and 72 (day 4) hours after administration of TPIP-A or placebo. PK assessments in the multi-dose groups were performed within 30 minutes before administration, at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after administration on day 1, pre-administered only on days 2, 3, 4, 5, and 6, and pre-administered on day 7 and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 24 (day 8), 48 (day 9), and 72 (day 10) hours after administration.

[0579] result

[0580] Triprostacyclin PK is a linear chain (i.e., CL / F, Vd / F, and t). 1 / 2 It is dose-independent, and systemic exposure is associated with a dose-chain correlation with low to moderate inter-individual variability. Steady-state accumulation was not observed. Rapid C-reduction was observed in both single-dose and multiple-dose administration. max and length t 1 / 2 (7-12 hours). Tables 30A (single-dose group) and 30B (multiple-dose group) provide the pharmacokinetic characteristics of the single-dose and multiple-dose groups. C max AUC and t 1 / 2 It can be within 80-125% of the values ​​provided in Tables 30A and 30B.

[0581]

[0582]

[0583]

[0584] For Tables 30A and 30B: AUC, the region under the plasma concentration versus time curve; CL / F, apparent total drug clearance after oral administration; CV, coefficient of variation; C max Observed maximum plasma concentration; PK, pharmacokinetics; QD, once daily; t 1 / 2 End-of-life; TPIP, treprostacyclin palmitate inhalation powder; Vd / F, apparent distribution after non-intravenous drug administration.

[0585] a The AUC of the single-dose group is equal to the AUC extrapolated from time 0 to infinity.

[0586] b n = 5.

[0587] c The AUC of the multi-dose group is the AUC at steady state from time 0 to 24 hours.

[0588] Single and multiple TPIP-B administrations were generally well tolerated in healthy adults. The up-titering strategy in the multiple-dose groups improved tolerability. Treatment-related adverse events (TEAEs) were dose-related and generally mild (80.6%). No serious or severe TEAEs were observed. TEAEs are provided in Tables 31A (single-dose group) and 31B (multiple-dose group).

[0589]

[0590]

[0591]

[0592] *******

[0593] Although the invention has been described with reference to specific embodiments, those skilled in the art will understand that various changes and substitutions can be made without departing from the true spirit and scope of the invention. Furthermore, many modifications can be made to adapt particular circumstances, materials, combinations of substances, processes, or one or more processing steps to the purpose, spirit, and scope of the described invention. All such modifications are intended to fall within the scope of the appended claims.

[0594] For all purposes, the patents, patent applications, patent application publications, journal articles and agreements cited in this article are incorporated herein by reference in their entirety.

Claims

1. A dry powder composition comprising: (a) 0.5 wt% to 5 wt% of compound (I): （I）， Or a pharmaceutically acceptable salt thereof, wherein R 1 It is a hexadecyl group. (b) 25 wt% to 61 wt% leucine, and The remaining portion is (c) mannitol. The total weight of (a), (b) and (c) is 100 wt%.

2. The dry powder composition according to claim 1, wherein the dry powder composition is a spray-dried dry powder composition.

3. The dry powder composition according to claim 1, wherein R 1 It is a straight-chain hexadecyl group.

4. The dry powder composition according to claim 3, wherein the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is present at 2 wt% to 4 wt% of the total weight of the dry powder composition.

5. The dry powder composition according to claim 4, wherein the dry powder composition comprises 45 wt% to 61 wt% leucine.

6. The dry powder composition according to claim 5, wherein the leucine is L-leucine.

7. The dry powder composition according to claim 1, wherein the composition is selected from one of the following compositions: 。 8. The dry powder composition according to claim 1, comprising: (a) 2 wt% of the compound of formula (I), wherein R 1 (a) a straight-chain hexadecyl group; (b) 45 wt% to 61 wt% leucine; and the remainder is (c) mannitol.

9. The dry powder composition according to claim 1, comprising: (a) 4 wt% of the compound of formula (I), wherein R 1 (a) a straight-chain hexadecyl group; (b) 45 wt% to 61 wt% leucine; and the remainder is (c) mannitol.

10. The dry powder composition according to any one of claims 1 to 9, wherein it is contained in one or more dry powder capsules.

11. The dry powder composition of claim 10, wherein the one or more dry powder capsules are one or more hydroxypropyl methylcellulose (HPMC) dry powder capsules.

12. The dry powder composition according to any one of claims 1 to 9, comprising a compound of formula (I) selected in doses of 80 µg, 160 µg, 240 µg, 320 µg, 400 µg, 480 µg and 640 µg.

13. The dry powder composition according to claim 12, comprising a dose of 80 µg, 160 µg, 240 µg, 320 µg, or 640 µg.

14. The dry powder composition of claim 12, wherein the dry powder composition is present in a single dry powder capsule.

15. The dry powder composition according to claim 12, wherein the dry powder composition is present in a plurality of dry powder capsules.

16. The dry powder composition according to any one of claims 1 to 9, comprising 80 µg to 675 µg of the compound of formula (I).

17. The dry powder composition according to claim 16, comprising 80 µg to 640 µg of the compound of formula (I).

18. The dry powder composition according to claim 16, comprising 112.5 µg to 675 µg of the compound of formula (I).

19. The dry powder composition according to claim 16, wherein R 1 It is a straight-chain hexadecyl group and, upon once-daily inhalation via a dry powder inhaler, provides one of the following properties: (a) Maximum plasma concentrations of treprostacyclin in the range of 80% to 125% of the range of 17 pg / mL to 1150 pg / mL (C max );or (b) Area under the curve (AUC) of 80% to 125% of treprostacyclin plasma concentrations in the range of 475 pg*h / mL to 8000 pg*h / mL.

20. Use of the dry powder composition according to any one of claims 1 to 9 in the preparation of a medicament for treating pulmonary hypertension (PH) in patients in need.

21. The use according to claim 20, wherein the PH is pulmonary hypertension (PAH).

22. The use according to claim 21, wherein the pulmonary hypertension is pulmonary hypertension of class I, II, III or IV as characterized by the New York Heart Association (NYHA).

23. The use according to claim 20, wherein the PH is a PH associated with interstitial lung disease (ILD).

24. The use according to claim 23, wherein the ILD comprises one or more lung diseases selected from the group consisting of: idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), allergic pneumonia, interstitial pneumonia, connective tissue disease associated with ILD (CTD-ILD), sarcoidosis, or asbestosis.

25. The use according to claim 24, wherein the interstitial pneumonia is idiopathic interstitial pneumonia (IIP) or hypersensitivity pneumonitis.

26. The use according to claim 25, wherein the IIP is desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or acute interstitial pneumonia.

27. The use according to claim 24, wherein the one or more lung diseases is IPF.

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