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JP-7857292-B2 - A dry powder composition of treprostinyl prodrug and its method of use.

JP7857292B2JP 7857292 B2JP7857292 B2JP 7857292B2JP-7857292-B2

Inventors

  • ドゥー，ジュー
  • プラウント，アダム
  • マリニン，ウラジミール
  • パリーク，マウリッククマール
  • アミン，ハーシュ
  • パルワイ，ナヴィーン

Assignees

  • インスメッド インコーポレイテッド

Dates

Publication Date
20260512
Application Date
20211028
Priority Date
20201028

Claims (20)

  1. (a ) Formula (I) for 0.1 wt% to 5 wt%, In the formula, R1 is a compound that is hexadecyl , 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. The dried powder composition according to claim 1 or 2, wherein R1 is a 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 thereof, or a 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. R 1 The dried powder composition according to any one of claims 1 to 7, wherein the sugar 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 dry 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 dry 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.

Description

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. 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. It can also lead to hypertension in other systems, such as portal-pulmonary hypertension, where the patient has both portal and pulmonary hypertension. 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). 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, significantly limiting their ability to perform physical activities. The New York Heart Association (NYHA) classified PAH patients into four functional classes to assess the severity of their condition. 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. Patients with Class IV PAH 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. 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®), sitaxentan, 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. 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. In one embodiment, the present disclosure relates to (a) formula (I) in amounts of about 0.5 wt% to about 5 wt%, The present invention relates to a dry powder composition comprising (a) a compound of formula (I), its stereoisomer, or a pharmaceutically a