A dry powder composition of treprostinyl prodrug and its method of use.

Abstract

The present disclosure provides dry powder compositions of treprostinil prodrugs and methods for treating pulmonary hypertension (e.g., pulmonary arterial hypertension or PH associated with interstitial lung disease) in patients in need of such treatment. The dry powder compositions include: (a) about 0.5 wt% to about 5 wt% of a compound of Formula (I); and (b) about 10 wt% to about 61 wt% of leucine, and the remainder (c) a sugar selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%, and R 1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. A method for treating PH comprises administering an effective amount of the dry powder composition to the lungs of a patient by inhalation via a dry powder inhaler during an administration period. In certain compositions and methods provided herein, R 1 is hexadecyl, for example, linear hexadecyl. [Formula 1] JPEG2023548307000053.jpg40161

Description

[Background technology]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 106,818, filed on 28 October 2020, the disclosure of which is incorporated herein by reference in its entirety.

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

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

[0004] Pulmonary arterial hypertension (PAH) affects approximately 200,000 people worldwide, with about 30,000 to 40,000 of those cases occurring in the United States. PAH patients experience constriction of the pulmonary arteries, leading to elevated pulmonary blood pressure and making it difficult for the heart to pump blood to the lungs. Patients often suffer from shortness of breath and fatigue, severely limiting their ability to perform physical activities.

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

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

[0007] This invention addresses the need for novel therapeutic options for pulmonary hypertension (PH) (including pulmonary arterial hypertension (PAH) and PH associated with interstitial lung disease), portal pulmonary hypertension (PPH), and pulmonary fibrosis by providing a dry powder composition of a treprostinil prodrug useful for pulmonary administration, and a method for administering it to patients in need of treatment. [Overview of the project]

[0008] In one aspect, this disclosure relates to (a) formula (I) in amounts of approximately 0.5 wt% to approximately 5 wt%, [ka] In the formula, R 1It relates to a dry powder composition comprising (a) a compound that is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (b) about 10 wt% to about 61 wt% leucine, and the balance (c) a sugar selected from the group consisting of trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%. In a further embodiment, the composition comprises about 29 wt% to about 61 wt% leucine. In yet another embodiment, the composition comprises 0.5 wt% to about 4 wt% of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, the stereoisomer is a diastereomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, the stereoisomer is a diastereomer of the compound of formula (I). In another embodiment, the stereoisomer is a diastereomer of a pharmaceutically acceptable salt of the compound of formula (I).

[0010] In one embodiment, R 1 is tetradecyl. In a further embodiment, R 1 is linear tetradecyl.

[0011] In one embodiment, R 1 is pentadecyl. In a further embodiment, R 1 is linear pentadecyl.

[0012] In one embodiment, R 1 is heptadecyl. In a further embodiment, R 1 is linear heptadecyl.

[0013] In one embodiment, R 1 is octadecyl. In a further embodiment, R 1 is linear octadecyl.

[0014] In one embodiment, R 1 is hexadecyl. In a further embodiment, R 1It is a linear hexadecyl.

[0015] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 wt% to about 4 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl. In yet another embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 2 wt% to about 4 wt% of the total weight of the dry powder composition.

[0016] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 4 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0017] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 3.5 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0018] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 3 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0019] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5 wt% to about 4 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1It is a linear hexadecyl.

[0020] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.8 wt% to about 4 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0021] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 0.8 wt% to about 3.3 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0022] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 2 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0023] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0024] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0025] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 2 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

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

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

[0028] In one embodiment, leucine is present in an amount of about 20 wt% to about 40 wt% of the total weight of the dry powder composition. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl. In yet another embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0029] In another embodiment, leucine is present in an amount of about 29 wt% to about 61 wt% of the total weight of the dry powder composition. In yet another embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl. In yet another embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0030] In another embodiment, leucine is present in an amount of about 25 wt% to about 35 wt% of the total weight of the dry powder composition. In yet another embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl. In yet another embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0031] In another embodiment, leucine is present in an amount of about 40 wt% to 61 wt% of the total weight of the dry powder composition. In yet another embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 is a linear hexadecyl. In yet another embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 4 wt% of the total weight of the dry powder composition. In yet another embodiment, leucine is present in an amount of about 45 wt% to 61 wt% of the total weight of the dry powder composition. In yet another embodiment, leucine is present in an amount of about 55 wt% to 61 wt% of the total weight of the dry powder composition.

[0032] In another embodiment, leucine is present in an amount of about 28 wt% to about 33 wt% of the total weight of the dry powder composition. In yet another embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl. In further embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0033] In another embodiment, leucine is present in an amount of about 25 wt% to about 33 wt% of the total weight of the dry powder composition, for example, 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 a further embodiment, R 1 is hexadecyl. In yet another embodiment, R 1It is a linear hexadecyl.

[0034] In one embodiment, the dry powder composition provided herein has a leucine-to-mannitol weight ratio of about 0.40:1 (leucine to mannitol) to about 0.50:1 (leucine to mannitol). In another embodiment, the dry powder composition provided herein has a leucine-to-mannitol weight ratio of about 0.75:1 (leucine to mannitol) to about 0.90:1 (leucine to mannitol). In yet another embodiment, the dry powder composition provided herein has a leucine-to-mannitol weight ratio of about 0.5:1 (leucine to mannitol) to about 1.7:1 (leucine to mannitol).

[0035] In one embodiment, the sugar is mannitol. In further embodiments, R 1 is hexadecyl. In further embodiments, R 1 It is a linear hexadecyl.

[0036] 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 (c) mannitol. In further embodiments, R 1 is hexadecyl. In further embodiments, R 1 It is a linear hexadecyl.

[0037] 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 (c) mannitol. In further embodiments, R 1 is hexadecyl. In further embodiments, R 1 It is a linear hexadecyl.

[0038] Another aspect of the present invention provides a method for treating pulmonary hypertension (PH) in a patient requiring treatment for pulmonary hypertension (PH). The method comprises administering an effective amount of the dry powder composition disclosed herein to the patient's lungs by inhalation via a dry powder inhaler.

[0039] In one embodiment, PH is a Group 1 PH as characterized by the World Health Organization (WHO).

[0040] In one embodiment, pulmonary hypertension is pulmonary arterial hypertension (PAH). In one embodiment, PAH is Class I PAH as characterized by the New York Heart Association (NYHA). In another embodiment, PAH is Class II PAH as characterized by the NYHA. In another embodiment, PAH is Class III PAH as characterized by the NYHA. In yet another embodiment, PAH is Class IV PAH as characterized by the NYHA.

[0041] In another embodiment, PH is a group 2 PH as characterized by the WHO. In yet another embodiment, PH is a group 3 PH as characterized by the WHO. In yet another embodiment, group 3 PH is PH associated with interstitial lung disease (ILD). In yet another embodiment, PH is a group 4 PH as characterized by the WHO. In yet another embodiment, PH is a group 5 PH as characterized by the WHO.

[0042] In one embodiment of the treatment method described herein, administration is performed once or twice a day.

[0043] In yet another embodiment, the 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 pre-measured or device-measured.

[0044] A further aspect of the present invention relates to a method for treating PH (e.g., PAH or PH-ILD) in adult human patients requiring treatment for PH (e.g., PAH or PH-ILD), wherein approximately 80 μg to approximately 675 μg of formula (I) is administered once daily during the administration period. [ka] In the formula, R 1 The method involves administering a dry powder composition containing a compound of tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, its stereoisomer, or a pharmaceutically acceptable salt thereof, to the patient's lungs by inhalation. During the administration period, the patient will have at least one of the following characteristics: (a) Maximum plasma concentration of treprostinil in the range of approximately 80% to 125% of the range of approximately 17 pg / mL to approximately 1150 pg / mL (C max ),or (b) Approximately 475pg * h / mL~about 8000pg * Area under the curve (AUC) of treprostinil plasma concentrations in the range of approximately 80% to 125% of h / mL. 0-inf In further embodiments, R 1 This is a hexadecyl, for example, a linear hexadecyl.

[0045] In further embodiments, the composition comprises doses selected from the group consisting of 80 μg, 160 μg, 240 μg, 320 μg, 400 μg, 480 μg, and 640 μg of the compound of formula (I). The dose may be present, for example, in one dry powder capsule or in multiple capsules.

[0046] In another aspect, this disclosure relates to formula (I) in amounts of approximately 80 μg to approximately 675 μg. [ka] The present invention relates to a dry powder composition comprising a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof. In this embodiment, the dry powder composition provides at least one of the following features: (a) Maximum treprostinil plasma concentration (C) of approximately 80% to 125% in the range of approximately 17 pg / mL to approximately 1150 pg / mL max ),or (b) Approximately 475pg * h / mL~about 8000pg * Area under the plasma concentration curve (AUC) is approximately 80% to 125% of the h / mL range. 0-inf ).

[0047] In further embodiments, the composition comprises doses selected from the group consisting of 80 μg, 160 μg, 240 μg, 320 μg, 400 μg, 480 μg, and 640 μg of the compound of formula (I). The dose may be present, for example, in one dry powder capsule or in multiple capsules.

[0048] In some embodiments, the dry powder composition used in the methods described herein and herein is comprised of about 1 wt% to about 5 wt% of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, with the remainder being one or more pharmaceutically acceptable excipients suitable for use in a dry powder inhaler. In some embodiments, the one or more pharmaceutically acceptable excipients suitable for use in a dry powder inhaler are sugars, amino acids, and optionally distearoylphosphoethanolamine-polyethylene glycol 2000 (DPSE-PEG2000). In some embodiments of the dry powder composition or method described herein, the dry powder composition is comprised of about 25 wt% to about 61 wt% of leucine, with the remainder being one or more sugars. In some embodiments, the one or more sugars are selected from trehalose and mannitol. In some embodiments of the dry powder composition or method described herein, the dry powder composition is not comprised of distearoylphosphoethanolamine-polyethylene glycol 2000 (DPSE-PEG2000). [Brief explanation of the drawing]

[0049] [Figure 1] Figure 1 is a graph showing the concentration of treprostinyl palmityl (TP) in the lungs after inhaling TPIP-A or TPIP-B.

[0050] [Figure 2] Figure 2 is a graph showing the concentration of TRE in the lungs after inhaling TPIP-A or TPIP-B.

[0051] [Figure 3] Figure 3 is a graph showing the concentration of treprostinyl palmityl (TP) equivalent in the lungs after inhaling TPIP-A or TPIP-B.

[0052] [Figure 4] Figure 4 is a graph showing the concentration of TRE in plasma after inhaling TPIP-A or TPIP-B.

[0053] [Figure 5] Figure 5 is a graph showing the concentration of TP in the BAL cell fraction after inhalation of TPIP-A or TPIP-B.

[0054] [Figure 6] Figure 6 is a graph showing the concentration of TRE in the BAL cell fraction after inhalation of TPIP-A or TPIP-B.

[0055] [Figure 7] Figure 7 is a graph showing the concentration of TP equivalents in the BAL cell fraction after inhalation of TPIP-A or TPIP-B.

[0056] [Figure 8] Figure 8 is a graph showing the concentration of TP in BAL solution after inhaling TPIP-A or TPIP-B.

[0057] [Figure 9] Figure 9 is a graph showing the concentration of TRE in BAL solution after inhaling TPIP-A or TPIP-B.

[0058] [Figure 10]Figure 10 is a graph showing the concentration of TP equivalents in the BAL solution after inhaling TPIP-A or TPIP-B.

[0059] [Figure 11] Figure 11 is a graph showing the ΔRVPP response to a hypoxic challenge in rats exposed to TPIP-B via inhalation at a dose of 6 μg / kg.

[0060] [Figure 12] Figure 12 is a graph showing the ΔRVPP response to a hypoxic challenge in rats exposed to TPIP-B at a dose of 23 μg / kg inhalation.

[0061] [Figure 13] Figure 13 is a graph showing the response of RVPP to a hypoxic challenge in rats exposed to TPIP-B at a dose of 57 μg / kg inhalation.

[0062] [Figure 14] Figure 14 is a graph showing the response of RVPP to a hypoxic challenge in rats exposed to TPIP-B at a dose of 138 μg / kg inhalation.

[0063] [Figure 15] Figure 15 is a graph showing the TRE concentration in plasma after TPIP-B inhalation.

[0064] [Figure 16] Figure 16 is a graph showing the TP concentration in the lungs after TPIP-B inhalation.

[0065] [Figure 17] Figure 17 is a graph showing the TRE concentration in the lungs after TPIP-B inhalation.

[0066] [Figure 18] Figure 18 is a graph showing the concentration of TP homogeneous material in the lungs after TPIP-B inhalation.

[0067] [Figure 19] Figure 19 is a schematic diagram of a study design to examine the pharmacokinetic (PK) profiles of TPIP-B administered daily in single and multiple doses in healthy adults. D: Day, PK: Pharmacokinetics, QD: Once daily, Scn: Screening, TPIP: Treprostinyl Palmityl Inhalation Powder.

[0068] [Figure 20A] Figure 20A is a graph showing the PK results of TPIP-A in healthy adults (single dose).

[0069] [Figure 20B] Figure 20B is a graph showing the PK findings of TPIP-A in healthy adults (multiple doses).

[0070] [Figure 21] The upper part of Figure 21 shows one embodiment of a dose titration schedule for a compound of formula (I) or (II). The lower part of Figure 21 shows the capsule doses used according to the titration schedule in the upper part of Figure 21. [Modes for carrying out the invention]

[0071] Throughout this disclosure, the term “about” may be used in conjunction with numbers and / or ranges. The term “about” is understood to mean values ​​that are close to the listed values. For example, “about 40 [units]” may mean within ±25%, ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, or any other value or a range of values ​​in or below that value.

[0072] The term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. The properties of the salt are irrelevant if it is pharmaceutically acceptable. A suitable pharmaceutically acceptable acid addition salt may be prepared from an inorganic or organic acid. Exemplary pharmaceutically acceptable salts are described in Stahl, PH, Wermuth, CG, Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica Acta / Wiley-VCH:Zurich, 2002, the contents of which are incorporated herein by reference in their entirety. Specific non-limiting examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids include, but are not limited to, fatty acids, alicyclic acids, aromatic acids, aryl fatty acids, and heterocyclines containing 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, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic (pamonic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acids, 3-hydroxybutyric acid, galactaric acid, or galacturonic acid. Suitable pharmaceutically acceptable salts of free acid-containing compounds disclosed herein include, but are not limited to, metal salts and organic salts. Exemplary metal salts include, but are not limited to, suitable alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiologically acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.Exemplary organic salts can be prepared from primary amines, secondary amines, tertiary amines, and quaternary ammonium salts, such as tromethamine, diethylamine, tetra-N-methylammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0073] As used herein, the term "stereoisomer" refers to two molecules having the same molecular formula and sequence of bonded atoms, but different three-dimensional orientations of those atoms in space. One preferred stereoisomer according to the present invention is a diastereomer. Stereoisomers are, in one embodiment, diastereomers of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the stereoisomers are diastereomers of a compound of formula (I). In another embodiment, the stereoisomers are diastereomers of a pharmaceutically acceptable salt of a compound of formula (I). In yet another embodiment, the stereoisomers are diastereomers of a compound of formula (II). In yet another embodiment, the stereoisomers are diastereomers of a pharmaceutically acceptable salt of a compound of formula (II).

[0074] Throughout this specification, numerical ranges are provided for particular quantities. It should be understood that these ranges include all sub-ranges therewithin. Thus, the range "50 to 80" includes all possible ranges therein (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Further, all values within a given range may also be endpoints for ranges thereby subsumed (e.g., the range 50 to 80 includes ranges having endpoints such as 55 to 80, 50 to 75, etc.).

[0075] Throughout this specification, numerical ranges are described as including "about 80% to about 125%" or "about 80 - 125%" of a range of values. These are to be understood as including from 80% of the lowest endpoint of the range to 125% of the highest endpoint of the range, and all values therebetween.

[0076] The term "C max " means the maximum (or peak) treprostinil serum concentration measured after administration of a compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to the lungs of a subject via the dry powder composition described herein. Further, C max may be measured after a single administration of a compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof described herein, or treprostinil C max may be measured at steady state. Unless otherwise indicated, C max refers to the average treprostinil C max measured after a single administration in a subject population (e.g., a population of PH patients).

[0077] The term "AUC" means the area under the plasma concentration-time curve of treprostinil, measured from 0 hours to a certain time after administration to the lungs of a subject and calculated by combining the linear and logarithmic trapezoidal methods (linear up / log down method). In some embodiments, AUC may be measured from 0 to 24 hours after administration ("AUC 0-24」 "), or AUC may be measured from 0 hours until extrapolated to infinity ("AUC 0-inf "). Further, treprostinil AUC may be measured after a single administration or at steady state values. Unless otherwise indicated, AUC refers to the average AUC measured after a single administration in a subject population (e.g., a population of PH patients).

[0078] The term "plasma trough concentration" refers to the treprostinil plasma concentration before administration of a subsequent dose of a compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. For example, the treprostinil plasma trough concentration can be measured within 2 hours, 1 hour, or 30 minutes after administration of a subsequent dose. The plasma trough concentration may be measured after a single administration or at steady state. Unless otherwise indicated, the plasma trough level refers to the average treprostinil trough level measured in a subject population (e.g., a population of PH patients).

[0079] The term “adult” refers to a human subject, e.g., a human patient who is at least 18 years of age. In some embodiments, an adult is between 18 and 100 years of age, e.g., including all values ​​and the ranges between them: 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, The numbers are 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100.

[0080] In one aspect of the present invention, a dry powder composition of treprostinyl prodrug is provided. The dry powder composition is (a) Formula (I), present in an amount of approximately 0.5 wt% to approximately 5 wt% of the total weight of the dry powder composition. [ka] In the formula, R 1 The compounds of tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, or pharmaceutically acceptable salts thereof, (b) Approximately 10 wt% to 61 wt% leucine and the remainder (c) A sugar selected from the group consisting of trehalose and mannitol, comprising (a), (b), and (c) in total, which is 100 wt%.

[0081] In further embodiments, the composition contains about 25 wt% to about 61 wt% of leucine. In yet another embodiment, the composition contains about 25 wt% to about 45 wt% of leucine. In yet another embodiment, the composition contains about 45 wt% to about 61 wt% of leucine.

[0082] In some embodiments, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is present in amounts of about 0.4 wt%, about 0.5 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.5 wt%, about 1.7 wt%, about 2.0 wt%, about 2.3 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 4 wt%, about 3.5 wt%, or about 5 wt% of the total weight of the dry powder composition.

[0083] Compounds of formula (I) and their pharmaceutically acceptable salts are treprostinyl prodrugs disclosed in International Patent Publication WO2015 / 061720, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, leucine is present in amounts of 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.

[0084] In one embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R 1 is tetradecyl. In further embodiments, R 1 It is a linear tetradecyl.

[0085] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 1 is pentadecyl. In further embodiments, R 1 It is a linear pentadecyl.

[0086] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 1 is heptadecyl. In further embodiments, R 1 It is a linear heptadecyl.

[0087] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R1 is octadecyl. In further embodiments, R 1 It is a linear octadecyl.

[0088] In another embodiment of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 1 is hexadecyl. In further embodiments, R 1 is a linear hexadecyl, that is, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, and formula (II), [ka] The compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. In further embodiments, the compound of formula (I) is the compound of formula (II). 1 Compounds of formula (I) in which R is a linear hexadecyl are also referred to herein as C16TR or its international generic name, treprostinylpalmytil. In this application, C16TR and treprostinylpalmytil are used interchangeably. Similarly, compounds of formula (II) are equivalent to compounds of formula (I), where R 1 It is a linear hexadecyl.

[0089] In one embodiment, (a) is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, (a) is a compound of formula (II) or a pharmaceutically acceptable salt thereof. In a further embodiment, (a) is a compound of formula (II).

[0090] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1 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 in an amount of 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 in an amount of about 1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0091] 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.

[0092] 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.

[0093] 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 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.

[0094] 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.

[0095] In one embodiment, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.8 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 in an amount of 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 in an amount of about 2.7 wt% to about 3.5 wt%, for example, about 2.8 wt% to about 3.2 wt%, or about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0096] In one embodiment, leucine is present in an amount of about 25 wt% to about 61 wt% of the total weight of the dry powder composition. In a further embodiment, leucine is present in an amount of about 25 wt% to about 50 wt% of the total weight of the dry powder composition. In a further embodiment, leucine is present in an amount of about 25 wt% to about 40 wt% of the total weight of the dry powder composition. In a further embodiment, leucine is present in an amount of about 20 wt% to about 33 wt% of the total weight of the dry powder composition, for example, 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 a further embodiment, leucine is present in an amount of about 25 wt% to about 33 wt% of the total weight of the dry powder composition. In further embodiments, leucine is present in an amount of about 27 wt% to about 33 wt% of the total weight of the dry powder composition. In further embodiments, leucine is present in an amount of about 27 wt% to about 31 wt% of the total weight of the dry powder composition. In further embodiments, leucine is present in an amount of about 27 wt% to about 30 wt% of the total weight of the dry powder composition. In further embodiments, leucine is present in an amount of about 28 wt% to about 30 wt% of the total weight of the dry powder composition.

[0097] In another embodiment, leucine is present at approximately 30 wt% of the total weight of the dry powder composition.

[0098] In yet another embodiment, leucine is present in an amount of about 45 wt% to about 61 wt%, for example, about 45 wt% to about 55 wt%, or about 50 wt% to about 55 wt%, of the total weight of the dry powder composition. In yet another embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 3 wt% to about 4 wt%, of the total weight of the dry powder composition. In yet another embodiment, R 1 This is a hexadecyl, for example, a linear hexadecyl.

[0099] In some embodiments, the sugar in the dry powder composition is trehalose. In other embodiments, the sugar in the dry powder composition is mannitol.

[0100] In one embodiment, the composition has the weight percentages shown in Table A below. In another embodiment, the composition has the weight percentages shown in Table A below, with a tolerance of ±5% for each component. In yet another embodiment, the composition has the leucine-to-mannitol weight ratio ("leucine:mannitol" or "leucine vs. mannitol") shown in Table A. [Table 1]

[0101] In one embodiment, the dry powder composition has the components and weight percentages shown in Table B. [Table 2]

[0102] In one embodiment, the weight ratio of leucine to sugar (i.e., mannitol or trehalose) in the compositions provided herein is about 0.4:1 (leucine to mannitol or trehalose) to about 1.7:1 (leucine to mannitol or trehalose). In further embodiments, the composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in about 1 wt% to about 4 wt% of the total weight of the dry powder composition. In further embodiments, the leucine to sugar weight ratio is about 0.4:1 (leucine to mannitol or trehalose) to 0.9:1 (leucine to mannitol or trehalose). In yet another embodiment, the leucine to sugar weight ratio is about 0.4:1 (leucine to mannitol or trehalose) to 0.5:1 (leucine to mannitol or trehalose). In further embodiments, the sugar is mannitol. In one embodiment, the leucine is L-leucine.

[0103] In another embodiment, the sugar is mannitol, and the weight ratio of leucine to mannitol is about 0.75:1 (leucine to mannitol) to 0.9:1 (leucine to mannitol). In a further embodiment, the composition contains about 1 wt% to about 4 wt% of the total weight of the dry powder composition, the compound of formula (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the weight ratio of leucine to mannitol is about 0.8:1 (leucine to mannitol) to 0.9:1 (leucine to mannitol). In another embodiment, the sugar is trehalose, and the weight ratio of leucine to trehalose is about 0.75:1 (leucine to trehalose) to 0.9:1 (leucine to trehalose). In a further embodiment, the composition contains about 1 wt% to about 4 wt% of the total weight of the dry powder composition, the compound of formula (I), or a pharmaceutically acceptable salt thereof. In further embodiments, the weight ratio of leucine to trehalose is approximately 0.8:1 (leucine to trehalose) to 0.9:1 (leucine to trehalose). In one embodiment, leucine is L-leucine.

[0104] In yet another embodiment, the sugar is mannitol, and the weight ratio of leucine to mannitol is about 1.5:1 (leucine to mannitol) to 1.7:1 (leucine to mannitol). In yet another embodiment, the composition contains about 1 wt% to about 4 wt% of the total weight of the dry powder composition, the compound of formula (I), or a pharmaceutically acceptable salt thereof. In yet another embodiment, the weight ratio of leucine to mannitol is about 1.6:1 (leucine to mannitol) to 1.7:1 (leucine to mannitol). In yet another embodiment, the sugar is trehalose, and the weight ratio of leucine to trehalose is about 1.5:1 (leucine to trehalose) to 1.7:1 (leucine to trehalose). In yet another embodiment, the composition contains about 1 wt% to about 4 wt% of the total weight of the dry powder composition, the compound of formula (I), or a pharmaceutically acceptable salt thereof. In further embodiments, the weight ratio of leucine to mannitol is approximately 1.6:1 (leucine to trehalose) to 1.7:1 (leucine to trehalose).

[0105] 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 (c) mannitol. In a further embodiment, (a) the dry powder composition contains about 1 wt% of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In another embodiment, (a) the dry powder composition contains about 2 wt% of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0106] 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 (c) mannitol. In further embodiments, R 1 is a linear hexadecyl in the compound of formula (I).

[0107] In another embodiment, the dry powder composition comprises (a) about 3 wt% of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% of leucine, and the balance (c) mannitol. In a further embodiment, R 1 is the straight-chain hexadecyl in the compound of formula (I).

[0108] In another embodiment, the dry powder composition comprises (a) about 3 wt% of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% of leucine, and the balance (c) mannitol. In a further embodiment, R 1 is the straight-chain hexadecyl in the compound of formula (I).

[0109] In another embodiment, the dry powder composition comprises (a) about 1 wt% of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, (b) about 29 wt% of leucine, and the balance (c) mannitol. In a further embodiment, R 1 is the straight-chain hexadecyl in the compound of formula (I).

[0110] In another embodiment, the dry powder composition comprises (a) about 1 wt% of a compound of formula (I) or (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, (b) about 29.6 wt% of leucine, and the balance (c) mannitol. In a further embodiment, R 1 is the straight-chain hexadecyl in the compound of formula (I).

[0111] In some embodiments, the dry powder composition does not contain distearoylphosphoethanolamine-polyethylene glycol 2000 (DPSE-PEG2000).

[0112] In one embodiment, the dry powder composition contains approximately 80 μg to approximately 700 μg of the compound of formula (I) or (II), for example, all values ​​and ranges therein, such as approximately 80 μg, approximately 100 μg, approximately 110 μg, approximately 112.5 μg, approximately 120 μg, approximately 130 μg, approximately 140 μg, approximately 150 μg, approximately 160 μg, and approximately 170 μg. , about 180μg, about 190μg, about 200μg, about 210μg, about 220μg, about 225μg, about 230μg, about 240μg, about 250μg, about 260μg, Approximately 270μg, approximately 280μg, approximately 290μg, approximately 300μg, approximately 310μg, approximately 320μg, approximately 330μg, approximately 340μg, approximately 350μg, approximately 360μg, approximately 370μg, about 380μg, about 390μg, about 400μg, about 410μg, about 420μg, about 430μg, about 440μg, about 450μg, about 460μg, about 4 70μg, about 480μg, about 490μg, about 500μg, about 510μg, about 520μg, about 530μg, about 540μg, about 550μg, about 560μg, about 57 The composition contains 0 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 the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the dry powder composition contains approximately 80 μg to approximately 640 μg of the compound of formula (I) or (II). In one embodiment, the composition contains approximately 80 μg, approximately 160 μg, approximately 240 μg, approximately 320 μg, approximately 400 μg, approximately 480 μg, or approximately 640 μg of the compound of formula (I). In one embodiment, the composition may be present in one dry powder capsule or in multiple (two or more) dry powder capsules. If present in multiple capsules, one of the aforementioned doses of the compound of formula (I) is divided into capsules. In one embodiment, the capsule is a size #3 HPMC capsule.

[0113] Embodiments of the TPIP composition at different unit strengths are provided in Table C below. It should be understood that the unit strengths of the components provided herein can be calculated based on the weight percentage of the components and the desired dosage. For example, for a dosage of 80 μg of TP, each component is multiplied by 80 to obtain the unit strength of each component.

Table 3

[0114] In one embodiment, the dry powder composition comprises about 80 μg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 is linear hexadecyl.

[0115] In one embodiment, the dry powder composition comprises about 160 μg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 is linear hexadecyl.

[0116] In another embodiment, the dry powder composition comprises about 240 μg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 is linear hexadecyl.

[0117] In one embodiment, the dry powder composition comprises about 320 μg of the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof. In a further embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 is linear hexadecyl.

[0118] In another embodiment, the dry powder composition comprises about 400 μg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, R1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0119] In another embodiment, the dry powder composition contains about 480 μg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further embodiment, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0120] In one embodiment, the dry powder composition contains about 640 μg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In further embodiments, R 1 is hexadecyl. In yet another embodiment, R 1 It is a linear hexadecyl.

[0121] In preferred embodiments of the dried powder compositions provided herein, leucine is L-leucine.

[0122] In another embodiment, the disclosure provides a dry powder composition comprising a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, which provides a specific pharmacokinetic profile after once-daily administration. Advantageously, the pharmacokinetic profile is C compared to the current treprostinil inhalation solution, Tyvaso®. max It has a low half-life and a long half-life.

[0123] In one embodiment, a dry powder composition exhibiting one of the pharmacokinetic profiles described herein is the composition described in U.S. Patent Application Publication No. 2020 / 0338005, which is incorporated herein by reference for all purposes.

[0124] In another embodiment, a dry powder composition exhibiting one of the pharmacokinetic profiles described herein comprises (a) a compound of formula (I) or (II) in about 1 wt% to about 5 wt% of the total weight of the dry powder composition, (b) leucine in about 25 wt% to about 61 wt%, and the remainder (c) a sugar selected from trehalose and mannitol. The total of (a), (b), and (c) is 100 wt%.

[0125] As discussed in Example 5, the pharmacokinetic (PK) profiles measured for compounds of formula (I) or (II), their stereoisomers, or pharmaceutically acceptable salts thereof were linear over the dose range of 112.5 μg to 675 μg. Based on this data, those skilled in the art can determine the pharmacokinetic parameters for doses outside this range or for doses within this range that were not specifically tested in Example 5. For example, to find the pharmacokinetic parameters at doses, Cmax and AUC associated with specific doses (112.5 μg, 225 μg, 450 μg, and / or 675 μg) may be plotted. The scatter plot may be fitted to a straight line, y = mx + b, where m is the slope of the line and b is the y-intercept, and the value of the unknown pharmacokinetic parameter (y) may be calculated by plugging in the dose for x. Furthermore, the dose range of 112.5 μg to 675 μg is R 1 It was based on the molecular weight of the compound of formula (I) when is hexadecyl (i.e., the compound of formula (II)). Other treprostinyl prodrugs (R 1 The equivalent dose (if R is tetradecyl, pentadecyl, heptadecyl, or octadecyl) can be calculated using the molecular weight of the treprostinyl prodrug in question. For example, 112.5 μg of formula II(R 1 R is equivalent to the compound (which is hexadecyl). 1 When is tetradecyl, the dose of the compound of formula (I) is 112.5 μg, R 1 This can be calculated by multiplying the molecular weight of the compound in formula (II) (614.95 μg / mol) when tetradecyl by the ratio of the molecular weight of the compound in formula (I) (586.9 μg / mol).

[0126] In embodiments, the dry powder composition of the present disclosure is formulated to administer a dose of about 80 μg to about 675 μg of a compound of formula (I) or (II), a stereoisomer, or a pharmaceutically acceptable salt thereof to a target lung once daily by inhalation, and provides at least one of the following features: (a) Maximum plasma concentration of treprosinthyl in the range of approximately 14 pg / mL to approximately 1430 pg / mL (C max ),or (b) Approximately 500pg * h / mL~approx. 10000pg * Area under the curve (AUC) of treprostinil plasma concentrations in the range of h / mL.

[0127] In further embodiments, 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 the compound of formula (I). In further embodiments, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of the compound of formula (I). In further embodiments, R 1 is hexadecyl, for example, linear hexadecyl. In one embodiment, the composition may be present in one dry powder capsule or in multiple (two or more) dry powder capsules. If present in multiple capsules, one of the aforementioned doses of the compound of formula (I) is divided into capsules.

[0128] In embodiments, the dry powder composition of the present disclosure is formulated to administer a dose of about 80 μg to about 640 μg of the compound of formula (II) or a pharmaceutically acceptable salt thereof to the lungs of a subject (e.g., a patient) once daily by inhalation, and provides at least one of the following features: (a) Maximum plasma concentration of treprosinthyl in the range of approximately 14 pg / mL to approximately 1430 pg / mL (C max ),or (b) Approximately 380pg * h / mL~approx. 10000pg *The treprostinil region below the plasma concentration curve (AUC) in the h / mL range.

[0129] In further embodiments, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of the compound of formula (II). In one embodiment, the composition may be present in one dry powder capsule or in multiple (two or more) dry powder capsules. If present in multiple capsules, one of the aforementioned doses of the compound of formula (II) is divided among the multiple capsules.

[0130] In one embodiment, a dry powder composition is formulated to deliver a dose of about 112.5 μg to about 675 μg of the compound of formula (II), a stereoisomer, or a pharmaceutically acceptable salt thereof to the lungs of a subject (e.g., a patient) once daily by inhalation, and provides at least one of the following features: (a) Maximum plasma concentration of treprosinthyl in the range of approximately 17 pg / mL to approximately 1370 pg / mL (C max ),or (b) Approximately 700pg * h / mL ~ approx. 7800pg * Area under the curve (AUC) of treprostinil plasma concentrations in the range of h / mL.

[0131] In further embodiments, the composition comprises about 80 μg, about 160 μg, about 240 μg, about 320 μg, about 400 μg, about 480 μg, or about 640 μg of the compound of formula (II). In one embodiment, the composition may be present in one dry powder capsule or in multiple (two or more) dry powder capsules. If present in multiple capsules, one of the aforementioned doses of the compound of formula (II) is divided among the multiple capsules.

[0132] In the embodiment, the dry powder composition comprises one of the pharmacokinetic profiles described herein and contains about 80 μg to about 675 μg of the 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 profiles described herein includes all values ​​and ranges therein, approximately 80 μg, approximately 100 μg, approximately 110 μg, approximately 112.5 μg, approximately 120 μg, approximately 130 μg, approximately 140 μg, approximately 150 μg, approximately 160 μg, approximately 170 μg, approximately 180 μg, approximately 190 μg, approximately 200 μg, approximately 210 μg, approximately 220 μg, approximately 225 μg, approximately 230 μg, approximately 240 μg, approximately 250 μg, approximately 260 μg, approximately 270 μg, approximately 280 μg, 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 3 70μg, about 380μg, about 390μg, about 400μg, about 410μg, about 420μg, about 430μg, about 440μg, about 450μg, about 460μg, Approximately 470μg, approximately 480μg, approximately 490μg, approximately 500μg, approximately 510μg, approximately 520μg, approximately 530μg, approximately 540μg, approximately 550μg, approximately 560μg , comprising 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 the compound of formula (I) or a pharmaceutically acceptable salt thereof. In further embodiments, R 1 This is a hexadecyl, for example, a linear hexadecyl.

[0133] In some embodiments, a once-daily administration of a dry powder composition containing approximately 80 μg to approximately 675 μg (e.g., approximately 80 μg to approximately 640 μg, or approximately 112.5 μg to approximately 675 μg) of the compound of formula (I), its stereoisomer (or an equivalent dose of a pharmaceutically acceptable salt thereof, e.g., the compound of formula (II)), followed by a method of using the dry powder composition or the dry powder composition or method of use, in which the maximum plasma concentration of treprostinil (C) ranges from approximately 10 pg / mL to approximately 2000 pg / mL. max) provides, for example, all values ​​and ranges within that range, including 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, and approximately 150 pg / mL. L, approximately 160pg / mL, approximately 170pg / mL, approximately 180pg / mL, approximately 190pg / mL, approximately 200pg / mL, approximately 210pg / mL, approximately 220pg / mL, approximately 230pg / mL, approximately 240pg / mL, approximately 250pg / mL, approximately 260pg / mL, approximately 270pg / mL, approximately 2 80pg / mL, approximately 290pg / mL, approximately 300pg / mL, approximately 310pg / mL, approximately 320pg / mL, approximately 330pg / mL, approximately 340pg / mL, approximately 350pg / mL, approximately 360pg / mL, approximately 370pg / mL, approximately 380pg / mL, approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, approximately 430pg / mL, approximately 440pg / mL, approximately 450pg / mL, approximately 460pg / mL, approximately 470pg / mL, approximately 480pg / mL, approximately 490pg / mL, approximately 500pg / mL, approximately 510pg / mL, approximately 520pg / mL, Approximately 530pg / mL, approximately 540pg / mL, approximately 550pg / mL, approximately 560pg / mL, approximately 570pg / mL, approximately 580pg / mL, approximately 590pg / mL, approximately 600pg / mL, approximately 610pg / mL, approximately 620pg / mL, approximately 630pg / mL, approximately 640pg / mL, approximately 650 pg / mL, approximately 660pg / mL, approximately 670pg / mL, approximately 680pg / mL, approximately 690pg / mL, approximately 700pg / mL, approximately 750pg / mL, approximately 800pg / mL, approximately 850pg / mL, approximately 900pg / mL, approximately 950pg / mL, approximately 1000pg / mL, approximately 1050pg / mL, approximately 1100pg / mL, approximately 1150pg / mL, approximately 1200pg / mL, approximately 1250pg / mL, approximately 1300pg / mL, approximately 1350pg / mL, approximately 1400pg / mL, approximately 1450pg / mL, approximately 1500pg / mL, approximately 1550pg / mL, approximately 1600pg / mL,These are approximately 1650 pg / mL, 1700 pg / mL, 1750 pg / mL, 1800 pg / mL, 1850 pg / mL, 1900 pg / mL, or 2000 pg / mL.

[0134] In some embodiments, the drying capacity composition of the present disclosure or the method of use thereof is followed by approximately 80 μg to approximately 675 μg (e.g., approximately 80 μg to approximately 640 μg, or approximately 112.5 μg to approximately 675 μg) of the compound of formula (I), which is approximately 300 pg. * h / mL~approx. 11000pg * This provides area under the plasma concentration curve (AUC) for a range of h / mL, including all values ​​and ranges within that range, such as approximately 300 pg*h / mL, 400 pg*h / mL, 500 pg*h / mL, 600 pg*h / mL, 700 pg*h / mL, 800 pg*h / mL, 900 pg*h / mL, 1000 pg*h / mL, 1100 pg*h / mL, 1200 pg*h / mL, and 1300 pg*h / mL. *h / mL, approx. 1400pg*h / mL, approx. 1500pg*h / mL, approx. 1600pg*h / mL, approx. 1700pg*h / mL, approx. 1800pg*h / mL, approx. 1900pg*h / mL, approx. 2000pg *h / mL, approx. 2100pg*h / mL, approx. 2200pg*h / mL, approx. 2300pg*h / mL, approx. 2400pg*h / mL, approx. 2500pg*h / mL, approx. 2600pg*h / mL, approx. 2700ng * h / mL, approximately 2800ng * h / mL, approx. 2900pg*h / mL, approx. 3000pg*h / mL, approx. 3100pg*h / mL, approx. 3200pg*h / mL, approx. 3300pg*h / mL, approx. 3400pg*h / m L, approx. 3500pg*h / mL, approx. 3600pg*h / mL, approx. 3700pg*h / mL, approx. 3800pg*h / mL, approx. 3900pg*h / mL, approx. 4000pg*h / mL, approx. 4 100pg*h / mL, approx. 4200pg*h / mL, approx. 4300pg*h / mL, approx. 4400pg*h / mL, approx. 4500pg*h / mL, approx. 4600pg*h / mL, approx. 4700 pg*h / mL, approx. 4800pg*h / mL, approx. 4900pg*h / mL, approx. 5000pg*h / mL, approx. 5100pg*hr / mL, approx. 5200pg*hr / mL, approx. 5300pg *hr / mL, approx. 5400pg*hr / mL, approx. 5500pg*hr / mL, approx. 5600pg*hr / mL, approx. 5700pg*hr / mL, approx. 5800pg*hr / mL, approx. 5900pg*hr / mL, approximately 6000pg*hr / mL, approximately 6100pg*hr / mL, approximately 6200pg*hr / mL, approximately 6300pg*hr / mL, approximately 6400pg*hr / mL, approximately 6500pg*hr / m L, approximately 6600pg*hr / mL, approximately 6700pg*hr / mL, approximately 6800pg*hr / mL, approximately 6900pg*hr / mL, approximately 7000pg*hr / mL, approximately 7100pg*hr / mL, Approx. 7200pg*hr / mL, approx. 7300pg*hr / mL, approx. 7400pg*hr / mL, approx. 7500pg*hr / mL, approx. 7600pg*hr / mL, approx. 7700pg*hr / mL, approx. 7 800pg*hr / mL, approx. 7900pg*hr / mL, approx. 8000pg*hr / mL, approx. 8100pg*hr / mL, approx. 8200pg*hr / mL, approx. 8300pg*hr / mL, approx. 840 0pg*hr / mL, approx. 8500pg*hr / mL, approx. 8600pg*hr / mL, approx. 8700pg*hr / mL, approx. 8800pg*hr / mL, approx. 8900pg*hr / mL, approx. 9000p g*hr / mL, approx. 9100pg*hr / mL, approx. 9200pg*hr / mL, approx. 9300pg*hr / mL, approx. 9400pg*hr / mL, approx. 9500pg*hr / mL, approx. 9600pg* hr / mL, approx. 9700pg*hr / mL, approx. 9800pg*hr / mL, approx. 9900pg*hr / mL, approx. 10000pg*hr / mL, approx. 10100pg*hr / mL, approx. 10200pg * *hr / mL, approximately 10300pg*hr / mL, approximately 10400pg*hr / mL, approximately 10500pg*hr / mL, approximately 10600pg*hr / mL, approximately 10700pg*hr / mL, approximately 10800pg*hr / mL, approximately 10900pg*hr / mL, or approximately 11000pg*hr / mL.

[0135] In some embodiments, the dry powder composition or method of the present disclosure achieves a treprostinil plasma trough concentration 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 contains about 80 μg to about 675 μg of the compound of formula (I) or its stereoisomer (e.g., R 1In the case of hexadecyl, for example linear hexadecyl, after once-daily administration, all values ​​and ranges within that range are included, at least about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL The dry powder composition provides treprostinil plasma trough concentrations of approximately 75 pg / mL, 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, 100 pg / mL, 100 pg / mL, 110 pg / mL, 120 pg / mL, 130 pg / mL, 140 pg / mL, 150 pg / mL, 160 pg / mL, 170 pg / mL, 180 pg / mL, 190 pg / mL, and 200 pg / mL, or the subject (e.g., a patient) has these concentrations. In some embodiments, the dry powder composition contains about 80 μg to about 640 μg of the compound of formula (II), and the treprostinil plasma trough concentration is in the range of about 3 pg / mL to about 125 pg / mL, for example, including all values ​​and ranges within that range, such as 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, and about 3 pg / mL. The concentrations are 0 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 100 pg / mL, approximately 110 pg / mL, and approximately 120 pg / mL. In some embodiments, the dry powder composition contains approximately 80 μg to approximately 640 μg of the compound of formula (II), and the treprostinil plasma trough concentration is in the range of approximately 10 pg / mL to approximately 100 pg / mL.

[0136] In some embodiments, once-daily administration of a dry powder composition containing about 80 μg to about 675 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), the dry powder composition provides at least one of the following features, or the subject (e.g., patient) has at least one of the following features. (a) Maximum treprostinil plasma concentration (C) within approximately 80% to 125% of the range of approximately 17 pg / mL to approximately 1150 pg / mL max), for example, including all values ​​and ranges within that, 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 mL, approximately 150pg / mL, approximately 160pg / mL, approximately 170pg / mL, approximately 180pg / mL, approximately 190pg / mL, approximately 200pg / mL, approximately 210pg / mL, approximately 220pg / mL, approximately 230pg / mL, approximately 240pg / mL, approximately 250pg / mL, approximately 260pg / m L, about 270pg / mL, about 280pg / mL, about 290pg / mL, about 300pg / mL, about 310pg / mL, about 320pg / mL, about 330pg / mL, about 340pg / mL, about 350pg / mL, about 360pg / mL, about 370pg / mL, about 380pg / mL, Approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, approximately 430pg / mL, approximately 440pg / mL, approximately 450pg / mL, approximately 460pg / mL, approximately 470pg / mL, approximately 480pg / mL, approximately 490pg / mL, approximately 500pg / mL, approximately 510pg / mL, approximately 520pg / mL, approximately 530pg / mL, approximately 540pg / mL, approximately 550pg / mL, approximately 560pg / mL, approximately 570pg / mL, approximately 580pg / mL, approximately 590pg / mL, approximately 600pg / mL, approximately 610pg / mL, approximately 620pg / mL, approximately 63 0 pg / mL, approximately 640 pg / mL, approximately 650 pg / mL, approximately 660 pg / mL, approximately 670 pg / mL, approximately 680 pg / mL, approximately 690 pg / mL, approximately 700 pg / mL, approximately 750 pg / mL, approximately 800 pg / mL, approximately 850 pg / mL, approximately 900 pg / mL, 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. (b) Area under the curve (AUC) of treprostinil plasma concentrations within approximately 80% to 125% of the range from approximately 475 pg*h / mL to approximately 8000 pg*h / mL 0-inf ) is, for example, approximately 370pg, which includes all values ​​and ranges within it. * h / mL, approximately 400pg * h / mL, approximately 450pg * h / mL, approximately 500pg * h / mL, approximately 550pg * h / mL, approximately 600pg * h / mL, approximately 650pg * h / mL, approximately 700pg * h / mL, approximately 800pg * h / mL, approximately 900pg * h / mL, approximately 1000pg * h / mL, approximately 1100pg * h / mL, approximately 1200pg * h / mL, approximately 1300pg * h / mL, approximately 1400pg * h / mL, approximately 1500pg * h / mL, approximately 1600pg * h / mL, approximately 1700pg * h / mL, approximately 1800pg * h / mL, approximately 1900pg * h / mL, approximately 2000pg * h / mL, approximately 2100pg * h / mL, approximately 2200pg * h / mL, approximately 2300pg * h / mL, approximately 2400pg * h / mL, approximately 2500pg * h / mL, approximately 2600pg * h / mL, approximately 2700ng * h / mL, approximately 2800ng * h / mL, approximately 2900pg * h / mL, approximately 3000pg * h / mL, approximately 3100pg * h / mL, approximately 3200pg * h / mL, approximately 3300pg * h / mL, approximately 3400pg * h / mL, approximately 3500pg * h / mL, approximately 3600pg* h / mL, approximately 3700 pg * h / mL, approximately 3800 pg * h / mL, approximately 3900 pg * h / mL, approximately 4000 pg * h / mL, approximately 4100 pg * h / mL, approximately 4200 pg * h / mL, approximately 4300 pg * h / mL, approximately 4400 pg * h / mL, approximately 4500 pg * h / mL, approximately 4600 pg * h / mL, approximately 4700 pg * h / mL, approximately 4800 pg * h / mL, approximately 4900 pg * h / mL, approximately 5000 pg * h / mL, approximately 5100 pg * h / mL, approximately 5200 pg * h / mL, approximately 5300 pg * h / mL, approximately 5400 pg * h / mL, approximately 5500 pg * h / mL, approximately 5600 pg * h / mL, approximately 5700 pg * h / mL, approximately 5800 pg * h / mL, approximately 5900 pg * h / mL, approximately 6000 pg * h / mL, approximately 6100 pg * h / mL, approximately 6200 pg * h / mL, approximately 6300 pg * h / mL, approximately 6400 pg * h / mL, approximately 6500 pg * h / mL, approximately 6600 pg * h / mL, approximately 6700 pg * h / mL, approximately 6800 pg*h / mL, approximately 6900 pg * h / mL, approximately 7000 pg * h / mL, approximately 7100 pg * h / mL, approximately 7200 pg*h / mL, approximately 7300 pg * h / mL, approximately 7400 pg * h / mL, approximately 7500 pg * h / mL, approximately 7600 pg*h / mL, approximately 7700 pg *h / mL, approximately 7800pg * h / mL, approximately 7900pg * h / mL, approx. 8000pg*h / mL, approx. 8100pg * h / mL, approximately 8200pg * h / mL, approximately 8300pg * h / mL, approx. 8400pg*h / mL, approx. 8500pg * h / mL, approximately 8600pg * h / mL, approximately 8700pg * h / mL, approx. 8800pg*h / mL, approx. 8900pg * h / mL, approximately 9000pg * h / mL, approximately 9100pg * h / mL, approx. 9200pg*h / mL, approx. 9300pg * h / mL, approximately 9400pg * h / mL, approximately 9500pg * h / mL, approx. 9600pg*h / mL, approx. 9700pg * h / mL, approximately 9800pg * h / mL, approximately 9900pg * h / mL, or approximately 10,000 pg * The concentration is h / mL.

[0137] In some embodiments, the dry powder composition contains about 80 μg of the compound of formula (II), administered once daily, in a concentration of treprostinil C ranging from about 14 pg / mL to about 155 pg / mL. maxIt provides, for example, all values ​​and ranges within that range, including 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 The concentrations are approximately pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, 100 pg / mL, 105 pg / mL, 110 pg / mL, 115 pg / mL, 120 pg / mL, 125 pg / mL, 130 pg / mL, 135 pg / mL, 140 pg / mL, 145 pg / mL, 150 pg / mL, and 155 pg / mL. In some embodiments, approximately 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, containing approximately 80% to 125% treprostinil C in the range of approximately 17 pg / mL to approximately 125 pg / mL. max In some embodiments, approximately 80 μg of 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, with approximately 80% to 125% of treprostinil C in the range of approximately 35 pg / mL to approximately 105 pg / mL. max To provide.

[0138] In some embodiments, the dry powder composition contains about 112.5 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), and treprostinil C in an amount ranging from about 80% to about 125% of about 78.4 (72.9) pg / mL. max (CV%) is provided.

[0139] In some embodiments, the dry powder composition contains about 160 μg of the compound of formula (II), administered once daily, in a concentration of treprostinil C ranging from about 30 pg / mL to about 335 pg / mL. maxIt provides, for example, all values ​​and ranges within that range, including 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, approx. 110 pg / mL, approx. 115 pg / mL, approx. 120 pg / mL, approx. 125 pg / mL, approx. 130 pg / mL, approx. 135 pg / mL, approx. 140 pg / mL, approx. 145 pg / m L, about 150pg / mL, about 155pg / mL, about 160pg / mL, about 165pg / mL, about 170pg / mL, about 175pg / mL, about 180pg / mL, about 1850pg / mL, about 190pg / mL, approx. 195pg / mL, approx. 200pg / mL, approx. 205pg / mL, approx. 210pg / mL, approx. 215pg / mL, approx. 220pg / mL, approx. 225pg / mL, approx. 230 pg / mL, approx. 235pg / mL, approx. 240pg / mL, approx. 245pg / mL, approx. 250pg / mL, approx. 255pg / mL, approx. 260pg / mL, approx. 265pg / mL, approx. 270pg / m The concentrations are approximately 275 pg / mL, 280 pg / mL, 285 pg / mL, 290 pg / mL, 295 pg / mL, 300 pg / mL, 305 pg / mL, 310 pg / mL, 315 pg / mL, 320 pg / mL, 325 pg / mL, 330 pg / mL, 335 pg / mL, 340 pg / mL, 345 pg / mL, or 350 pg / mL. In some embodiments, approximately 160 μg of the compound of formula (II), 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, along with approximately 80% to 125% treprostinil C in the range of approximately 35 pg / mL to approximately 270 pg / mL. max In some embodiments, approximately 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, with approximately 80% to 125% treprostinil C in the range of approximately 76 pg / mL to approximately 230 pg / mL. maxTo provide.

[0140] In some embodiments, the dry powder composition contains about 225 μg of the compound of formula (II), administered once daily, and contains about 80% to about 125% of treprostinil C at a concentration of about 287 (46.6) pg / mL. max The present invention provides: In some embodiments, the dry powder composition comprises about 225 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), and steady-state treprostinil C in the range of about 80% to about 125% at about 193 (32.9) pg / mL. max The present invention provides: In some embodiments, the dry powder composition comprises about 225 μg of the compound of formula (II), administered once daily, to a steady-state treprostinil C at a concentration of about 228 (46.4) pg / mL, ranging from about 80% to about 125%. max (CV%) is provided.

[0141] In some embodiments, the dry powder composition contains about 240 μg of the compound of formula (II), administered once daily, in a concentration of treprostinil C ranging from about 45 pg / mL to about 520 pg / mL. maxIt provides, for example, all values ​​and ranges within it, including 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 These are approximately mL, 280 pg / mL, 290 pg / mL, 300 pg / mL, 310 pg / mL, 320 pg / mL, 330 pg / mL, 340 pg / mL, 350 pg / mL, 360 pg / mL, 370 pg / mL, 380 pg / mL, 390 pg / mL, 400 pg / mL, 410 pg / mL, 420 pg / mL, 430 pg / mL, 440 pg / mL, 450 pg / mL, 460 pg / mL, 470 pg / mL, 480 pg / mL, 490 pg / mL, 500 pg / mL, 510 pg / mL, or 520 pg / mL. In some embodiments, approximately 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, along with approximately 80% to 125% treprostinil C in the range of approximately 55 pg / mL to approximately 415 pg / mL. max In some embodiments, approximately 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, with approximately 80% to 125% of treprostinil C in the range of approximately 115 pg / mL to approximately 355 pg / mL. max To provide.

[0142] In some embodiments, the dry powder composition contains about 320 μg of the compound of formula (II), administered once daily, in a concentration of treprostinil C ranging from about 60 pg / mL to about 700 pg / mL. maxIt provides, for example, all values ​​and ranges within that, including 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 190pg / mL, approx. 200pg / mL, approx. 210pg / mL, approx. 220pg / mL, approx. 230pg / mL, approx. 240pg / mL, approx. 250pg / mL, approx. 260pg / mL, approx. 270pg / m L, approx. 280pg / mL, approx. 290pg / mL, approx. 300pg / mL, approx. 310pg / mL, approx. 320pg / mL, approx. 330pg / mL, approx. 340pg / mL, approx. 350pg / mL, approx. 360pg / mL, approximately 370pg / mL, approximately 380pg / mL, approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, approximately 430pg / mL, approximately 440pg / mL, approximately 45 0pg / mL, approx. 460pg / mL, approx. 470pg / mL, approx. 480pg / mL, approx. 490pg / mL, approx. 500pg / mL, approx. 510pg / mL, approx. 520pg / mL, approx. 530pg / mL, approx. The dosages are 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, or approximately 700 pg / mL. In some embodiments, approximately 320 μg of the compound of formula (II) is administered once daily, containing approximately 80% to 125% of treprostinil C in the range of approximately 80 pg / mL to approximately 560 pg / mL. max In some embodiments, approximately 320 μg of the compound of formula (II) is administered once daily, comprising approximately 80% to 125% of treprostinil C in the range of approximately 160 pg / mL to approximately 480 pg / mL. max To provide.

[0143] In some embodiments, the dry powder composition contains about 400 μg of the compound of formula (II), administered once daily, in a concentration of treprostinil C ranging from about 80 pg / mL to about 885 pg / mL. maxIt provides, for example, all values ​​and ranges within that, including 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, Approx. 250pg / mL, approx. 260pg / mL, approx. 270pg / mL, approx. 280pg / mL, approx. 290pg / mL, approx. 300pg / mL, approx. 310pg / mL, approx. 320pg / mL, approx. 330pg / mL, approx. 340pg / mL, approx. 350pg / mL, approximately 360pg / mL, approximately 370pg / mL, approximately 380pg / mL, approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, approximately 430pg / mL, approximately 440pg / mL, approximately 450pg / mL, approximately 460p g / 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 5 70pg / mL, approximately 580pg / mL, approximately 590pg / mL, approximately 600pg / mL, approximately 610pg / mL, approximately 620pg / mL, approximately 630pg / mL, approximately 640pg / mL, approximately 650pg / mL, approximately 660pg / mL, approximately 670pg / mL, These are approximately 680 pg / mL, 690 pg / mL, 700 pg / mL, 710 pg / mL, 720 pg / mL, 730 pg / mL, 740 pg / mL, 750 pg / mL, 760 pg / mL, 770 pg / mL, 780 pg / mL, 790 pg / mL, 800 pg / mL, 810 pg / mL, 820 pg / mL, 830 pg / mL, 840 pg / mL, 850 pg / mL, 860 pg / mL, 870 pg / mL, or 880 pg / mL. In some embodiments, approximately 400 μg of the compound of formula (II) is administered once daily, containing approximately 80% to 125% treprostinil C in the range of approximately 100 pg / mL to approximately 705 pg / mL. maxIn some embodiments, about 400 μg of the compound of formula (II) is administered once daily, and about 80% to 125% of treprostinil C in the range of about 200 pg / mL to about 605 pg / mL is provided. max To provide.

[0144] In some embodiments, the dry powder composition comprises about 450 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), and about 80% to about 125% of treprostinyl C at about 387 (38.6) pg / mL. max To provide.

[0145] In some embodiments, the dry powder composition contains about 480 μg of the compound of formula (II), administered once daily, in a concentration of treprostinil C ranging from about 95 pg / mL to about 1065 pg / mL. maxIt provides, for example, all values ​​and ranges within that range, including approximately 95 pg / mL, approximately 100 pg / mL, approximately 110 pg / mL, approximately 120 pg / mL, approximately 130 pg / mL, approximately 135 pg / mL, approximately 140 pg / mL, approximately 140 pg / mL, approximately 150 pg / mL, approximately 160 pg / mL, approximately 170 pg / mL, approximately 180 pg / mL, approximately 190 pg / mL, approximately 200 pg / mL, approximately 210 pg / mL, approximately 220 pg / mL, approximately 230 pg / mL, approximately 240 pg / mL, approximately 250 pg / mL, approximately 260 pg / mL, approximately 270 pg / mL, approximately 280 pg / mL, approximately 290 pg / mL, approximately 300 pg / mL, approximately 310 pg / mL, approximately 320 pg / mL, approximately 330 pg / mL, 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 , about 420pg / mL, about 430pg / mL, about 440pg / mL, about 450pg / mL, about 460pg / mL, about 470pg / mL, about 480pg / mL, about 490pg / mL, about 500pg / mL, about 510pg / mL, about 520pg / mL, about 530pg / mL, about 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 , about 670pg / mL, about 680pg / mL, about 690pg / mL, about 700pg / mL, about 710pg / mL, about 720pg / mL, about 730pg / mL, about 740pg / mL, about 750pg / mL, about 760pg / mL, about 770pg / mL, about 780pg / mL, about 790 pg / mL, approximately 800pg / mL, approximately 810pg / mL, approximately 820pg / mL, approximately 830pg / mL, approximately 840pg / mL, approximately 850pg / mL, approximately 860pg / mL, approximately 870pg / mL, approximately 880pg / mL, approximately 890pg / mL, approximately 900pg / mL, approximately 910pg / mL , about 920pg / mL, about 930pg / mL, about 940pg / mL, about 950pg / mL, about 960pg / mL, about 970pg / mL, about 980pg / mL, about 1000pg / mL, about 1010pg / mL, about 1020pg / mL, about 1030pg / mL, about 1040pg / mL,The concentrations are approximately 1050 pg / mL, 1060 pg / mL, or 1065 pg / mL. In some embodiments, approximately 480 μg of the compound of formula (II) is administered once daily, representing approximately 80% to 125% of treprostinil C at a concentration of approximately 120 pg / mL to approximately 855 pg / mL. max In some embodiments, approximately 480 μg of the compound of formula (II) is administered once daily, comprising approximately 80% to 125% of treprostinil C in the range of approximately 240 pg / mL to approximately 730 pg / mL. max To provide.

[0146] In some embodiments, the dry powder composition contains about 640 μg of the compound of formula (II), administered once daily, with treprostinil C in a concentration ranging from about 130 pg / mL to about 1430 pg / mL. maxIt provides, for example, all values ​​and ranges within it, including 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 330pg / mL, approximately 340pg / mL, approximately 350pg / mL, approximately 360pg / mL, approximately 370pg / mL, approximately 380pg / mL, approximately 390pg / mL, approximately 400pg / mL, approximately 410pg / mL, approximately 420pg / mL, approximately 430pg / mL, approximately 440pg / mL, approximately 450p g / 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 580pg / mL, approximately 590pg / mL, approximately 600pg / mL, approximately 610pg / mL, approximately 620pg / mL, approximately 630pg / mL, approximately 640pg / mL, approximately 650pg / mL, approximately 660pg / mL, approximately 670pg / mL, approximately 680pg / mL, approximately 690pg / mL, approximately 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 , about 830pg / mL, about 840pg / mL, about 850pg / mL, about 860pg / mL, about 870pg / mL, about 880pg / mL, about 890pg / mL, about 900pg / mL, about 910pg / mL, about 920pg / mL, about 930pg / mL, about 940pg / mL, about 95 0pg / mL, approximately 960pg / mL, approximately 970pg / mL, approximately 980pg / mL, approximately 1000pg / mL, approximately 1010pg / mL, approximately 1020pg / mL, approximately 1030pg / mL, approximately 1040pg / mL, approximately 1050pg / mL, approximately 1060pg / mL, approximately 1070pg / mL,Approx. 1080pg / mL, approx. 1090pg / mL, approx. 1100pg / mL, approx. 1110pg / mL, approx. 1120pg / mL, approx. 1130pg / mL, approx. 1140pg / mL, approx. 1150pg / mL, approx. 1160pg / mL, approx. 1170pg / mL, approximately 1180pg / mL, approximately 1190pg / mL, approximately 1200pg / mL, approximately 1210pg / mL, approximately 1220pg / mL, approximately 1230pg / mL, approximately 1240pg / mL, approximately 1250pg / mL, approximately 12 The concentrations are 60 pg / mL, approximately 1270 pg / mL, approximately 1280 pg / mL, approximately 1290 pg / mL, approximately 1300 pg / mL, approximately 1310 pg / mL, approximately 1320 pg / mL, approximately 1330 pg / mL, approximately 1340 pg / mL, approximately 1350 pg / mL, approximately 1360 pg / mL, approximately 1370 pg / mL, approximately 1380 pg / mL, approximately 1390 pg / mL, approximately 1400 pg / mL, approximately 1410 pg / mL, approximately 1420 pg / mL, or approximately 1430 pg / mL. In some embodiments, approximately 640 μg of the compound of formula (II) is administered once daily, containing approximately 80% to 125% treprostinil C in the range of approximately 160 pg / mL to approximately 1140 pg / mL. max In some embodiments, approximately 640 μg of the compound of formula (II) is administered once daily, and treprostinil C is administered in a range of approximately 80% to 125% of approximately 325 pg / mL to approximately 980 pg / mL. max To provide.

[0147] In some embodiments, the dry powder composition contains about 675 μg of the compound of formula (II), with treprostinyl C in an amount ranging from about 80% to about 125% of about 717 (52.8) pg / mL. max To provide.

[0148] In some embodiments, the dry powder composition contains about 80 μg of the compound of formula (II), and upon administration, treprostinil AUC in the range of about 375 pg*h / mL to about 1800 pg*h / mL. 0-inf It provides, for example, 375pg, including all values ​​and ranges within it. * h / mL, 400pg * h / mL, 500pg * h / mL, 600pg * h / mL, approximately 700pg* h / mL, approximately 800pg * h / mL, approximately 900pg * h / mL, approximately 1000pg * h / mL, approximately 1100pg * h / mL, approximately 1200pg * h / mL, approximately 1300pg * h / mL, approximately 1400pg * h / mL, approximately 1500pg * h / mL, approximately 1600pg * h / mL, approximately 1700pg * h / mL, or approximately 1800 pg * The concentration is h / mL. In some embodiments, approximately 80 μg of the compound of formula (II) is administered once daily, totaling approximately 475 pg. * h / mL~approx. 1430pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf In some embodiments, the dry powder composition contains about 80 μg of the compound of formula (II), and at administration, about 660 pg * h / mL~approx. 1240pg * Treprostinyl AUC of approximately 80% to 125% of h / mL 0-inf To provide.

[0149] In some embodiments, the dry powder composition contains about 112.5 μg of the compound of formula (II) and about 1090 (91.8) pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf To provide.

[0150] In some embodiments, the dry powder composition contains about 160 μg of the compound of formula (II), and at the time of administration, about 630 pg * Treprostinil AUC in the range of h / mL to approximately 3000 pg*h / mL 0-inf It provides, for example, 630pg, including all values ​​and ranges within it. * h / mL, approximately 700pg * h / mL, approximately 800pg * h / mL, approximately 900pg * h / mL, approximately 1000pg *h / mL, approx. 1100pg*h / mL, approx. 1200pg * h / mL, approximately 1300pg * h / mL, approximately 1400pg * h / mL, approx. 1500pg*h / mL, approx. 1600pg * h / mL, approximately 1700pg * h / mL, approximately 1800pg * h / mL, approx. 1900pg*h / mL, approx. 2000pg * h / mL, approximately 2100pg * h / mL, approximately 2200pg * h / mL, approx. 2300pg*h / mL, approx. 2400pg * h / mL, approximately 2500pg * h / mL, approximately 2600pg * h / mL, approx. 2700pg*h / mL, approx. 2800pg * h / mL, approximately 2900pg * h / mL, or approximately 3000 pg * The concentration is h / mL. In some embodiments, the dry powder composition contains about 160 μg of the compound of formula (II), and at administration, about 785 pg * h / mL ~ approx. 2370pg * Treprostinil AUC from approximately 80% to 125% in the h / mL range 0-inf In some embodiments, the dry powder composition contains about 160 μg of the compound of formula (II), and at administration, about 1100 pg * h / mL ~ approx. 2050pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf To provide.

[0151] In some embodiments, the dry powder composition contains about 225 μg of the compound of formula (II), and at administration, about 2130 (30.0) ng. * AUC in the range of approximately 80% to 125% of h / mL 0-inf In some embodiments, the dry powder composition contains about 225 μg of the compound of formula (II) and about 1680 (28.7) ng. * Steady-state treprostinyl AUC0- 24Provides (CV%). In some embodiments, the dry powder composition contains about 225 μg of the compound of formula (II) or its stereoisomer (or an equivalent dose of its pharmaceutically acceptable salt, or the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt), and about 1790 (39.6) ng * Steady-state treprostinyl AUC0- 24 (CV%) is provided.

[0152] In some embodiments, the dry powder composition contains about 450 μg of the compound of formula (II), and at administration, about 4040 (27.4) pg * Treprostinil AUC in the range of approximately 80% to 125% of h / mL 0-inf To provide.

[0153] In some embodiments, the dry powder composition contains about 240 μg of the compound of formula (II), and at the time of administration, about 880 pg * h / mL ~ approx. 4130pg * Treprostinil AUC in the range of h / mL 0-inf It provides, for example, approximately 800pg, including all values ​​and ranges within it. * h / mL, approximately 900pg * h / mL, approximately 950pg * h / mL, approximately 1000pg * h / mL, approximately 1050pg * h / mL, approximately 1100pg * h / mL, approximately 1150pg * h / mL, approximately 1200pg * h / mL, approximately 1250pg * h / mL, approximately 1300pg * h / mL, approximately 1350pg * h / mL, approximately 1400pg * h / mL, approximately 1450pg * h / mL, approximately 1500pg * h / mL, approximately 1550pg * h / mL, approximately 1600pg * h / mL, approximately 1650pg * h / mL, approximately 1700pg *h / mL, approximately 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, 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, 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 3850pg * h / mL, approximately 3950pg * h / mL, approximately 4000pg * h / mL, approximately 4050pg * h / mL, approximately 4100pg * h / mL, approximately 4130pg * The concentration is h / mL. In some embodiments, the dry powder composition contains about 240 μg of the compound of formula (II), and at the time of administration, about 1100 pg * h / mL ~ approx. 3305pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf In some embodiments, the dry powder composition contains about 240 μg of the compound of formula (II), and at administration, about 1540 pg * h / mL ~ approx. 2865pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf To provide.

[0154] In some embodiments, the dry powder composition contains about 320 μg of the compound of formula (II), and upon administration, treprostinil AUC in the range of about 1130 pg*h / mL to about 5310 pg*h / mL. 0-infIt provides, for example, all values ​​and ranges within that range, including 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, and approximately 190 0pg*h / mL, approx. 2000pg*h / mL, approx. 2100pg*h / mL, approx. 2200pg*h / mL, approx. 2300pg*h / mL, approx. 2400pg*h / mL, approx. 2500p g*h / mL, approximately 2600pg*h / mL, approximately 2700pg*h / mL, approximately 2800pg*h / mL, approximately 2900pg*h / mL, approximately 3000pg*h / mL, approximately 3100pg*h / mL, approx. 3200pg*h / mL, approx. 3300pg*h / mL, approx. 3400pg*h / mL, approx. 3500pg*h / mL, approx. 3600pg*h / mL, approx. 3700pg*h / m L, approx. 3800pg*h / mL, approx. 3900pg*h / mL, approx. 4000pg*h / mL, approx. 4100pg*h / mL, approx. 4200pg*h / mL, approx. 4300pg*h / mL, approx. The AUC levels are approximately 4400 pg*h / mL, about 4500 pg*h / mL, about 4600 pg*h / mL, about 4700 pg*h / mL, about 4800 pg*h / mL, about 4900 pg*h / mL, about 5000 pg*h / mL, about 5100 pg*h / mL, about 5200 pg*h / mL, about 5300 pg*h / mL, about 5300 pg*h / mL, or about 5310 pg*h / mL. In some embodiments, the dry powder composition contains about 320 μg of the compound of formula (II), and at administration, about 80% to 125% of the treprostinil AUC in the range of about 1400 pg*h / mL to about 4250 pg*h / mL. 0-inf In some embodiments, approximately 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, yielding approximately 1975 pg. * h / mL ~ approx. 3680pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf To provide.

[0155] In some embodiments, the dry powder composition contains about 400 μg of the compound of formula (II), and upon administration, treprostinil AUC in the range of about 1380 pg*h / mL to about 6480 pg*h / mL. 0-inf It provides, for example, all values ​​and ranges within that range, including 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, and approximately 230 0pg*h / mL, approx. 2400pg*h / mL, approx. 2500pg*h / mL, approx. 2600pg*h / mL, approx. 2700pg*h / mL, approx. 2800pg*h / mL, approx. 2900pg*h / mL, approx. 3000p g*h / mL, approximately 3100pg*h / mL, approximately 3200pg*h / mL, approximately 3300pg*h / mL, approximately 3400pg*h / mL, approximately 3500pg*h / mL, approximately 3600pg*h / mL, approximately 3700pg*h / mL, approx. 3800pg*h / mL, approx. 3900pg*h / mL, approx. 4000pg*h / mL, approx. 4100pg*h / mL, approx. 4200pg*h / mL, approx. 4300pg*h / mL, approx. 4400pg*h / m L, approx. 4500pg*h / mL, approx. 4600pg*h / mL, approx. 4700pg*h / mL, approx. 4800pg*h / mL, approx. 4900pg*h / mL, approx. 5000pg*h / mL, approx. 5100pg*h / mL, approx. The AUC levels are approximately 5200 pg*h / mL, about 5300 pg*h / mL, about 5400 pg*h / mL, about 5500 pg*h / mL, about 5600 pg*h / mL, about 5700 pg*h / mL, about 5800 pg*h / mL, about 5900 pg*h / mL, about 6000 pg*h / mL, about 6100 pg*h / mL, about 6200 pg*h / mL, about 6300 pg*h / mL, about 6400 pg*h / mL, or about 6480 pg*h / mL. In some embodiments, the dry powder composition contains about 400 μg of the compound of formula (II), and at administration, about 80% to 125% of the treprostinil AUC in the range of about 1725 pg*h / mL to about 5180 pg*h / mL. 0-infThe present invention provides: In some embodiments, the dry powder composition contains about 400 μg of the compound of formula (II), and upon administration, about 80% to 125% of the treprostinil AUC in the range of about 2415 pg*h / mL to about 4490 pg*h / mL. 0-inf To provide.

[0156] In some embodiments, the dry powder composition contains about 480 μg of the compound of formula (II), and upon administration, treprostinil AUC in the range of about 1630 pg*h / mL to about 7650 pg*h / mL. 0-inf It provides, for example, all values ​​and ranges within it, approximately 1630pg * h / mL, approximately 1700pg * h / mL, approximately 1800pg * h / mL, approximately 1900pg * h / mL, approximately 2000pg * h / mL, approximately 2100pg * h / mL, approximately 2200pg * h / mL, approximately 2300pg * h / mL, approximately 2400pg * h / mL, approximately 2500pg * h / mL, approximately 2600pg * h / mL, approximately 2700pg * h / mL, approximately 2800pg * h / mL, approximately 2900pg * h / mL, approximately 3000pg * h / mL, approximately 3100pg * h / mL, approximately 3200pg * h / mL, approximately 3300pg * h / mL, approximately 3400pg * h / mL, approximately 3500pg * h / mL, approximately 3600pg * h / mL, approximately 3700pg * h / mL, approximately 3800pg * h / mL, approximately 3900pg * h / mL, approximately 4000pg * h / mL, approximately 4100pg * h / mL, approximately 4200pg * h / mL, approximately 4300pg * h / mL, approximately 4400pg* h / mL, approximately 4500pg * h / mL, approximately 4600pg * h / mL, approximately 4700pg * h / mL, approximately 4800pg * h / mL, approximately 4900pg * h / mL, approximately 5000pg * h / mL, approximately 5100pg * h / mL, approximately 5200pg * h / mL, approximately 5300pg * h / mL, approximately 5400pg * h / mL, approximately 5500pg * h / mL, approximately 5600pg * h / mL, approximately 5700pg * h / mL, approximately 5800pg * h / mL, approximately 5900pg * h / mL, approximately 6000pg * h / mL, approximately 6100pg * h / mL, approximately 6200pg * h / mL, approximately 6300pg * h / mL, approximately 6400pg * h / mL, approximately 6500pg * h / mL, approximately 6600pg * h / mL, approximately 6700pg * h / mL, approximately 6800pg * h / mL, approximately 6900pg * h / mL, approximately 7000pg * h / mL, approximately 7100pg * h / mL, approximately 7200pg * h / mL, approximately 7300pg * h / mL, approximately 7400pg * h / mL, approximately 7500pg * h / mL, or approximately 7650 pg * The concentration is h / mL. In some embodiments, the dry powder composition contains about 480 μg of the compound of formula (II), and at administration, about 2040 pg * h / mL ~ approx. 6120 pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-infIn some embodiments, the dry powder composition contains about 480 μg of the compound of formula (II), and at administration, about 2855 pg * h / mL ~ approx. 5310 pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf To provide.

[0157] In some embodiments, the dry powder composition contains about 640 μg of the compound of formula (II), and at administration, about 2130 pg * Treprostinil AUC in the range of h / mL to approximately 10,000 pg*h / mL 0-inf It provides, for example, all values ​​and ranges within it, approximately 2130pg * h / mL, approximately 2200pg * h / mL, approximately 2300pg * h / mL, approximately 2400pg * h / mL, approximately 2500pg * h / mL, approximately 2600pg * h / mL, approximately 2700pg * h / mL, approximately 2800pg * h / mL, approximately 2900pg * h / mL, approximately 3000pg * h / mL, approximately 3100pg * h / mL, approximately 3200pg * h / mL, approximately 3300pg * h / mL, approximately 3400pg * h / mL, approximately 3500pg * h / mL, approximately 3600pg * h / mL, approximately 3700pg * h / mL, approximately 3800pg * h / mL, approximately 3900pg * h / mL, approximately 4000pg * h / mL, approximately 4100pg * h / mL, approximately 4200pg * h / mL, approximately 4300pg * h / mL, approximately 4400pg * h / mL, approximately 4500pg * h / mL, approximately 4600pg * h / mL, approximately 4700pg *h / mL, approximately 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 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 8900pg * h / mL, approximately 9000pg * h / mL, approximately 9100pg * h / mL, approximately 9200pg * h / mL, approximately 9300pg * h / mL, approximately 9350pg * h / mL, approximately 9400pg * h / mL, approximately 9450pg * h / mLL, approximately 9500pg * h / mL, approximately 9600pg * h / mL, approximately 9700pg * h / mL, approximately 9800pg * h / mL, approximately 9900pg * h / mL, or approximately 10,000 pg * The concentration is h / mL. In some embodiments, the dry powder composition contains about 640 μg of the compound of formula (II), and at administration, about 2650 pg * h / mL~about 8000pg * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf In some embodiments, the dry powder composition contains about 640 μg of the compound of formula (II), and at administration, about 3730 to about 6935 pg. * Treprostinyl AUC in the range of approximately 80% to 125% of h / mL 0-inf To provide.

[0158] In some embodiments, the dry powder composition contains about 675 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), and about 5480 (13.8) pg * Treprostinil AUC in the range of approximately 80% to 125% of h / mL 0-24 This provides. In further embodiments, the compound is a compound of formula (II).

[0159] In some embodiments, the dry powder composition contains about 80 μg to about 675 μg of the compound of formula (II), and the dry composition provides treprostinil plasma trough concentrations in the range of about 3 pg / mL to about 150 mg / mL, or, following once-daily administration, the subject (e.g., patient) has treprostinil plasma trough concentrations in the range of about 3 pg / mL to about 150 mg / mL. For example, including all values ​​and ranges within that range, about 4 pg / mL, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL These are approximately 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, 100 pg / mL, 100 pg / mL, 105 pg / mL, 110 pg / mL, 115 pg / mL, 120 pg / mL, 125 pg / mL, 130 pg / mL, 135 pg / mL, 140 pg / mL, 145 pg / mL, or 150 pg / mL.

[0160] In some embodiments, the dry powder composition comprises about 80 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 3 pg / mL to about 25 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 3 pg / mL to about 25 mg / mL. For example, including all values ​​and ranges therein, such as 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. In further embodiments, the treprostinil plasma trough concentration ranges from about 6 pg / mL to about 18 mg / mL.

[0161] In some embodiments, the dry powder composition comprises about 112.5 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 4 pg / mL to about 30 mg / mL, or, if administered once daily, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 4 pg / mL to about 30 mg / mL. For example, this includes all values ​​and ranges within that range, 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, and about 30 pg / mL.

[0162] In some embodiments, the dry powder composition comprises about 160 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 5 pg / mL to about 35 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 5 pg / mL to about 35 mg / mL. For example, including all values ​​and ranges therein, about 5 pg / mL, about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, and about 35 pg / mL. In further embodiments, the treprostinil plasma trough concentration ranges from about 10 pg / mL to about 30 mg / mL, or from 15 pg / mL to about 25 pg / mL.

[0163] In some embodiments, the dry powder composition comprises about 225 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 15 pg / mL to about 45 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 15 pg / mL to about 45 mg / mL. For example, including all values ​​and ranges therein, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, about 35 pg / mL, about 40 pg / mL, and about 45 pg / mL.

[0164] In some embodiments, the dry powder composition comprises about 240 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 7 pg / mL to about 50 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 7 pg / mL to about 50 mg / mL. For example, including all values ​​and ranges therein, 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. In some embodiments, the treprostinil plasma trough concentration ranges from about 15 pg / mL to about 50 mg / mL, or from 20 pg / mL to about 45 pg / mL.

[0165] In some embodiments, the dry powder composition comprises about 320 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 9 pg / mL to about 65 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 9 pg / mL to about 65 mg / mL. For example, including all values ​​and ranges therein, 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. In some embodiments, the treprostinil plasma trough concentration is in the range of approximately 15 pg / mL to approximately 50 mg / mL, or 20 pg / mL to approximately 45 pg / mL.

[0166] In some embodiments, the dry powder composition comprises about 400 μg of the compound of formula (II), and the dry powder composition provides treprostinil plasma trough concentrations in the range of about 10 pg / mL to about 80 mg / mL, or, following once-daily administration, the subject (e.g., patient) has treprostinil plasma trough concentrations in the range of about 10 pg / mL to about 80 mg / mL. For example, including all values ​​and ranges therein, 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, and about 80 pg / mL. In some embodiments, the treprostinil plasma trough concentration is in the range of approximately 35 pg / mL to approximately 70 mg / mL, or 40 pg / mL to approximately 65 pg / mL.

[0167] In some embodiments, the dry powder composition comprises about 480 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 13 pg / mL to about 95 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 13 pg / mL to about 95 mg / mL. For example, including all values ​​and ranges within that range, are approximately 13 pg / mL, 15 pg / mL, 20 pg / mL, 25 pg / mL, 30 pg / mL, 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, 75 pg / mL, 80 pg / mL, 85 pg / mL, 90 pg / mL, and 95 pg / mL. In some embodiments, the treprostinil plasma trough concentration ranges from approximately 25 pg / mL to approximately 75 mg / mL, or from 30 pg / mL to approximately 70 pg / mL.

[0168] In some embodiments, the dry powder composition comprises about 640 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 15 pg / mL to about 125 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 15 pg / mL to about 125 mg / mL. For example, these include all values ​​and ranges within that range: approximately 15 pg / mL, approximately 20 pg / mL, approximately 25 pg / mL, approximately 30 pg / mL, approximately 35 pg / mL, approximately 40 pg / mL, approximately 45 pg / mL, approximately 50 pg / mL, approximately 55 pg / mL, approximately 60 pg / mL, approximately 65 pg / mL, approximately 70 pg / mL, approximately 75 pg / mL, approximately 80 pg / mL, approximately 85 pg / mL, approximately 90 pg / mL, approximately 95 pg / mL, approximately 100 pg / mL, approximately 105 pg / mL, approximately 110 pg / mL, approximately 115 pg / mL, approximately 120 pg / mL, and approximately 125 pg / mL. In some embodiments, the treprostinil plasma trough concentration is in the range of approximately 35 pg / mL to approximately 100 mg / mL, or 50 pg / mL to approximately 90 pg / mL.

[0169] In some embodiments, the dry powder composition comprises about 450 μg of the compound of formula (II), and the dry powder composition provides a treprostinil plasma trough concentration in the range of about 30 pg / mL to about 75 mg / mL, or, following once-daily administration, the subject (e.g., patient) has a treprostinil plasma trough concentration in the range of about 30 pg / mL to about 75 mg / mL. For example, including all values ​​and ranges therein, 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.

[0170] In some embodiments, the dry powder composition comprises about 675 μg of the compound of formula (II), and the dry powder composition provides treprostinil plasma trough concentrations in the range of about 50 pg / mL to about 100 mg / mL, or, following once-daily administration, the subject (e.g., patient) has treprostinil plasma trough concentrations in the range of about 50 pg / mL to about 100 mg / mL. For example, including all values ​​and ranges therein, 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 about 100 pg / mL.

[0171] Aerosolized composition In some embodiments, the dry powder compositions described herein are aerosolized via DPI to provide an aerosolized composition. The aerosolized composition is administered to patients requiring treatment for PH. In other embodiments, the aerosolized composition is administered to patients requiring treatment for pulmonary fibrosis (e.g., PH-ILD, where ILD is pulmonary fibrosis). The aerosolized composition may be characterized by certain parameters known to those skilled in the art, such as aerodynamic median mass diameter (MMAD) and particulate fraction (FPF).

[0172] The aerodynamic median mass diameter (MMAD) is the aerodynamic diameter value such that 50% of the mass in a given aerosol is associated with particles smaller than the median aerodynamic diameter (MAD), and 50% of the mass is associated with particles larger than the MAD. The MMAD can be determined by impactor measurements, such as those using an Andersen cascade impactor (ACT) or a next-generation impactor (NGI). In some embodiments, the aerosolized dry powder composition contains particles having 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, the dry powder composition exhibiting one of the MMAD profiles provided above contains mannitol. In another embodiment, the dry powder composition exhibiting the MMAD profile provided above contains trehalose.

[0173] "Fine particle fraction" or "FPF (Fine particle fraction)" refers to the proportion of aerosols having a particle size of less than 5 μm in diameter, as measured by cascade impaction. FPF is usually expressed as a percentage. FPF has been shown to correlate with the proportion of powder deposited in the lungs of a subject (e.g., a patient). In some embodiments, the dry powder composition is in the form of an aerosol containing particles having 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 contains particles having 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, the dry powder composition exhibiting one of the FPF profiles provided above contains mannitol. In another embodiment, the dry powder composition exhibiting the FPF profile provided above comprises trehalose.

[0174] The dry powder compositions of this disclosure may be prepared from liquid compositions using freeze-drying or spray-drying techniques. When freeze-drying is used, the freeze-dried composition can be pulverized to obtain finely divided dry powder containing particles within the desired size range described above. When spray-drying is used, the process is carried out under conditions that result in finely divided dry powder containing particles within the desired size range described above. Examples of methods for preparing the dry powder form of pharmaceutical compositions are disclosed in WO96 / 32149, WO97 / 41833, WO98 / 29096, and U.S. Patents 5,976,574, 5,985,248, and 6,001,336, each of which disclosures are incorporated herein by reference in their entirety. Exemplary spray-drying methods are described in U.S. Patent Application Publication 2020 / 0338005, and U.S. Patents 6,848,197, and 8,197,845, each of which disclosures are incorporated herein by reference in their entirety.

[0175] In some embodiments, the dry powder compositions of the present disclosure are prepared by the following process: A stock solution of the 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). Aqueous stock solutions of sugars (e.g., mannitol or trehalose) and leucine are also prepared. The required amount of the above stock solution is then 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 about 3:2 to about 1:1.

[0176] Spray drying is initiated by starting the drying gas flow and heating the drying gas by setting a desired inlet temperature, such as approximately 120°C to 180°C or approximately 135°C to 150°C. After the spray dryer outlet temperature reaches a suitable temperature, such as approximately 55°C to 65°C, the liquid skid inlet is set so that the blank solution is sprayed into the spray dryer with the help of nitrogen, allowing the system to cool and stabilize. Pulsing of the product filter is initiated, and the purge flow rate of the product filter is set to, for example, 10 to 20 scfh. After the system has stabilized, the liquid skid inlet is switched to the supply solution adjusted above, and the process continues until the supply solution is depleted. When the supply solution is depleted, the liquid skid inlet is switched to the blank solution, which allows spraying for approximately 5 to 20 minutes. At this point, the powder is collected at the bottom of the product filter. After spraying the blank solution for approximately 5 to 20 minutes, the system is shut down by stopping the liquid line, spray gas, drying gas heater, drying gas inlet, and finally the exhaust.

[0177] The dry powder compositions of this disclosure are delivered to the lungs of a subject (e.g., a patient) via inhalation using a dry powder inhaler (DPI). In one embodiment, the dry powder inhaler is a single-dose dry powder inhaler. The DPI, being a device that does not contain pressurized gas, uses the subject's (e.g., patient's) inhaled air to deliver the dry powder to the subject's (e.g., patient's) lungs. The unit dose of the dry powder composition used in the DPI device is often a dry powder blister disc in a hard capsule. Exemplary DPI devices suitable for delivering the dry powder compositions of this disclosure include the devices described in the following paragraphs, as well as the DPIs described in U.S. Patents 6,766,799, 7,278,425 and 8,496,002, each of which disclosures are incorporated herein by reference in their entirety.

[0178] The AIR® inhaler (Alkermes) includes a small exhalation activation system that delivers porous powder from a capsule. The aerodynamic diameter of the porous particles is 1–5 μm. See International Patent Application Publications WO 99 / 66903 and WO 00 / 10541. The disclosures of each thereof are incorporated herein by reference in their entirety.

[0179] Aerolizer® (Novartis) is a single-dose dry powder inhaler. In this device, the dry powder pharmaceutical is stored in a capsule and released by puncturing the capsule wall with a Teflon-coated steel pin. See U.S. Patent Nos. 6,488,027 and 3,991,761. Each of those disclosures is incorporated herein by reference in its entirety.

[0180] Bang Olufsen offers an exhalation-activated inhaler using blister strips containing up to sixty doses. The doses are available only during inhalation via a novel trigger mechanism. The device includes a dose counter and can be discarded after all doses have been used. See EP1522325, the entirety of which is incorporated herein by reference.

[0181] Clickhaler® (Innovata PLC) is a large storage-type respiratory-activated multiple-dose device. See U.S. Patent No. 5,437,270. Its disclosure is incorporated herein by reference in its entirety.

[0182] DirectHaler® (Direct-Haler A / S) is a single-dose, pre-measured, pre-filled, disposable DPI device made from polypropylene. See U.S. Patent No. 5,797,392, the entirety of which is incorporated herein by reference.

[0183] Diskus® (GlaxoSmithKline) is a disposable, miniature DPI device that contains up to 60 doses in a double foil blister strip and provides moisture protection. See GB2242134. Its disclosure is incorporated herein by reference in its entirety.

[0184] Eclipse® (Aventis) is a breath-activated, reusable capsule device capable of delivering up to 20 mg of a dry powder composition. When the subject (e.g., a patient) inhales the powder from the capsule, a rotating ball draws it into a vortex chamber that assists in the disintegration of the powder. See U.S. 6,230,707 and WO9503846. Each of these disclosures is incorporated herein by reference in its entirety.

[0185] Flexhaler® is a plastic exhalation-activated dry powder inhaler that can be used in combination with the dry powder compositions provided herein.

[0186] FlowCaps® (Hovione) are capsule-based, refillable, reusable passive dry powder inhalers that hold up to 14 capsules. The inhaler itself is moisture-resistant. See U.S. Patent No. 5,673,686, the entirety of which is incorporated herein by reference.

[0187] Gyrohaler® (Vectura) is a passive, disposable DPI containing a blister strip. See GB2407042. Its disclosure is incorporated herein by reference in its entirety.

[0188] HandiHaler® (Boehringer Ingelheim GmbH) is a single-dose DPI device capable of delivering up to 30 mg of a dry powder composition in a capsule. See International Patent Application Publication W04 / 024156, the disclosure of which is incorporated herein by reference in its entirety.

[0189] MicroDose DPI (Microdose Technologies) is a miniature electronic DPI device. It uses a piezoelectric transducer (ultrasonic frequency) to disintegrate drug powder in aluminum blisters (single or multi-dose). See U.S. Patent No. 6,026,809, the entirety of which is incorporated herein by reference.

[0190] The Nektar Dry Powder Inhaler® (Nektar) is a palm-sized, easy-to-use device. It offers convenient administration from standard capsules and flow-independent lung deposition.

[0191] The Nektar Pulmonary Inhaler® (Nektar) efficiently removes powder from packaging, breaks down particles, and generates an aerosol cloud suitable for deep lung delivery. This allows the aerosolized particles to be delivered from the device to the deep lungs during the subject's (e.g., patient's) respiration, reducing loss in the throat and upper airway. Compressed gas is used to aerosolize the powder. See AU4090599 and U.S. 5,740,794. Each of those disclosures is incorporated herein by reference in its entirety.

[0192] NEXT DPI® is a device characterized by multiple-dose capability, moisture resistance, and dose counting. The device can be used regardless of orientation (inverted) and dose, only when an appropriate respiratory flow rate is reached. See EP1196146, U.S. 6,528,096, WO0178693, and WO0053158. Each of those disclosures is incorporated herein by reference in its entirety.

[0193] Neohaler® is a capsule-based plastic exhalation-activated dry powder inhaler.

[0194] Oriel™ DPI is an active DPI that aerosolizes powder formulations using a piezoelectric film and nonlinear vibration. See International Patent Application Publication W01 / 68169, the disclosure of which is incorporated herein by reference in its entirety.

[0195] In one embodiment, the DPI is a capsule-based DPI. In a further 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.

[0196] Pressair® is a plastic exhalation-activated dry powder inhaler.

[0197] Pulvinal® inhaler (Chesi) is an exhalation-operated multi-dose (100-dose) dry powder inhaler. The dry powder is stored in a clear storage compartment that is clearly marked to indicate when the 100th dose has been delivered. See U.S. Patent No. 5,351,683, the entirety of which is incorporated herein by reference.

[0198] Rotohaler® (GlaxoSmithKline) is a single-use device utilizing a capsule. See U.S. documents 5,673,686 and 5,881,721. Each of those disclosures is incorporated herein by reference in its entirety.

[0199] Rexam DPI (Rexam Pharma) is a single-dose, reusable device designed for use in capsules. See U.S. 5,651,359 and EP0707862. Each of those disclosures is incorporated herein by reference in its entirety.

[0200] S2 (Innovata PLC) is a reusable or disposable single-dose DPI for delivering high-concentration dry powder compositions. Its dispersion mechanism requires minimal effort to achieve excellent drug delivery to the target (e.g., patient) lungs. S2 is easy to use and features a passive engine, thus requiring no batteries or power supply. See AU3320101. Its disclosure is incorporated herein by reference in its entirety.

[0201] SkyeHaler® DPI (SkyePharma) is a multi-dose device containing up to 300 individual doses in a single-use or replaceable cartridge. The device is activated by respiration and requires no adjustment between respiration and activation. See U.S. 6,182,655 and WO97 / 20589. Each of those disclosures is incorporated herein by reference in its entirety.

[0202] Taifun® DPI (LAB International) is a multi-dose (up to 200) DPI device. It is breath-operated and flow rate is independent. The device includes a unique water-balanced drug storage unit connected to a volumetric dosing system for consistent dosing. See U.S. Patent No. 6,132,394, the entirety of which is incorporated herein by reference.

[0203] TurboHaler® (AstraZeneca) is described in U.S. Patent No. 5,983,893, the disclosure of which is incorporated herein by reference in its entirety. This DPI device is an inspiratory flow-driven multi-dose dry powder inhaler with a multi-dose storage compartment that provides up to 200 doses of dry powder composition and dose ranges from a few micrograms to 0.5 mg.

[0204] Twisthaler® (Schering-Plough) is a multi-dose device with dose counting capabilities, capable of 14 to 200 operations. The dry powder composition is packaged in a cartridge containing a desiccant. See U.S. Patent No. 5,829,434, the entirety of which is incorporated herein by reference.

[0205] Ultrahaler® (Aventis) combines accurate dose measurement with excellent dispersibility. It is an easy-to-use, detachable, pocket-sized device with a dose counter, dose intake indicator, and lockout mechanism. The device can deliver up to 20 mg of dry powder composition. Ultrahaler® is described in U.S. Patent No. 5,678,538 and WO2004026380, the respective disclosures of which are incorporated herein by reference in their entirety.

[0206] Xcelovair® (Meridica / Pfizer) holds 60 pre-measured sealed doses in the range of 5–20 mg. The device provides moisture protection under accelerated conditions of 40°C / 75%RH. The dispersion system maximizes the particulate fraction, delivering up to 50% particulate mass.

[0207] In another embodiment, 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 storage unit containing the dry powder composition disclosed herein, and (b) means for introducing the dry powder composition into the lungs of a target via inhalation. In one embodiment, the storage unit contains the dry powder composition of the present invention in a capsule or blister pack. The material of the capsule shell may be gelatin, a cellulose derivative, starch, a starch derivative, chitosan, or a synthetic plastic. The DPI may be a single-dose or multi-dose inhaler. Furthermore, the DPI may be pre-measured or device-measured. In one embodiment, the dry powder inhaler is a single-dose dry powder inhaler.

[0208] In one embodiment, the system is used for the treatment of pulmonary hypertension (e.g., group 1 or group 3 PH), portal pulmonary hypertension, or pulmonary fibrosis, as will be described in more 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 stereoisomer, 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 as described above, a single-dose or multi-dose inhaler, and / or pre-measured or device-measured. In one embodiment, the dry powder inhaler is a single-dose dry powder inhaler.

[0209] The term “to treat” includes (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or pathology in patients who suffer from or are at risk of contracting a condition, disorder, or pathology but have not yet experienced or shown any clinical or subclinical symptoms of the condition, disorder, or pathology; (2) inhibiting the condition, disorder, or pathology (e.g., stopping, reducing, or delaying the onset of the disease with respect to at least one of its clinical or subclinical symptoms, or, in the case of maintenance therapy, stopping, reducing, or delaying its recurrence); and / or (3) alleviating the pathology (e.g., resulting in the reduction of at least one of the condition, disorder, or pathology, or its clinical or subclinical symptoms). In one embodiment, “to treat” means inhibiting the condition, disorder, or pathology (e.g., stopping, reducing, or delaying the onset or recurrence of the disease, in the case of maintenance therapy, with respect to at least one of its clinical or subclinical symptoms). In another embodiment, “to treat” means to alleviate a medical condition (for example, by reducing a condition, disorder, or disease, or at least one of its clinical or subclinical symptoms). The benefit to the treated patient is either statistically significant compared to the same patient’s condition or disease before treatment, or compared to the condition or disease of an untreated control patient, or the benefit is at least perceptible to the patient or physician.

[0210] "Effective dose" means the amount of the dry powder composition of this disclosure sufficient to produce a desired therapeutic response. "Effective dose" is the amount of the compound of formula (I) or (II) administered in a single dosing session.

[0211] One aspect of the present invention provides a method for treating pulmonary hypertension (PH) in a patient requiring treatment for pulmonary hypertension (PH). The method comprises administering an effective amount of one of the dry powder compositions disclosed herein to the patient's lungs once daily during the administration period via a dry powder inhaler (DPI). 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 via inhalation with a DPI.

[0212] 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., scleroderma), congenital shunts between the 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, e.g., atrial or ventricular disease, or valvular disease (e.g., mitral stenosis). WHO Group 3 pulmonary hypertension is characterized as pulmonary hypertension associated with lung disease, e.g., chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and / or hypoxemia. Group 4 pulmonary hypertension is pulmonary hypertension due to chronic thrombotic and / or embolic disease. Group IV PH is also called chronic thromboembolic pulmonary hypertension. Patients with Group IV PH experience occlusion or narrowing of blood vessels due to thrombosis. Group V PH is a “miscellaneous” category and includes PH caused by blood disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis), and / or metabolic disorders (e.g., thyroid disorders, glycogen storage disorders).

[0213] The methods provided herein can be used to treat patients with PH in Group 1, Group 2, Group 3, Group 4, or Group 5, as characterized by the WHO.

[0214] In one embodiment of this method, the pulmonary hypertension being treated is chronic thromboembolic pulmonary hypertension.

[0215] In one preferred embodiment, pulmonary hypertension is a Class I PH as characterized by the WHO. In a further embodiment, the method provided herein is a method for treating pulmonary arterial hypertension (PAH). In a further embodiment, PAH is a Class I PAH, a Class II PAH, a Class III PAH, or a Class IV PAH as characterized by the New York Heart Association (NYHA).

[0216] In one embodiment, the PAH is a Class I PAH characterized by the NYHA.

[0217] In another embodiment, the PAH is a Class II PAH characterized by NYHA.

[0218] In yet another embodiment, the PAH is a Class III PAH characterized by the NYHA.

[0219] In yet another embodiment, the PAH is a Class IV PAH characterized by NYHA.

[0220] In one embodiment, pulmonary hypertension (PH) is portal pulmonary hypertension (PPH). PPH is defined by the coexistence of portal and pulmonary hypertension. The diagnosis of portal pulmonary hypertension is based on hemodynamic criteria: (1) portal hypertension and / or liver disease (clinical diagnosis - ascites / varices / splenomegaly), (2) mean pulmonary artery pressure at rest > 25 mmHg, (3) pulmonary vascular resistance > 240 dyne s / cm 5 (4) Pulmonary artery occlusion pressure <15 mmHg or transpulmonary gradient >12 mmHg. PPH is a serious complication of liver disease and is present in 0.25–4% of patients with cirrhosis. PPH is present in an estimated 4–6% of patients referred for liver transplantation.

[0221] In one preferred embodiment, pulmonary hypertension is a group 3 PH as characterized by the WHO. In a further embodiment, the method provided herein is a method for treating PH associated with interstitial lung disease (PH-ILD).

[0222] In the methods for treating PH-ILD provided herein, ILD may include one or more pulmonary conditions. One or more pulmonary conditions include, in one embodiment, idiopathic pulmonary fibrosis (IPF), idiopathic pleural effusion (COP), desquamative interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, acute interstitial pneumonia, interstitial pneumonia (e.g., idiopathic interstitial pneumonia), connective tissue disease, sarcoidosis, or asbestosis. In one embodiment, ILD is connective tissue disease-associated interstitial lung disease (CTD-ILD). In another embodiment, ILD is sarcoidosis. In yet another embodiment, ILD is IPF. In yet another embodiment, ILD is idiopathic interstitial pneumonia (IIP).

[0223] In one embodiment of treating PH-ILD provided herein, ILD includes pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF). Pulmonary fibrosis is a respiratory disease in which scarring occurs in the lung tissue, causing severe respiratory problems. Scarring, i.e., the accumulation of excessive fibrous connective tissue, leads to thickening of the lung walls and a decrease in oxygen supply to the blood. As a result, patients with pulmonary fibrosis suffer from persistent shortness of breath. In some patients, a specific cause of the disease is diagnosed, but in others, a suspected cause cannot be identified, a condition known as IPF.

[0224] The duration of administration in any given case may depend on the nature and severity of the PH being treated, as well as the patient's tolerance to and response to the treatment. The treatment methods provided herein are offered as long-term therapies, and therefore, the patient continues to receive treatment as long as the treatment is safe and effective. Thus, in one embodiment, the duration of administration continues until the patient dies. In another embodiment, the duration of administration is the length of time the treatment is effective.

[0225] In one embodiment, if a patient experiences side effects from the treatment, the patient is provided with a reduced dose during the course of treatment. Similarly, if the patient demonstrates sufficient tolerance to a lower dose, the dose may be gradually increased. In one embodiment, the dose escalation occurs only after the patient has demonstrated tolerance to a lower dose for two days or more, for example, two, three, four, five, six, or seven days.

[0226] In some embodiments, the administration period is approximately 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 15 years, 20 years, or 30 years.

[0227] In another embodiment, the duration of administration 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 duration of administration is about 30 days to about 2 years. In another embodiment, the duration of administration is 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.

[0228] In one embodiment, the administration period is at least about one year.

[0229] In one embodiment, the administration period is at least about 5 years.

[0230] In one embodiment, the administration period is approximately 1 to 15 years. In another embodiment, the administration period is approximately 5 to 15 years. In yet another embodiment, the administration period is approximately 10 to 20 years. In yet another embodiment, the administration period is approximately 1 to 20 years.

[0231] In one embodiment of the method of the present disclosure, the patient is administered the dry powder composition once daily in a single administration session during the administration period. In another embodiment, the patient is administered the dry powder composition twice daily, i.e., in two separate administration sessions. In one embodiment, the administration is accompanied by food. In one embodiment, each administration session comprises 1 to 5 inhalations (puffs) from a DPI, such as 1 inhalation (1 puff), 2 inhalations (2 puffs), 3 inhalations (3 puffs), 4 inhalations (4 puffs), or 5 inhalations (5 puffs). As used herein, “administration session” refers to 1 to 5 inhalations (puffs) from a DPI required to administer about 80 μg to about 700 μg of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the DPI is small and transportable by the patient. In one embodiment, the DPI is a single-dose DPI.

[0232] To achieve a specific dose, in one embodiment, multiple DPI capsules containing the composition may be employed. For example, for a dose of 640 μg, two 320 μg DPI capsules can be used. Each capsule may be administered, for example, by one or two inhalations.

[0233] The effective amount of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof may include a fixed dose of the 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 (either increased or decreased) from a previous dose. In another embodiment, the fixed dose is the same dose as or substantially the same dose as a previous dose. In one embodiment, the effective amount is the amount of the compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof administered during each dosing session. In some embodiments, the amount “administered” refers to the amount of the compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in a capsule in a DPI, or in multiple capsules, administered in a single dosing session. In some embodiments, the fixed dose is a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in the range of about 80 μg to about 700 μg, 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 stereoisomer, or a pharmaceutically acceptable salt thereof. For example, if the dry powder composition is administered once daily in a single-dose session, the effective dose can be considered to be the amount of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in the capsule or multiple capsules administered during the single-dose session. For example, in one embodiment, one or more capsules may be formulated with a dry powder composition, and one or more capsules have a total dose of a compound of formula (I) or (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in a total dose of 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, each of the aforementioned doses may be an effective dose and may also be referred to as the amount administered once daily in a single dose session during the administration period.As a further example, in one embodiment, the capsule comprises a dry powder composition containing about 320 μg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, and for the purposes of the present disclosure, the amount administered is 640 μg, even if two or more puffs from two capsules are required to administer 640 μg. Similarly, in this embodiment, the amount administered is 640 μg even if a residual amount of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof remains in the DPI (e.g., about 5%, 10%, 20%, 30%, 40%, or 50% remains in the DPI).

[0234] The dose “administered” in a single-dose session also includes situations where the DPI is refilled or reloaded one or more times (e.g., by changing capsules) to achieve the desired effective dose. In such situations, “administered” refers to the total dose in the capsule administered in the dosing session. For example, one 80 μg capsule and one 160 μg capsule may be used to administer a dose of 240 μg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. The DPI may be refilled with the first 80 μg capsule, and after emptying the cartridge with one or more puffs, the 160 μg capsule may be loaded into the DPI and emptied with one or more puffs. Both capsules are used in the same dosing session, and therefore the dose administered is 240 μg.

[0235] In another embodiment, the effective dose includes increasing doses during the administration period. In a further embodiment, the effective dose is based on dose escalation, based on the patient's maximum tolerable dose. In one embodiment, the patient is initially administered 80 μg. If this dose is well tolerable, the dose is escalated until the patient's maximum tolerable dose is reached. During the titration period, the patient remains on the same dose for a minimum cumulative number of days, such as 2, 3, or 4 days, before escalating to the next higher dose. For embodiments of dose titration, see, for example, Figure 21. If the dose is not tolerable, the dose may be reduced to a previous dose level.

[0236] During the titration period, the dose for each patient can be gradually increased up to the patient's maximum tolerable dose. For example, in one embodiment, the patient initiates the method of the present invention with a single 80 μg DPI capsule once daily. If this dose is well tolerable, the dose is gradually increased until the patient's maximum tolerable dose is reached. During the titration period, the patient remains on the investigational drug for a minimum cumulative number of days (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) before initiating the next higher dose. Titration of the investigational drug may occur more slowly than in the above example, but not more quickly. Figure 21 provides an exemplary embodiment of dose titration for a patient requiring treatment. If the dose is not tolerable, the dose may be reduced to a previous dose level.

[0237] In some embodiments, patients treated by the disclosed method exhibit one or more of the following therapeutic responses during the treatment period compared to before the treatment period: (1) a decrease in the pulmonary vascular resistance index (PVRI), (2) a decrease in mean pulmonary artery pressure, (3) an increase in the hypoxemia score, (4) a decrease in the oxygenation index, (5) an improvement in right ventricular function, and (6) an improvement in exercise capacity (e.g., measured by a six-minute walk test).

[0238] The 6MWT is a validated method for measuring exercise capacity and assessing lung function, and is performed according to the guidelines of the American Thoracic Society (ATS). See American Thoracic Society. ATS Statement: Guidelines for the six minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-17. The entire statement is incorporated herein by reference for all purposes. In one embodiment, the 6MWT is performed at approximately the same time on the day before and during the administration period. In a further embodiment, the 6MWT is performed using the same device. In yet another embodiment, the same person performs the 6MWT.

[0239] In one embodiment, the patient's walking distance during a 6MWT increases 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 treatment period compared to before the treatment period. In another embodiment, the patient's walking distance during a 6MWT increases by about 5 to 60 meters, about 5 to 50 meters, about 10 to 50 meters, about 15 to 50 meters, or about 20 to 40 meters during the treatment period compared to before the treatment period. In yet another embodiment, the patient's walking distance during a 6MWT increases by at least about 30 meters during the treatment period compared to before the treatment period.

[0240] In one embodiment, the patient's walking distance during a 6MWT increases by approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% during the administration period compared to before the administration period. In another embodiment, the patient's walking distance during a 6MWT increases 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% during the treatment period compared to before the treatment period. In another embodiment, the patient's walking distance during a 6MWT 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% during the treatment period compared to before the treatment period.

[0241] In one embodiment for treating PH, treatment includes improving the patient's quality of life during the treatment period compared to the patient's quality of life before the treatment period. In one embodiment, quality of life is measured by the Cambridge Pulmonary Hypertension Outcome Assessment (CAMPHOR) questionnaire. See McCabe et al. (2013). Chest. 2013;144(2):522-30. This document is incorporated herein by reference in its entirety for all purposes. The CAMPHOR questionnaire is a health-related quality of life (QOL) measure specific to pulmonary hypertension and consists of three sections that assess a total of 65 items (25 related to symptoms, 15 related to activities, and 25 related to QOL). CAMPHOR scores are negatively weighted, so a higher score indicates worse QOL and greater functional limitations. Both symptom and QOL items are scored out of 25 points, and the activity item is scored out of 30 points with three possible responses (score 0-2). Each CAMPHOR assessment takes an average of 10 minutes. In one embodiment for treating PH, the treatment includes reducing the patient's CAMPHOR questionnaire score during the treatment period compared to the CAMPHOR questionnaire score before the treatment period. In one embodiment, the reduction is 1 to about 10, 1 to about 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.

[0242] In one embodiment of a method for treating PH, the method includes increasing the saturation of the patient's resting peripheral capillary oxygen supply (SpO2), as assessed by pulse oximetry during the administration period, compared to the patient's resting SpO2 prior to the administration period.

[0243] Oxygen saturation indicates the amount of oxygen bound to hemoglobin in the blood, and is typically expressed as the ratio of oxygenated hemoglobin to total hemoglobin. SpO2 indicates oxygen saturation in peripheral capillaries. Exemplary methods for measuring SpO2 include, but are not limited to, pulse oximetry using a pulse oximeter. One embodiment of a method for treating PH provided herein 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 administration period compared to before the administration period. In another embodiment, a method for treating PH includes increasing the patient's resting SpO2 by approximately 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 50%, 15% to 50%, 20% to 50%, or 25% to 50% during the administration period compared to before the administration period.

[0244] In one embodiment, a method for treating PH provided herein includes improving the patient's lung function during the administration period compared to the patient's lung function before the administration period. The improvement in lung function in one embodiment is measured by vital capacity measurement.

[0245] Improvement in patient lung function, in one embodiment, involves increasing the patient's forced vital capacity (FVC), increasing the patient's percentage predicted forced vital capacity (ppFVC), increasing the patient's forced inspiratory vital capacity (FEV1), increasing the patient's percentage predicted forced inspiratory vital capacity (ppFEV1), and increasing the patient's FVC (FEF) during the administration period, compared to the values ​​prior to the administration period. (25~75%) This includes increasing the forced expiratory flow rate between 25% and 75% of the total vital capacity (TLC) of the patient, or increasing the patient's pulmonary diffusion capacity (DLCO) to carbon monoxide.

[0246] For example, FVC, ppFVC, FEV 1、 ppFEV1, FEF (25~75%) In one embodiment, the assessment of lung function via TLC or DLCO measurement includes, for example, comparing the patient's lung function prior to the administration period, such as immediately before treatment, to the average of measurements taken at a point in time during the administration period or during the administration period.

[0247] As described herein, in one embodiment, a method for treating PH includes improving the patient's lung function during the administration period, compared to each value before the administration period, when lung function is measured by vital capacity measurement. Vital capacity measurement is a physiological test that measures how much air an individual inhales or exhales. The primary signal measured by vital capacity measurement may be volume or flow rate. In the method described herein, vital capacity measurement (e.g., FEV1) 1、 FVC, FEF (25~75%)Pulmonary function tests (PFT) using , and TLC) are performed according to the standards of the American Thoracic Society (ATS) / European Respiratory Society (ERS), as shown, for example, by Miller et al. (See Miller et al., “Standardization of Spirometry,” Eur.Respir.J.26:319-38 (2005), which is incorporated herein by reference in its entirety.) DLCO can be measured using the technique described in Modi P, Cascella M, “Diffusing Capacity Of The Lungs For Carbon Monoxide,” [Updated 2021 Mar 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2021 Jan-. Available from: www.ncbi.nlm.nih.gov / books / NBK556149 / Graham et al., “2017 ERS / ATS standards for single-breath carbon monoxide uptake in the lung,” European Respiratory Journal 49:1600016(2017); each of these is incorporated herein by reference in whole for all purposes.

[0248] In one embodiment, the spirometer can accumulate volume for 15 seconds or more, for example, 20 seconds or more, 25 seconds or more, 30 seconds or more, or 35 seconds or more. In one embodiment, the spirometer can accumulate volume for 0 and 14 L·s with an accuracy of at least ±3% of the reading or ±0.050 L, whichever is greater. -1 With this flow rate, a volume of 8 L or more (BTPS) can be measured. In one embodiment, 14 L·s -1 The total resistance to airflow in the spirometer is 1.5 cmH2O·L. -1 ·s -1 (0.15 kPa? L -1 ·s -1) is less than. In one embodiment, the total resistance of the spirometer is measured with any tube, valve, prefilter, etc. that may be inserted between the patient and the spirometer. With respect to devices exhibiting resistance changes due to water vapor condensation, in one embodiment, the accuracy requirements of the spirometer are met under BTPS (body temperature, ambient pressure, water vapor saturation) conditions, performing up to eight consecutive FVC operations in 10 minutes without receiving inhalation from the instrument.

[0249] With respect to the forced exhalation procedures described herein, in one embodiment, the range and precision recommendations shown in Table 6 of Miller et al. are met (see Miller et al., “Standardization of Spirometry,” Eur.Respir.J.26:319-38(2005), the full text of which is incorporated herein for all purposes by reference).

[0250] In one embodiment, improvement in lung function includes improvement in the patient's forced vital capacity (FVC), i.e., improvement in the maximum volume of air exhaled with maximum effort from maximum inspiration during the administration period, compared to the FVC before administration. FVC is expressed in liters at body temperature and ambient pressure saturated with water vapor (BTPS). In another embodiment, improvement in lung function is an improvement in predicted forced vital capacity (ppFVC) percentage.

[0251] Forced vital capacity (FVC) refers to the volume of gas exhaled during forced exhalation, starting from a position of full inspiration and ending with full exhalation, and is one measure of therapeutic effect. FVC may 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 of treating PH, improvement in 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 before 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 approximately 1% to approximately 20%, approximately 1% to approximately 15%, approximately 1% to approximately 10%, approximately 1% to approximately 5%, approximately 5% to approximately 50%, approximately 5% to approximately 40%, approximately 5% to approximately 30%, approximately 5% to approximately 20%, approximately 10% to approximately 50%, approximately 15% to approximately 50%, approximately 20% to approximately 50%, or approximately 25% to approximately 50%. In one embodiment, the increase in FVC or ppFVC is an increase in FVC or ppFVC before administration of a bronchodilator. In another embodiment, the increase in FVC or ppFVC is an increase in FVC or ppFVC after administration of a bronchodilator.

[0252] In one embodiment, the patient's ppFVC is 80% or less before the administration period. In a further embodiment, the patient's ppFVC is 70% or less before the administration period. In a further embodiment, the patient's ppFVC is 60% or less before the administration period. In a further embodiment, the patient's ppFVC is 50% or less before the administration period. In another embodiment, the patient's ppFVC is 30% to 80%, 40% to 70%, or 50% to 60% before the administration period.

[0253] The FVC procedure can be performed according to procedures known to those skilled in the art. Briefly, the three distinct stages of the FVC procedure are (1) maximal inspiration, (2) expulsion, and (3) complete exhalation (EOT) until the end of the test. The procedure can be performed via closed or open circulation. In either case, the patient inhales rapidly and completely with a pause of less than one second at total vital capacity (TLC). The patient then exhales maximally while maintaining an upright posture until no more air can be exhaled. Exhalation begins with expulsion of air from the lungs, followed by encouragement to exhale completely. Enthusiastic coaching of the patient should be continued for at least three procedures.

[0254] FEV1 is the amount of gas exhaled in a specified time (usually 1 second, i.e., FEV1) from the start of a forced vital capacity (see Quanjer et al. (1993). Eur.Respir.J.6, Suppl.16, pp.5-40. This literature is incorporated herein by reference in its entirety for all purposes.) FEV1 may also be expressed as a percentage of the predicted FEV1 (i.e., ppFEV1) obtained from a normal population, based on the patient's sex, height, and age, and sometimes race and weight.

[0255] In one embodiment, improvement in patient 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%, and 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%.

[0256] In one embodiment, the increase in FEV1 or ppFEV1 is the increase in FEV1 or ppFEV1 before administration of a bronchodilator. In another embodiment, the increase in FEV1 or ppFEV1 is the increase in FEV1 or ppFEV1 after administration of a bronchodilator.

[0257] In one embodiment, the patient's ppFEV1 is 80% or less before the administration period. In a further embodiment, the patient's ppFEV1 is 70% or less before the administration period. In a further embodiment, the patient's ppFEV1 is 60% or less before the administration period. In a further embodiment, the patient's ppFEV1 is 50% or less before the administration period. In another embodiment, the patient's ppFEV1 is 30% to 80%, 40% to 70%, or 50% to 60% before the administration period.

[0258] In another embodiment, improvement in the patient's lung function includes increasing the patient's FEV1 during the administration period 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 compared to the patient's FEV1 before the administration period. In one embodiment, the increase in FEV1 is the increase in FEV1 before administration of the bronchodilator. In another embodiment, the increase in FEV1 is the increase in FEV1 after administration of the bronchodilator.

[0259] In one embodiment, improvement in the patient's lung function is achieved by reducing the patient's FEF before the administration period. (25~75%) In comparison, the average forced expiratory flow rate (FEF) between 25% and 75% of the patient's FVC during the administration period. (25~75%) This includes increasing the FEF (also known as the maximum intermediate expiratory flow rate). (25~75%) Measurement depends on the effectiveness of FVC measurement and the level of expiratory effort. (25~75%) The exponent is the maximum sum of FEV1 and FVC, obtained by exhaling.

[0260] In one embodiment, the patient's FEF during the administration period (25~75%) An increase in the FEF of a patient during the administration period includes increasing it 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, the FEF of a patient during the administration period is increased by at least about 50%. (25~75%)The increase includes increases of approximately 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 50%, 15% to 50%, 20% to 50%, or 25% to 50%. In one embodiment, FEF (25~75%) The increase is due to pre-bronchodilator administration FEF (25~75%) This is an increase in FEF (25~75%) The increase is due to FEF after bronchodilator administration. (25~75%) It increases.

[0261] Total vital capacity (TLC) is the sum of vital capacity and residual volume, representing the total volume of air that can be held in the lungs. Total vital capacity (TLC) is divided into four volumes: tidal volume (V) T Maximum inhalation volume (IRV) is the amount of air inhaled or exhaled during normal, quiet breathing. Inspiratory reserve volume (IRV) is the maximum amount of air that can be inhaled after normal, quiet breathing. Expiratory reserve volume (ERV) is the maximum amount of air that can be exhaled after normal, quiet breathing. Residual volume (RV) is the amount of air remaining in the lungs after maximum exhalation. Vital capacity (VC) is the maximum amount of air that can be exhaled after maximum inhalation, where 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%.

[0262] The pulmonary diffusion capacity of carbon monoxide (DLCO), also known as a transport element, is a measure of the lungs' ability to transport 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 in this test because of its high affinity for hemoglobin (200-250 times that of oxygen). Since anemia can reduce DLCO, DLCO may be adjusted for hemoglobin levels. DLCO may also need to be adjusted for several other elements, such as carboxyhemoglobin and FiO. See Modi P, Cascella M, “Diffusing Capacity of The Lungs For Carbon Monoxide,” [Updated 2021 Mar 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan, which is incorporated herein by reference in its entirety for all purposes. In one embodiment, improvement in patient lung function includes increasing the patient's DLCO during the administration period compared to the patient's DLCO before the administration period. In another embodiment, DLCO is adjusted for hemoglobin levels, i.e., improvement in patient lung function includes increasing the patient's DLCO adjusted for hemoglobin during the administration period compared to the patient's DLCO adjusted for hemoglobin before the administration period. In yet another embodiment, improvement in patient lung function includes increasing the patient's predicted DLCO percentage (DLCO%) during the administration period compared to the patient's predicted DLCO percentage before the administration period. The predicted normal DLCO value may be calculated according to the equation established by Crapo et al., Am Rev Respir Dis. 123(2):185-9 (1981), or according to the equation established by Miller et al., Am Rev Respir Dis. 127(3):270-7 (1983), each of which is incorporated by reference in whole for all purposes. In a further embodiment, the patient's DLCO% prediction is adjusted for hemoglobin.

[0263] In one embodiment, improvement in lung function includes increasing the patient's DLCO or expected 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, improvement in lung function includes increasing the patient's DLCO or expected 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 a further embodiment, the patient's DLCO or expected DLCO% is adjusted relative to hemoglobin.

[0264] In one embodiment, the predicted DLCO% of the patient is 80% or less, 70% or less, 60% or less, or 50% or less before the administration period. In a further embodiment, the predicted DLCO% of the patient is adjusted for hemoglobin. In another embodiment, the predicted DLCO% of the patient is 30% to 80%, 40% to 70%, or 50% to 60% before the administration period. In a further embodiment, the predicted DLCO% of the patient is adjusted for hemoglobin.

[0265] In one embodiment of a method for treating PH provided herein, the method comprises extending the time to clinical deterioration compared to an untreated PH patient or a PH patient not treated with a compound of formula (I) or (II), wherein clinical deterioration is selected from the group consisting of death, hospitalization due to respiratory signs (e.g., dyspnea and / or deterioration of lung function indicated by a decrease in FVC, DLOC, and / or SpO2), a decrease of 10% or more in the proportion predicted FVC (ppFVC) over two consecutive measurements spaced 4 to 14 weeks apart compared to the patient's ppFVC before the administration period, lung transplantation, and a decrease of 15% or more in the walking distance of a 6-minute walk test (6MWT) over two consecutive measurements spaced at least 24 hours apart compared to the walking distance of a patient in a 6MWT before the administration period.

[0266] In one embodiment, the time to clinical worsening increases by approximately 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In another embodiment, the time to clinical worsening increases by at least approximately 1 day, at least approximately 3 days, at least approximately 1 week, at least approximately 2 weeks, at least approximately 3 weeks, at least approximately 4 weeks, at least approximately 5 weeks, or at least approximately 6 weeks. In yet another embodiment, the time to clinical worsening increases by approximately 20 to 100 days, 30 to 100 days, 20 to 75 days, 20 to 50 days, or 20 to 40 days. In yet another embodiment, the time to clinical worsening increases by at least 1 month, for example, approximately 1 to 6 months, 1 to 4 months, or 1 to 3 months.

[0267] In one embodiment, a method for treating PH provided herein includes increasing the patient's lobe volume and / or airway volume, as assessed by computed tomography (CT) during the administration period, compared to the patient's lobe volume and / or airway volume before the administration period. The CT may be performed via a chest CT scan during the respiratory cycle, so as to be able to generate a CT image at functional residual volume (FRC) and / or total vital capacity (TLC). In one embodiment, lobe volume is the volume of the lobe structure of the patient's respiratory system at TLC or FRC, and airway volume is the volume of the airway structure of the patient's respiratory system at TLC or FRC.

[0268] In one embodiment, the increase in the patient's 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 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%.

[0269] Additional Embodiments

[0270] Embodiment 1 (a) Formula (I) for approximately 0.1 wt% to approximately 5 wt%, [ka] In the formula, R 1 The compound is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl, or its enantiomer, diastereomer, or pharmaceutically acceptable salt. (b) Approximately 10 wt% to approximately 50 wt% leucine, The remainder (c) comprises a sugar selected from the group consisting of trehalose and mannitol, A dry powder composition in which (a), (b), and (c) together make up 100 wt%.

[0271] Embodiment 2 The dry powder composition according to Embodiment 1, wherein (a) is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0272] Embodiment 3 The dry powder composition according to Embodiment 1 or 2, wherein (a) is a compound of formula (I).

[0273] Embodiment 4 R 1 A dried powder composition according to any one of Embodiments 1 to 3, wherein the element is tetradecyl.

[0274] Embodiment 5 R 1 The dried powder composition according to Embodiment 4, wherein the linear tetradecyl is present.

[0275] Embodiment 6 R 1 A dried powder composition according to any one of Embodiments 1 to 3, wherein the compound is pentadecyl.

[0276] Embodiment 7 R 1The dried powder composition according to Embodiment 6, wherein the linear pentadecyl is present.

[0277] Embodiment 8 R 1 A dried powder composition according to any one of Embodiments 1 to 3, wherein the heptadecyl is present.

[0278] Embodiment 9 R 1 The dried powder composition according to Embodiment 8, wherein the linear heptadecyl is present.

[0279] Embodiment 10 R 1 A dried powder composition according to any one of Embodiments 1 to 3, wherein the compound is octadecyl.

[0280] Embodiment 11 R 1 The dried powder composition according to Embodiment 10, wherein the linear octadecyl is present.

[0281] Embodiment 12 R 1 A dried powder composition according to any one of Embodiments 1 to 3, wherein is hexadecyl.

[0282] Embodiment 13 R 1 The dried powder composition according to Embodiment 12, wherein the linear hexadecyl is present.

[0283] Embodiment 14 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 4.5 wt% of the total weight of the dry powder composition.

[0284] Embodiment 15 The dry powder composition according to Embodiment 14, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 4.5 wt% of the total weight of the dry powder composition.

[0285] Embodiment 16 The dry powder composition according to Embodiment 14 or 15, wherein the compound of formula (I) is present in an amount of about 0.1 wt% to about 4.5 wt% of the total weight of the dry powder composition.

[0286] Embodiment 17 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0287] Embodiment 18 The dry powder composition according to Embodiment 17, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0288] Embodiment 19 The dry powder composition according to Embodiment 17 or 18, wherein the compound of formula (I) is present in an amount of about 0.1 wt% to about 4 wt% of the total weight of the dry powder composition.

[0289] Embodiment 20 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0290] Embodiment 21 The dry powder composition according to Embodiment 20, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0291] Embodiment 22 The dry powder composition according to Embodiment 20 or 21, wherein the compound of formula (I) is present in an amount of about 0.1 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0292] Embodiment 23 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 3 wt% of the total weight of the dry powder composition.

[0293] Embodiment 24 The dry powder composition according to Embodiment 23, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.1 wt% to about 3 wt% of the total weight of the dry powder composition.

[0294] Embodiment 25 The dry powder composition according to Embodiment 23 or 24, wherein the compound of formula (I) is present in an amount of about 0.1 wt% to about 3 wt% of the total weight of the dry powder composition.

[0295] Embodiment 26 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of 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.

[0296] Embodiment 27 The dry powder composition according to Embodiment 26, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of 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.

[0297] Embodiment 28 The dry powder composition according to Embodiment 26 or 27, wherein the compound of formula (I) is present in an amount of 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.

[0298] Embodiment 29 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 1 wt% to about 2 wt% of the total weight of the dry powder composition.

[0299] Embodiment 30 The dry powder composition according to Embodiment 29, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1 wt% to about 2 wt% of the total weight of the dry powder composition.

[0300] Embodiment 31 The dry powder composition according to Embodiment 29 or 30, wherein the compound of formula (I) is present in an amount of about 1 wt% to about 2 wt% of the total weight of the dry powder composition.

[0301] Embodiment 32 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 1.2 wt% to about 1.8 wt% of the total weight of the dry powder composition.

[0302] Embodiment 33 The dry powder composition according to Embodiment 32, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1.2 wt% to about 1.8 wt% of the total weight of the dry powder composition.

[0303] Embodiment 34 The dry powder composition according to Embodiment 32 or 33, wherein the compound of formula (I) is present in an amount of about 1.2 wt% to about 1.8 wt% of the total weight of the dry powder composition.

[0304] Embodiment 35 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0305] Embodiment 36 The dry powder composition according to Embodiment 35, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0306] Embodiment 37 The dry powder composition according to Embodiment 35 or 36, wherein the compound of formula (I) is present in an amount of about 1 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0307] Embodiment 38 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 1.4 wt% to about 1.6 wt% of the total weight of the dry powder composition.

[0308] Embodiment 39 The dry powder composition according to Embodiment 38, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1.4 wt% to about 1.6 wt% of the total weight of the dry powder composition.

[0309] Embodiment 40: The dry powder composition according to Embodiment 38 or 39, wherein the compound of formula (I) is present in an amount of about 1.4 wt% to about 1.6 wt% of the total weight of the dry powder composition.

[0310] Embodiment 41 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 1 wt% of the total weight of the dry powder composition.

[0311] Embodiment 42 The dry powder composition according to Embodiment 41, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1 wt% of the total weight of the dry powder composition.

[0312] Embodiment 43 The dry powder composition according to Embodiment 41 or 42, wherein the compound of formula (I) is present in an amount of about 1 wt% of the total weight of the dry powder composition.

[0313] Embodiment 44 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 1.5 wt% of the total weight of the dry powder composition.

[0314] Embodiment 45 The dry powder composition according to Embodiment 44, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5 wt% of the total weight of the dry powder composition.

[0315] Embodiment 46 The dry powder composition according to Embodiment 44 or 45, wherein the compound of formula (I) is present in an amount of about 1.5 wt% of the total weight of the dry powder composition.

[0316] Embodiment 47 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.5 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0317] Embodiment 48 The dry powder composition according to Embodiment 47, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0318] Embodiment 49 The dry powder composition according to Embodiment 47 or 48, wherein the compound of formula (I) is present in an amount of about 0.5 wt% to about 1.5 wt% of the total weight of the dry powder composition.

[0319] Embodiment 50 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.7 wt% to about 1.3 wt% of the total weight of the dry powder composition.

[0320] Embodiment 51 The dry powder composition according to Embodiment 50, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.7 wt% to about 1.3 wt% of the total weight of the dry powder composition.

[0321] Embodiment 52 The dry powder composition according to Embodiment 50 or 51, wherein the compound of formula (I) is present in an amount of about 0.7 wt% to about 1.3 wt% of the total weight of the dry powder composition.

[0322] Embodiment 53 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.8 wt% to about 1.2 wt% of the total weight of the dry powder composition.

[0323] Embodiment 54 The dry powder composition according to Embodiment 53, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.8 wt% to about 1.2 wt% of the total weight of the dry powder composition.

[0324] Embodiment 55 The dry powder composition according to Embodiment 53 or 54, wherein the compound of formula (I) is present in an amount of about 0.8 wt% to about 1.2 wt% of the total weight of the dry powder composition.

[0325] Embodiment 56 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 0.9 wt% to about 1.1 wt% of the total weight of the dry powder composition.

[0326] Embodiment 57 The dry powder composition according to claim 56, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.9 wt% to about 1.1 wt% of the total weight of the dry powder composition.

[0327] Embodiment 58 The dry powder composition according to Embodiment 56 or 57, wherein the compound of formula (I) is present in an amount of about 0.9 wt% to about 1.1 wt% of the total weight of the dry powder composition.

[0328] Embodiment 59 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 1.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0329] Embodiment 60 The dry powder composition according to Embodiment 59, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0330] Embodiment 61 The dry powder composition according to Embodiment 59 or 60, wherein the compound of formula (I) is present in an amount of about 1.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0331] Embodiment 62 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 2.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0332] Embodiment 63 The dry powder composition according to Embodiment 62, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 2.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0333] Embodiment 64 The dry powder composition according to Embodiment 62 or 63, wherein the compound of formula (I) is present in an amount of about 2.5 wt% to about 3.5 wt% of the total weight of the dry powder composition.

[0334] Embodiment 65 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 2.7 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0335] Embodiment 66 The dry powder composition according to Embodiment 65, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 2.7 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0336] Embodiment 67 The dry powder composition according to Embodiment 65 or 66, wherein the compound of formula (I) is present in an amount of about 2.7 wt% to about 3.3 wt% of the total weight of the dry powder composition.

[0337] Embodiment 68 A dry powder composition according to any one of Embodiments 1 to 13, wherein the compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 2.8 wt% to about 3.2 wt% of the total weight of the dry powder composition.

[0338] Embodiment 69 The dry powder composition according to Embodiment 68, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2.8 wt% to about 3.2 wt% of the total weight of the dry powder composition.

[0339] Embodiment 70 The dry powder composition according to Embodiment 68 or 69, wherein the compound of formula (I) is present in an amount of about 2.8 wt% to about 3.2 wt% of the total weight of the dry powder composition.

[0340] Embodiment 71 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0341] Embodiment 72 The dry powder composition according to Embodiment 71, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0342] Embodiment 73 The dry powder composition according to Embodiment 71 or 72, wherein the compound of formula (I) is present in an amount of about 2.9 wt% to about 3.1 wt% of the total weight of the dry powder composition.

[0343] Embodiment 74 A dry powder composition according to any one of Embodiments 1 to 13, wherein a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of about 3 wt% of the total weight of the dry powder composition.

[0344] Embodiment 75 The dry powder composition according to Embodiment 74, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3 wt% of the total weight of the dry powder composition.

[0345] Embodiment 76 The dry powder composition according to Embodiment 74 or 75, wherein the compound of formula (I) is present in an amount of about 3 wt% of the total weight of the dry powder composition.

[0346] Embodiment 77 A dried powder composition according to any one of Embodiments 1 to 76, wherein leucine is present in an amount of about 12 wt% to about 42 wt% of the total weight of the dried powder composition.

[0347] Embodiment 78 The dried powder composition according to Embodiment 77, wherein leucine is present in an amount of about 15 wt% to about 40 wt% of the total weight of the dried powder composition.

[0348] Embodiment 79 The dry powder composition according to Embodiment 78, wherein leucine is present in an amount of about 18 wt% to about 33 wt% of the total weight of the dry powder composition.

[0349] Embodiment 80 The dried powder composition according to Embodiment 79, wherein leucine is present in an amount of about 20 wt% to about 33 wt% of the total weight of the dried powder composition.

[0350] Embodiment 81 The dried powder composition according to Embodiment 80, wherein leucine is present in an amount of about 25 wt% to about 33 wt% of the total weight of the dried powder composition.

[0351] Embodiment 82 The dried powder composition according to Embodiment 81, wherein leucine is present in an amount of about 27 wt% to about 33 wt% of the total weight of the dried powder composition.

[0352] Embodiment 83 The dried powder composition according to Embodiment 82, wherein leucine is present in an amount of about 27 wt% to about 31 wt% of the total weight of the dried powder composition.

[0353] Embodiment 84 The dried powder composition according to Embodiment 83, wherein leucine is present in an amount of about 27 wt% to about 30 wt% of the total weight of the dried powder composition.

[0354] Embodiment 85 The dry powder composition according to Embodiment 84, wherein leucine is present in an amount of about 28 wt% to about 30 wt% of the total weight of the dry powder composition.

[0355] Embodiment 86 The dry powder composition according to Embodiment 80, wherein leucine is present in an amount of about 20 wt% of the total weight of the dry powder composition.

[0356] Embodiment 87 The dry powder composition according to Embodiment 80, wherein leucine is present in an amount of about 30 wt% of the total weight of the dry powder composition.

[0357] Embodiment 88 A dried powder composition according to any one of Embodiments 1 to 87, wherein the sugar is trehalose.

[0358] Embodiment 89 A dried powder composition according to any one of Embodiments 1 to 87, wherein the sugar is mannitol.

[0359] Embodiment 90 A dry powder composition according to any one of Embodiments 1 to 13, comprising (a) about 1.5 wt% of a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, and (b) about 29.3 wt% of leucine and the remainder (c) mannitol.

[0360] Embodiment 91 The dry powder composition according to Embodiment 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 (c) mannitol.

[0361] Embodiment 92 A dry powder composition according to Embodiment 90 or 91, comprising (a) about 1.5 wt% of a compound of formula (I), (b) about 29.3 wt% of leucine, and the remainder (c) mannitol.

[0362] Embodiment 93 A dry powder composition according to any one of Embodiments 1 to 13, comprising (a) about 1 wt% of a compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, and (b) about 29.3 wt% of leucine and the remainder (c) mannitol.

[0363] Embodiment 94 The dry powder composition according to Embodiment 93, comprising (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 (c) mannitol.

[0364] Embodiment 95 A dry powder composition according to Embodiment 93 or 94, comprising (a) about 1 wt% of a compound of formula (I), (b) about 29.3 wt% of leucine, and the remainder (c) mannitol. [Examples]

[0365] The present invention will be further described by reference to the following embodiments. However, it should be noted that these embodiments, as with the embodiments described above, are illustrative examples and should not be construed as limiting the scope of the present invention in any way.

[0366] The following examples relate to two different treprostinyl palmityl inhalation powder (TPIP) formulations (TPIP-A and TPIP-B). The compositions of TPIP-A and TPIP-B, expressed as weight ratios, the target weight percentages calculated based on the weight ratios, and the actual weight percentages of components from a typical batch of each formulation are summarized in Tables D and E, respectively. [Table 4] [Table 5]

[0367] Example 1: Preparation, characterization, and encapsulation of an inhalable treprostinyl palmityl dry powder formulation. This example describes the production of TPIP-B by spray drying and encapsulation. This example also describes the characterization of TPIP-B in parallel with TPIP-A in terms of moisture content, residual solvent, particle morphology, particle size distribution, and thermal properties as measured by scanning electron microscopy (SEM). 1. Spray drying manufacturing of TPIP-B

[0368] Spray-dried TPIP-B was produced using a BLD-200 spray dryer with a drying gas flow rate capacity of 200 kg / hour. Specifically, the spray solutions were prepared according to the compositions shown in Table 1. [Table 6]

[0369] The composition of the final spray-dried TPIP-B is shown in Table 2. [Table 7]

[0370] The manufacturing process for spray-dried TPIP-B is summarized in Table 3. [Table 8]

[0371] 2. Analytical Characterization and Stability Testing of TPIP-B TPIP-B and TPIP-A were manufactured, packaged in high-density polyethylene bottles, sealed in low-density polyethylene bags with a desiccant, then placed in foil bags and sealed, and stored at 2–8°C. Subsequently, initial analytical characterization and stability tests were performed. Initial analytical characterization included moisture content, residual solvent, particle morphology using SEM, particle size distribution, and thermal properties. The methodology for the analytical characterization described above is described in U.S. Patent 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 for 1, 3, and 6 months under storage conditions of 25°C / 60%RH and 40°C / 75%RH, based on changes from the initial point in time in thermal properties, moisture content, particle size distribution, and particle morphology.

[0372] Table 4 summarizes the results of the initial characterization of TPIP-B and TPIP-A, showing that TPIP-B and TPIP-A have similar characteristics as measured. [Table 9]

[0373] Tables 5A, 5B, and 5C show the results of stability tests at 1, 3, and 6 months, respectively. The results indicate that TPIP-B and TPIP-A had similar stability profiles. [Table 10] [Table 11] [Table 12]

[0374] 3. Powder packaging Approximately 7.5 mg of spray-dried TPIP-B was filled into size #3 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 a desiccant, then sealed in foil bags, and stored at 2–8°C. The fine particle dose (FPD) and MMAD of the dried powder formulation from the stored capsules were then determined by NGI. The FPD and MMAD results are shown in Table 6. Furthermore, the amount of treprostinyl palmityl per capsule was determined to be 114.3 mcg. [Table 13]

[0375] Example 2: Pharmacokinetic evaluation of TPIP-B and TPIP-A in Sprague-Dawley rats material and method A. species These PK tests used male Sprague-Dawley rats weighing 300–350 g. The exact weight of the rats was recorded on the day of the experiment. B. Identification and randomization of the trial system 1. The animals arrived at the site at least three days before the planned experiment. 2. Upon arrival, the animals were identified in accordance with CCAC guidelines. 3. All animal rearing and maintenance of rearing equipment were recorded and the documents were kept at the testing facility. 4. The principal investigator randomly assigned animals before the experiment and recorded each animal's ID number. C. Drug administration and dosage selection 170 mg of TPIP-B or TPIP-A was loaded into a Vilnius Aerosol Generator (VAG), and the Vilnius Aerosol Generator was connected to a 12-port rodent nasal inhalation system (CH Technologies, Westwood, NJ, USA) located at the bottom of the tower. The airflow through the nasal chamber was set to 7 L / min. Material from the VAG was delivered at an output voltage of 1.0 volt, and the aerosol was turned off when all material had aerosolized, which took approximately 40 minutes. The actual duration of aerosolization was recorded for each exposure. A fiberglass filter was placed above one of the exposure ports and connected to a vacuum source for 5 minutes with a vacuum flow of 0.5 L / min (starting 5 minutes after the start of aerosolization and ending 10 minutes after). A Mercer-style cascade impactor was placed above one of the exposure ports and connected to a vacuum source for 5 minutes with a vacuum flow of 0.5 L / min. After administration of the test substance (i.e., TPIP-B or TPIP-A), the animals were euthanized at different time points for the collection of various biological samples (bronchobelloveolar lavage fluid, lungs, spleen, liver, kidneys, heart, stomach, and plasma) (Tables 7 and 8). The tower, nasal restraint tube, and all connecting tubes were washed between experiments with a 0.5% sodium dodecyl sulfate (SDS) aqueous solution, tap water, and distilled water. Powder in the VAG cup was removed, and all parts of the VAG system were cleaned by blowing air. D. Sample Analysis Powder collected from filters using a nasal inhalation tower and from Mercer-style cascade impactors was analyzed. The concentrations of treprostinyl palmityl (TP) and treprostinyl (TRE) in the lungs, liver, heart, kidneys, spleen, stomach, BALC, and BALF, as well as in plasma, were analyzed by LC-MS / MS. TP and TRE values ​​reported as below the level of quantification (BLQ) were assigned a value of zero, respectively. E. Experimental design and experimental procedure 1. Experimental Design Thirty-six rats were exposed to TPIP-A and thirty-six rats were exposed to TPIP-B. The rats were accustomed to the nasal cone chamber by placing them in the chamber once daily for three consecutive days, increasing the duration each time (starting at 5 minutes, increasing to 15 minutes, and ending at 20 minutes). On the day of administration, the first cohort of nine rats was placed in a nasal cone restraint chamber connected to a 12-port nasal-only inhalation chamber. The test substance was delivered by VAG at an airflow of 7 L / min, and the actual dose duration was recorded. A glass fiber filter was placed over 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 the start of aerosolization and ending 10 minutes later). A Mercer-style cascade impactor was placed over one of the exposure ports and connected to a vacuum source at a vacuum flow of 0.5 L / min for 5 minutes. After sampling, the impactor was disassembled and the aerosol was collected at each stage with 4 mL (4 × 1 mL) of 75% IPA. Collection using the Mercer Cascade Impactor was performed in cohorts 2 and 4. This experiment was performed twice, with each cohort containing nine rats. The following day, cohorts 3 and 4 were exposed to the test substance. At the end of compound exposure, blood and tissue samples were obtained according to the schedule outlined in Table 7. IPD autopsy times were recorded. At each time point, the rats that had completed the final time point were anesthetized by inhaling 2% isoflurane with pure oxygen. The rats were weighed. Approximately 3.0 mL of blood sample was obtained by cardiac puncture. The K2-EDTA tube was centrifuged at 3,000 rpm at 4°C for 10 minutes. Approximately 0.5 mL of plasma was dispensed into three 1 mL tubes and labeled with the test number, animal identification, dose group, and time point. Plasma samples were flash-frozen before drug concentration analysis and stored frozen (-80°C). Animals were bled by transecting the abdominal aorta. For BAL fluid collection in cohorts 3 and 4, the trachea was isolated and a 14G InSyte catheter was inserted towards the lung, just above the thoracic inlet, ensuring it was positioned above the keel. A syringe containing 2 mL of sterile PBS was flowed into the lung. The chest was gently massaged four times by applying intrathoracic pressure, after which the BAL fluid was returned to the syringe. The fluid was repeatedly washed with another 2 mL of sterile PBS and transferred to the same Eppendorf tube.The BALF solution was centrifuged, the supernatant was removed, and stored at -80°C. The last drop of BALF (to remove as much as possible) was discarded. The cell pellet was stored, flash-frozen, and stored at -80°C. The lungs, spleen, kidneys, heart, and liver lobes were collected, cleaned to remove excess tissue, and the stomach was dissected, opened, and emptied of solids. All organs were weighed, placed in 5.0 mL Eppendorf tubes, flash-frozen, and stored at -80°C for subsequent analysis of lung drug concentrations. [Table 14] F. Calculation of delivered drug dose based on filtered data The total dose and pulmonary delivery dose were calculated using the equation described in Alexander DJ et al. in Association of Inhalation Toxicologists (AIT) Working Party Recommendation for Standard Delivered Dose Calculation and Expression in Non-Clinical Aerosol Inhalation Toxicology Studies with Pharmaceuticals Inhal.Tox.20:p1179-1189, 2008, which is derived from the TP concentration (filter result) in a nasal inhalation tower, respiratory volume per minute, exposure time, deposition rate, and body weight.

number

[0376] result [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26]

[0377] This study evaluated the BAL (liquid and cellular) pharmacokinetics of plasma, tissue, and two different formulations, TPIP-A and TPIP-B. Exposure to TPIP-A and TPIP-B was well tolerable 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). C max The corresponding lung TPeq concentrations at 0.5 hours were mean 2768 and 2264 ng / g in lung tissue, respectively (Table 10). Because BAL extraction was performed in cohorts 3 and 4 (Table 10), the lung TPeq levels in cohorts 3 and 4 exposed to TPIP-B and TPIP-A were 1217 and 1084 ng / g, respectively, which were lower than in the comparative cohorts 1 and 2.

[0378] Over a 24-hour period, the peak pulmonary concentrations (Cmax) of TP, TRE, and TPeq occurred 0.5 hours after exposure to TPIP-B and TPIP-A in cohorts 1–2 (Table 11). Furthermore, a single exponential decrease in pulmonary drug concentrations was observed during this 24-hour period (Table 9 and Figures 1–3). The TPeq lung profile in cohorts 3–4 using TPIP-B differed slightly, as Cmax occurred 3 hours after exposure, and TRE Cmax also appeared 3 hours after exposure to TPIP-A (Table 11). This difference can be explained by BAL performed in these rats. In general, TPIP-B and TPIP-A have the same pharmacokinetic profile.

[0379] Plasma concentrations of TRE after inhalation of TPIP-A and TPIP-B were highest 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).

[0380] The pharmacokinetic profiles of TPIP-A and TPIP-B were also evaluated by bronchoalveolar lavage (BAL). TP, TRE, and TPeq concentrations were analyzed in cells and fluids collected from BAL after cell removal. Except for cohorts 3–4 exposed to TPIP, peak concentrations were found in cells and fluids at 0.5 hours for both formulations, and TRE Cmax was observed at 3 hours post-administration (Tables 15 and 17, and Figures 5–10).

[0381] In summary, the PK profiles of inhaled TPIP-A and TPIP-B showed similar drug profiles, with the highest concentrations of TPeq in the lungs and TRE in plasma observed up to 30 minutes, and a single exponential decline in drug levels over 24 hours. Several exceptions were observed for cohorts 1–2 and 3–4 exposed to TPIP-B. Plasma TRE concentrations increased slightly at 6 hours in cohorts 1–2, and lung TPeq increased slightly at 3 hours in cohorts 3–4.

[0382] Example 3: Efficacy of different doses of TPIP-B in telemetry-implanted rats undergoing hypoxia challenge. material and method A. species Male Sprague-Dawley rats weighing 300-500g at the time of transplantation using a dual-pressure telemetry implantation device (TRM-54-PP) were used at the start of the study. The rats' exact weight was recorded on the day of the experiment. B. Identification and randomization of the trial system 1. The animals arrived at the site at least three days before the planned experiment. 2. Upon arrival, the animals were identified in accordance with CCAC guidelines. 3. All animal rearing and maintenance of rearing equipment were recorded and the documents were kept at the testing facility. 4. The principal investigator randomly assigned animals before the experiment and recorded each animal's ID number. C. Drug administration and dosage selection TPIP-B was administered using a Vilnius aerosol generator (VAG). The VAG was connected to a 12-port rodent nasal inhalation system (CH Technologies, Westwood, NJ, USA) located at the bottom of the tower. Airflow from the top of the nasal inhalation chamber, connected to the bottom, was introduced into the VAG at a flow rate of 7 L / min. TPIP-B was introduced into the VAG chamber in amounts of 25 mg, 50 mg, 90 mg, and 170 mg for aerosolization of the material at VAG voltages of 0.125, 0.25, 0.5, and 1.0 volts (V), respectively. The aerosol was turned off when all material had been aerosolized and discharged from the VAG chamber, or when no drug was visible in the nasal inhalation outlet port. The time for complete aerosolization of the material was measured. The nasal inhalation tower, tubing, and other materials used in the dry powder process were cleaned by sequentially running them through a 0.5% sodium dodecyl sulfate (SDS) aqueous solution, tap water, and distilled water. After use, any remaining powder inside the aerosol generator was removed using blown air in a fume hood equipped with a HEPA filter. Following thorough cleaning of the tower and VAG, the following experiments were conducted. D. Sample Analysis Filters collected from a nasal inhalation tower were used for C16TR analysis by high-performance liquid chromatography (HPLC) and charged particle detector (CAD). Lung and plasma samples were also analyzed for C16TR and TRE concentrations in the lungs and plasma using LC-MS / MS. Values ​​of C16TR and TRE reported as below the level of quantification (BLQ) were assigned a value of zero, respectively. E. Acquisition System Networked personal computers running Microsoft Windows Office 2016 were used for data acquisition. Data on systemic arterial blood pressure (SAP) and RVPP were acquired at a frequency of 500 Hz / second using a Powerlab acquisition system (AD instrument), with Labchart software used. All records were stored on a server for further analysis. Data were recorded every minute, and results were presented within a normoxic-hypoxic-northoxic period. To avoid misinterpretation of data due to animal movement or probe position relative to the ventricular wall, typical pulses were manually selected for 3-4 consecutive pulses of both RVPP and SAP. Normal right ventricular pressure has a nearly square, spike-free waveform. Good signals were acquired within the last minute of the 10-minute duration of each of the three steps (northoxic-hypoxic-northoxic). Each of these values ​​was transcribed back into an Excel file containing data for individual rats at each point in time before drug exposure (baseline data) and at different points in time after drug exposure. F. Experimental design and experimental procedure 1. Experimental Design These studies used seven (7) telemetry-transplanted male Sprague-Dawley rats. For each dose, three (3) telemetry-transplanted rats were used for efficacy evaluation, and seven (7) PK rats were used for PK determination. In each experiment, the inhaled drug content was sampled by connecting a filter to the remaining port of a nasal-only inhalation chamber. Hypoxic challenges for telemetry-transplanted rats, as well as blood and tissue sampling from PK rats, are shown in Tables 19 and 20. In PK rats, blood samples were taken from the jugular vein, blood was collected by cardiac puncture at the final point, and lungs were collected, surrounding tissue removed, and weight measured. Plasma and lungs were stored at -80°C and filtered at 4°C. All telemetry-transplanted rats were acclimatized to the hypoxic exposure chamber, and rats dedicated to the inhalation studies (both telemetry-transplanted rats and PK rats) were acclimatized to a nasal-only inhalation tower once daily for three consecutive days, with the duration increasing each time (starting at 5 minutes and ending at 20 minutes at the end of the acclimatization period). [Table 27] [Table 28] 2. Normal / Hypoxic Challenge in Telemetry Transplanted Rats Each rat, housed individually in an 8 x 16 x 8 inch cage, was placed on top of a telemetry receiver (smart pad). A custom-made lid was placed on top of the cage, equipped with a port providing air inflow, another exhaust port for expelling air, and an oxygen probe (Vernier, Beaverton, OR, USA), and the oxygen concentration inside the cage was continuously measured. A separate mixing box was 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 at a flow rate of approximately 35 L / min to four separate chambers housing the telemetry-implanted rats. The rats were exposed to room air breathing, and cardiovascular data were collected for 10 minutes. Subsequently, a three-way stopcock was switched, directing the hypoxic gas from the mixing box towards the cages housing the rats. The hypoxic air then flowed through the inflow port, replacing the normal oxygen air in the rat cages. It took approximately 2 minutes for the rats to equilibrate until they were fully exposed to the 10% O2 / 90% N2 gas mixture. 。 Cardiovascular parameters were continuously recorded during a 10-minute exposure to hypoxic gas. At the end of this 10-minute hypoxic challenge, the inflow of hypoxic air from the mixing chamber was stopped, the sealed lid was opened, and the rats were returned to breathing normal oxygen gas. Cardiovascular parameters were continuously recorded during a 10-minute recovery period with normal oxygen following the hypoxic exposure. After collecting data on normal oxygen / hypoxic / normal oxygen exposure, the rats were returned to their enclosures. All rats were given free access to food and water after drug and hypoxic exposure. 3. Inhalation of TPIP-B Three telemetry-transplanted rats and seven PK rats were exposed to inhaled TPIP-B at voltages of 0.125, 0.25, 0.5, and 1.0 V using a nasal cone chamber connected to a 12-port nasal-only inhalation chamber (CH Technologies). Airflow was circulated through the nasal-only chamber using an air inflow at a flow rate of 7 L / min. A fiberglass filter was connected to one of the exposed ports during the test period. Airflow sampling was performed using a vacuum source established at 0.5 L / min for 5 minutes, starting 5 minutes after the start of aerosolization and ending at 10 minutes. Air circulation through the nasal-only inhalation tower entered at the bottom and exited through a port at the top of the tower. G. Method 1. These three trials used a total of seven (7) male Sprague-Dawley rats that had already received dual-pressure telemetry implants. In these experiments, three telemetry-implanted rats were used at 0.125, 0.25, 0.5V, and 1V. In addition, a cohort of seven rats was used for PK determination in each trial. A filter was connected to the remaining one port in each trial. 2. Telemetry-transplanted rats were subjected to a normoxic / hypoxic / northoxic challenge with cardiopulmonary responses (RVPP and SAP) 24 hours prior to exposure to the test substance, and measurements were taken continuously during this procedure. This procedure was repeated three times, performed for 1, 6, and 12 hours per day, and the mean response to these three determinations was used to represent the baseline, which is the pre-drug response to hypoxic conditions. 3. After a baseline hypoxic response was obtained, exposure to the test substance was carried out. Rats were exposed to TPIP-B until no powder remained in the VAG cup. Cardiovascular responses to the normoxic / hypoxic / return-normox challenge were performed as planned in Table 21. Blood and lung samples were collected from PK-dedicated rats at the time points shown in Table 20. 4. The filters were analyzed. 5. For blood collection, 0.5 mL of blood was collected 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. 6. Plasma was dispensed into 1 mL tubes, flash-frozen, and stored at approximately -80°C before analysis. 7. Rats that had undergone the final phase were anesthetized with 2% isoflurane inhaled with pure oxygen, and approximately 3.0 mL of blood sample was obtained by cardiac puncture. The K2-EDTA tube was centrifuged at 900 × g for 10 minutes at 4°C. 8. Prior to drug concentration analysis, the plasma was separated into three 1 mL tubes and stored at approximately -80°C. 9. The left and right lungs were collected, weighed, and flash-frozen for subsequent analysis of lung drug concentrations, and stored at -80°C.

[0383] result [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36]

[0384] This study evaluated the efficacy of different doses of DSPE-PEG free TPIP (TPIP-B). Experiments were conducted in rats adjusted using telemetry probes implanted in the right ventricle and descending aorta, and increases in RVPP and changes in SAP induced by exposure to acute hypoxia were measured. Exposure to TPIP-B was well tolerable and did not result in any deaths.

[0385] All doses of TPIP-B inhibited the ΔRVPP response to hypoxia over 24 hours. At the highest dose of 138 μg / kg, statistically significant inhibition (p<0.05) was observed over 24 hours, except for 12 hours, with an inhibitory effect of 40%–70%. A slightly lower dose of TPIP-B, 57 μg / kg, increased activity over time, reaching a maximum effect (71% inhibition) at 24 hours. The lowest doses of 23 and 6 μg / kg showed similar drug effects, with maximum activity (approximately 65% ​​inhibition) at 1 hour, decreasing to 57% and 40%, respectively, at 24 hours.

[0386] As the dose of TPIP-B increased, there was a dose-dependent increase in treprostinyl palmityl equivalent (C16TReq) concentration in the lungs and TRE concentration in plasma. Lung C16TReq concentration was highest at 0.5 hours and decreased by 94–97% over 24 hours with each dose of TPIP-B. Plasma TRE concentration was highest at 0.5 hours with the total dose of TPIP-B, decreased exponentially over 12 hours, and decreased by 89–92% over 24 hours.

[0387] In summary, efficacy studies in telemetry-implanted rats undergoing hypoxia challenge demonstrated that the highest dose of TPIP-B (138 μg / kg) showed a statistically significant inhibition of the 24-hour hypoxia-induced increase in RVPP. Lower doses of TPIP-B were less effective, exhibiting activity over 24 hours but not statistically significant at any time point.

[0388] Example 4: Evaluation of TPIP-B for coughing and ventilation in guinea pigs In this example, TPIP-B was evaluated for its effects on cough, changes in ventilation, and changes in Penh in conscious male guinea pigs. Penh is a dimensionless index of changes in respiratory pattern commonly observed during bronchoconstriction (see Chong BTY 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 Penh parameter. Exp. and Toxicol. Pathol. 57, 13-20). A. method 1. The experiment was conducted with male Hartley guinea pigs (230–430 g). After three days of acclimatization to the experimental environment, the guinea pigs were placed in a whole-body plethysmograph using established techniques for measuring ventilation (tidal volume, respiratory rate, and minute ventilation), penh, and cough. Cough was measured from plethysmographic recordings showing large inhalations followed by large exhalations, and confirmed by manual observation, video recording, and cough sounds. Ventilation, penh, and cough data were measured during a 15-minute baseline period prior to exposure to dry powder aerosol. 2. The administration of the test substance in this study was achieved by aerosolizing a specific amount of dry powder using a Vilnius Aerosol Generator (VAG) (CH Technologies, Westwood, NJ) at a specific voltage output and microdust range, followed by 120 minutes of observation after administration of the aerosolized compound. Approximately 110 mg of TPIP-B placebo was administered at 1 volt, 2500 mg / m³ until the powder was completely consumed. 3The microdust was aerosolized with the specified microdust range (Table 29). TPIP-B was then administered under similar conditions using approximately 110 mg or 200 mg. To reduce exposure time, the 200 mg dose was also adjusted to 25 g / m². 3 The substance was administered using a 0.3-volt output in the microdust range. To standardize the duration of exposure to the test substance, an excess of TPIP-B ranging from approximately 200 mg to 450 mg was administered for 15 minutes at increasing VAG outputs of 0.15 volts, 0.3 volts, and 0.5 volts, at a rate of 25 g / m². 3 Additional experiments were conducted to aerosolize within the microdust range. Finally, to compare TPIP-A and TPIP-B, approximately 250 mg to 400 mg of TPIP-A was applied at 25 g / m³ at 0.15 volts and 0.5 volts. 3 The samples were delivered for 15 minutes within the microdust range (Table 29). 3. Air for aerosol delivery for all experiments was supplied by an air compressor with a total inflow of 5.5 L / min of humidified air (30% RH). 4.5 L / min of air was combined with 1 L / min of humidified air to disperse the aerosols, facilitate aerosol delivery to the plethysmograph, and minimize the problem of static adhesion. Ventilation, pen (penh), and cough were measured before, during, and after exposure to the test substance. An 8 L / min vacuum suction was established at the bottom of the plethysmograph so that air and aerosols entered the top of the system and exited from the bottom. A separate 0.5 L / min vacuum source was also connected to a glass fiber filter assembly attached to a port in the plethysmograph to sample aerosol concentrations in TPIP-B placebo (containing 70 wt% mannitol and 30 wt% leucine), TPIP-B, and TPIP-A aerosols. Excluding the TPIP-B placebo, filter samples from TP-B and TPIP-A were analyzed for TP(C16TR) sample content using HPLC and CAD to determine TP aerosol concentrations. Filter sampling was maintained for the entire duration of the study, i.e., 135 minutes, but TP aerosol concentrations in the plethysmograph were calculated using either filter exposure time or drug delivery time (the entire period from drug delivery to depletion at the start of the study, and subsequently adjusted to a 15-minute drug delivery time in additional studies). 4. The total TP delivery dose by nasal inhalation in guinea pigs was calculated using the following equation, assuming a deposition factor (DF) of 100%:

number

[0389] Exposure to TPIP-B placebo, TPIP-B, and TPIP-A was well tolerable and did not result in any deaths. In the initial series of experiments in which the test substance was aerosolized until all of the substance was eliminated, aerosolization of 100–115 mg of TPIP-B placebo for 32–45 minutes did not induce coughing in any of the four guinea pigs tested. Aerosolization of 89–105 mg of TPIP-B for 23–32 minutes (average total inhaled dose delivered = 5.7 μg / kg body weight) did not induce coughing in two of the guinea pigs tested, while a TPIP-B trial increasing the amount of aerosolized drug to 184–201 mg (average total inhaled dose delivered = 69.1 μg / kg body weight, exposure time ranging from 62–74 minutes) caused coughing in one of the three guinea pigs. However, aerosolization of 197 mg of TPIP-B (average total inhaled dose = 69.2 μg / kg body weight) over 19 minutes did not induce coughing in the one guinea pig tested.

[0390] In a second series of tests in which an excess of the test substance was aerosolized for a fixed period of 15 minutes, aerosolization of 102-111 mg of TPIP-B (average total inhaled dose = 17.7 μg / kg body weight) caused coughing in one of the five guinea pigs tested. In the TPIP-B test, where the amount of aerosolized drug was increased to 115-139 mg (average total inhaled dose = 43.2 μg / kg body weight), the two guinea pigs tested did not cause coughing. However, in the TPIP-B test, where the amount of aerosolized drug was further increased to 211-457 mg (average total inhaled dose = 153.2 μg / kg body weight), coughing occurred in three of the four guinea pigs (Table 29).

[0391] In summary, the results of this study show that coughing was observed at a threshold inhalation dose of 17.7 μg / kg for TPIP-B. For comparison, 90-98 mg of TPIP-A was aerosolized for 15 minutes (mean total inhalation dose delivered = 8.3 μg / kg body weight), but neither of the two guinea pigs tested developed coughing. Similarly, in a TPIP-test with an increased aerosolized dose of 322 mg (mean total inhalation dose delivered = 185.4 μg / kg body weight), one guinea pig tested did not develop coughing. However, based on previous studies, coughing was observed at a threshold inhalation dose of 12.8 μg / kg for TPIP.

[0392] Administration of TPIP-B resulted in a 1-2 times increase in Penh compared to the values ​​obtained with TPIP-B placebo exposure. Based on past experience with bronchoconstrictors such as capsaicin or citrate, which typically showed values ​​in the range of over 1,000% during the challenge, the Penh parameter values ​​suggested that TPIP-B is unlikely to cause bronchoconstriction and that inhaled doses of TPIP-B do not result in consistent changes in ventilation.

[0393] Lung TPeq concentrations increased as a function of the dose of the inhaled drug (Table 29). [Table 37]

[0394] This study investigated the effects of TPIP-B on cough and ventilation in guinea pigs, a species that exhibits coughing after exposure to inhaled TRE administered by spray. The results of this study showed that coughing occurred with TPIP-B at a threshold delivery dose of 17.7 μg TP / kg body weight (equivalent to 11.2 μg TRE / kg body weight), which is approximately nine times higher than the threshold dose of 1.2 μg TRE / kg body weight that caused coughing in guinea pigs. The cough threshold for TPIP-B was similar to that for TPIP-A at 12.8 μg TP / kg body weight (equivalent to 8.1 μg TRE / kg body weight).

[0395] The TRE dose is derived from the formula: TRE (equivalent) dose = TP dose x 390.52 / 614.94, (614.94 and 390.52 are the molecular weights of TP and TRE, respectively).

[0396] Following exposure to TPIP-B at the cough threshold inhalation dose, the first coughing episode occurred at 34 minutes, which was later than the timing of coughs accompanied by sprayed TREs that occurred within the first 10 minutes of exposure. The coughing response was representative of those observed with treprostinil exposure and occurred as a distinct coughing episode (as seen in the TPIP-A trial), rather than as individual coughs.

[0397] In summary, coughing occurred at a delivery dose of 17.7 μg TP / kg body weight (equivalent to 11.2 μg TRE / kg body weight) of TPIP-B, which was nine times higher than the delivery dose of sprayed TRE that caused coughing in guinea pigs. There were no significant changes in coughing or ventilation response between TPIP-B and TPIP-A.

[0398] Example 5: Evaluation of the safety, tolerability, and PK profile of single and multiple daily doses of TPIP-B in healthy adults. design To evaluate the PK profile 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, as shown in Figure 19. The following single doses were tested: 112.5 μg, 225 μg, 450 μg, and 675 μg. The multi-dose group was structured as follows: 225 μg and 112.5 μg were administered on days 1–4, followed by an escalation to 225 μg on day 5.

[0399] All doses were administered using a 112.5 μg single-acting capsule. Blood samples for PK evaluation in the single-dose group were collected within 15 minutes prior to 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 evaluations in the multi-dose groups were performed within 30 minutes prior to administration, and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after administration on day 1, only before administration on days 2, 3, 4, 5, and 6, before administration 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. result

[0400] Treprostinil PK is linear (i.e., CL / F, Vd / F, and t 1 / 2 (dose-independent), systemic exposure was linearly associated with dose, with low to moderate inter-individual variability. No accumulation was observed at steady state. Rapid C max and long t 1 / 2 (7-12 hours) was observed in both single-dose and multi-dose daily administrations. PK profiles for the single-dose and multi-dose groups are provided in Tables 30A (single-dose group) and 30B (multi-dose group). max , AUC, and t 1 / 2 This can range from 80% to 125% of the values ​​provided in Tables 30A and 30B. [Table 38] [Table 39] Tables 30A and 30B: AUC, Area under the curve between plasma concentration and time, CL / F, obvious total drug clearance after oral administration, CV, coefficient of variation, C max Maximum observed plasma concentration, PK, pharmacokinetics, QD, once daily, t 1 / 2Terminal half-life, TPIP, treprostinyl palmitil inhalation powder, Vd / F, apparent volume of distribution after non-intravenous drug administration. a AUC for the single-dose group = AUC extrapolated from time 0 to infinity, b n=5. c AUC for the multi-dose group = AUC from 0 to 24 hours in steady state.

[0401] Single and multi-dose TPIP-B administrations were generally well-tolerated in healthy adults. Dose escalation strategies in the multi-dose group improved tolerance. Treatment-related adverse events (TEAEs) were dose-related and generally mild (80.6%). No serious or severe TEAEs were observed. TEAEs are shown in Tables 31A (single-dose group) and 31B (multi-dose group). [Table 40] [Table 41]

[0402] While the invention described herein is described in relation to its particular embodiments, those skilled in the art will understand that various modifications can be made and that the invention can be replaced by equivalents without departing from the true spirit and scope of the invention. Furthermore, many modifications can be made to adapt specific circumstances, materials, compositions, processes, and process steps(s) to the spirit and scope of the invention described herein. All such modifications are intended to fall within the claims appended herein.

[0403] Patents, patent applications, published patent applications, academic articles, and protocols referenced herein are incorporated by reference in their entirety for all purposes.

Claims

1. (a) Formula (I) for 0.1 wt% to 5 wt%, 【Chemistry 1】 In the formula, R １ This is a hexadecyl compound, or its enantiomer, diastereomer, or pharmaceutically acceptable salt, (b) 25 wt% to 61 wt% leucine, A dry powder composition comprising (a), (b), and (c) as a total of 100 wt%, wherein the remainder is (c) a sugar selected from the group consisting of trehalose and mannitol, and the dry powder composition is spray-dried.

2. The dried powder composition according to claim 1, wherein the composition contains 320 μg of the compound of formula (I).

3. R １ The dried powder composition according to claim 1 or 2, wherein the compound is linear hexadecyl.

4. The dry powder composition according to any one of claims 1 to 3, wherein the compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present in an amount of 0.5 wt% to 4 wt% of the total weight of the dry powder composition.

5. The dry powder composition according to any one of claims 1 to 3, wherein the compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof is present in an amount of 2 wt% to 4 wt% of the total weight of the dry powder composition.

6. The dried powder composition according to any one of claims 1 to 5, wherein the dried powder composition contains 45 wt% to 61 wt% leucine.

7. The dried powder composition according to any one of claims 1 to 6, wherein the sugar is mannitol.

8. The dried powder composition according to any one of claims 1 to 7, wherein R1 is linear hexadecyl, the dried powder composition contains 45 wt% to 61 wt% leucine, the sugar is mannitol, and the dried powder composition contains 80 μg, 160 μg, 240 μg, 320 μg, or 640 μg of the compound of formula (I).

9. A dry powder composition for treating pulmonary hypertension (PH) in a patient requiring the treatment described in any one of claims 1 to 8, wherein the dry powder composition is administered to the patient's lungs by inhalation using a dry powder inhaler.

10. The dry powder composition according to claim 9, wherein the dry powder composition is administered once daily during the administration period, and the dose of the compound of formula (I), or its enantiomer, diastereomer, or pharmaceutically acceptable salt in the dry powder composition is adjusted from the first dose during the administration period up to the patient's maximum tolerable dose, the first dose being well tolerable to the patient and lower than the patient's maximum tolerable dose.

11. The dried powder composition according to claim 10, wherein the initial dose is 80 to 160 μg of the compound of formula (I), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

12. The dried powder composition according to claim 10 or 11, wherein the initial dose is gradually increased by 80 μg increments to a higher dose of the compound of formula (I) up to the patient's maximum tolerable dose.

13. The dried powder composition according to claim 10 or 11, wherein the initial dose is gradually increased to a higher dose of 112.5 μg, 225 μg, 240 μg, 320 μg, 400 μg, 450 μg, 480 μg, or 640 μg of the compound of formula (I).

14. The dried powder composition according to any one of claims 9 to 13, wherein the PH is pulmonary arterial hypertension (PAH).

15. The dried powder composition according to any one of claims 9 to 14, wherein the PH is a PH associated with interstitial lung disease (ILD).

16. The dried powder composition according to claim 15, wherein the ILD comprises one or more lung conditions selected from the group consisting of idiopathic pulmonary fibrosis (IPF), idiopathic pulmonary pneumonia (COP), desquamative interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, acute interstitial pneumonia, interstitial pneumonia, connective tissue disease, sarcoidosis, or asbestosis.

17. The dried powder composition according to any one of claims 9 to 16, wherein treatment includes improving the patient's exercise capacity during the administration period compared to the patient's exercise capacity before the administration period.

18. The dry powder composition according to claim 17, wherein the improvement in motor function includes increasing the walking distance in the six-minute walk test (6MWT) of the patient during the administration period by at least 5 meters, at least 10 meters, at least 20 meters, at least 30 meters, at least 40 meters, or at least 50 meters compared to the walking distance in the 6MWT of the patient before the administration period.

19. The dried powder composition according to any one of claims 9 to 18, wherein treatment comprises reducing the pulmonary vascular index (PVRI) of the patient during the administration period compared to the patient's PVRI before the administration period.

20. The dried powder composition according to any one of claims 10 to 19, wherein after the patient has shown tolerance to the dose for two days or more, the dose is adjusted to a higher dose.

21. The dried powder composition according to claim 20, wherein the two or more days are selected from two days, three days, four days, five days, six days, or seven days.

22. The dry powder composition according to any one of claims 10 to 21, wherein the dose is adjusted to a lower dose after the patient has experienced adverse reactions to the compound of formula (I), or its enantiomer, diastereomer, or pharmaceutically acceptable salt.

23. The dry powder composition according to any one of claims 10 to 22, wherein the patient is administered two or more different doses of the compound of formula (I) during the administration period.

24. The dried powder composition according to claim 23, wherein the patient is administered three different doses of the compound of formula (I) during the administration period.

25. The dried powder composition according to claim 23, wherein the patient is administered four different doses of the compound of formula (I) during the administration period.

Images