Treprostinil-Iloprost combination therapy

Abstract

The present disclosure relates to the treatment of diseases such as pulmonary hypertension by inhalation with a combination of iloprost and treprostinil.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 307,919, filed February 8, 2022, the entirety of which is incorporated by reference herein. [Background technology]

[0002] This application relates generally to compositions comprising prostacyclin and methods of treating diseases using prostacyclin, including compositions comprising treprostinil and iloprost and methods of treating diseases with combinations comprising treprostinil and iloprost. Summary of the Invention

[0003] One embodiment is a method of treating pulmonary hypertension comprising administering by inhalation to a subject in need thereof iloprost, or a pharma- ceutically acceptable salt thereof, and treprostinil, or a pharma- ceutically acceptable salt thereof.

[0004] Yet another embodiment is a method of treating pulmonary hypertension comprising administering by inhalation to a subject in need thereof a composition comprising (i) iloprost or a pharma- ceutically acceptable salt thereof and (ii) treprostinil or a pharma- ceutically acceptable salt thereof in a single event dose, wherein the dosage of iloprost or a pharma- ceutically acceptable salt thereof delivered to the subject is at least 2.5 μg, and the dosage of treprostinil or a pharma- ceutically acceptable salt thereof delivered to the subject is at least 5 μg. [Brief description of the drawings]

[0005] [Figure 1] FIG. 2 shows chromatograms (arbitrary units vs. minutes) of iloprost dissolution solutions at various pH levels. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Throughout this specification, unless otherwise indicated, "comprise," "comprises," and "comprising" are used inclusively rather than exclusively, such that a recited integer or group of integers may include one or more other unrecited integers or groups of integers. The term "or" is inclusive unless modified, for example, by "any." Thus, unless the context dictates otherwise, the word "or" means any one member of a particular list, and also includes any combination of members of that list. "Consisting of" is intended to mean the exclusion of other ingredients and non-insubstantial elements of method steps. Embodiments defined by each of these transition terms are within the scope of the present technology. It should also be understood that when an embodiment is defined by one of these terms (e.g., "comprising"), the disclosure includes alternative embodiments, such as "consisting essentially of" and "consisting of" in place of the embodiment.

[0007] All numerical designations, e.g., amounts, times, and concentrations, including ranges, are approximations which are varied (+) or (-) by increments of 0.05%, 1%, 2%, 5%, 10%, or 20%. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term "about."

[0008] "Subject" refers to an animal, such as a mammal (including a human), that is or becomes the object of treatment, observation, or experiment. "Subject" and "patient" may be used interchangeably unless otherwise indicated. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0009] Where a range of values ​​is given, it is understood that each intervening value between the upper and lower limits of that range, and any other stated or intervening value in the stated range, to one tenth of the unit of the lower limit unless the context clearly indicates otherwise, is encompassed within the technology. The upper and lower limits of these smaller ranges may independently be included within the smaller ranges, and are also encompassed within the technology when falling within any specifically excluded limit of the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also encompassed within the technology of the present invention.

[0010] "Pulmonary hypertension" ("PH") refers to all forms of pulmonary hypertension, including all pulmonary hypertension encompassed by WHO Groups 1-5, unless otherwise indicated or apparent to one of skill in the art. Pulmonary hypertension (PH) is a condition characterized by increased blood pressure in the pulmonary arteries. Symptoms of PH may include one or more of the following: difficulty in breathing, fainting, fatigue, chest pain, leg swelling, and fast heartbeat. "Pulmonary hypertension" includes pulmonary arterial hypertension ("PAH") in all its forms (Group 1), including idiopathic and hereditary PAH. Pulmonary hypertension includes patients with NYHA functional class III symptoms. "Pulmonary hypertension" includes pulmonary hypertension resulting from left heart disease (Group 2). "Pulmonary hypertension" includes pulmonary hypertension resulting from lung disease (Group 3). "Pulmonary hypertension" includes thromboembolic pulmonary hypertension (Group 4). "Pulmonary hypertension" includes pulmonary hypertension secondary to other conditions, such as sarcoidosis, sickle cell disease, chronic hemolytic anemia, splenectomy, and certain metabolic disorders (Group 5). In general, the treatment methods described herein are most applicable to PAH (Group 1) and Group 3 pulmonary hypertension, including PH-ILD.

[0011] An embodiment is a method for treating pulmonary hypertension by administering a combination of iloprost and treprostinil to a subject, preferably a human suffering from pulmonary hypertension, by inhalation.Instead of or in addition to treprostinil or iloprost, pharmaceutically acceptable salt or ester or prodrug can be administered.For example, iloprost and the sodium salt of treprostinil can be administered to treat pulmonary hypertension.Unless otherwise indicated, when treprostinil and iloprost are referred to herein, they include pharmaceutically acceptable salt, ester and prodrug of these compounds.

[0012] Iloprost (trademarks: Ventavis®, Ilomedine) is used to treat pulmonary arterial hypertension (PAH), scleroderma, Raynaud's phenomenon, and other conditions in which blood vessels narrow and blood cannot flow to tissues. Iloprost was developed by the pharmaceutical company Schering AG and is marketed in Europe by Bayer Schering Pharma AG and in the United States by Actelion Pharmaceuticals. Iloprost has the following structure:

[0013] [ka] Prostacyclin PGI 2 It is a synthetic analogue of

[0014] In the United States, iloprost (Ventavis®) solution is approved for inhalation for use with the I-Neb AAD or Prodose AAD delivery systems. In Europe, iloprost, as Ventavis, is approved for use with two compressed air nebulizers with AAD delivery systems (Halolight and Prodose) and two ultrasonic nebulizers, Ventaneb and I-Neb.

[0015] Treprostinil is also used to treat pulmonary arterial hypertension. Treprostinil has the following structure:

[0016] [ka] Prostacyclin (PGI 2 ) is a synthetic analogue of

[0017] Treprostinil, the active ingredient of Remodulin® (treprostinil) injection, Tyvaso® (treprostinil) inhalation solution, and Orenitram® (treprostinil) sustained release tablets, was described in U.S. Patent No. 4,306,075. Methods for making treprostinil and other prostacyclin derivatives are described, for example, in Moriarty, et al., J. Org. Chem. 2004, 69, 1890-1902; Drug of the Future, 2001, 26(4), 364-374, U.S. Patent Nos. 6,441,245, 6,528,688, 6,700,025, 6,809,223, 6,756,117, 8,461,393, 8,481,782; 8,242,305, 8,497,393, 8,940,930, 9,029,607, 9,156,786, and 9,388,154, 9,346,738; U.S. Patent Nos. Nos. 2012-0197041, 2013-0331593, 2014-0024856, 2015-0299091, 2015-0376106, 2016-0107973, 2015-0315114, 2016-0152548, and 2016-0175319; PCT Publication Nos. WO 2016 / 0055819 and WO 2016 / 081658.

[0018] Various additional uses and / or forms of treprostinil are described, for example, in U.S. Pat. Nos. 5,153,222, 5,234,953, 6,521,212, 6,756,033, 6,803,386, 7,199,157, 6,054,486, 7,417,070, 7,384,978, 7,879,909, 8,563,614, 8,252,839, 8,536,363, 8,410,16 Specification No. 9, Specification No. 8,232,316, Specification No. 8,609,728, Specification No. 8,350,079, Specification No. 8,349,892, Specification No. 7,999,007, Specification No. 8,658,694, Specification No. 8,653,137, Specification No. 9,029,6 Specification No. 07, Specification No. 8,765,813, Specification No. 9,050,311, Specification No. 9,199,908, Specification No. 9,278,901, Specification No. 8,747,897, Specification No. 9,358,240, Specification No. 9,339,507, Specification No. 9,255, 064, 9,278,902, 9,278,903, 9,758,465; 9,422,223; 9,878,972; 9,624,156, 8,969,409, 10,716,793, 10,376,525; U.S. Patent Application Publication Nos. 2009-0036465, 2008-0200449, 2008-0280986, 2009-0124697, 2014-0275616 Specification No. 2014-0275262 Specification No. 2013-0184295 Specification No. 2014-0323567 Specification No. 2016-0030371 Specification No. 2016-0051505 Specification No. 2016-0030355 Specification No. 2016- Specification No. 0143868, Specification No. 2015-0328232, Specification No. 2015-0148414, Specification No. 2016-0045470, Specification No. 2016-0129087, Specification No. 2017-0095432; Specification No. 2018-0153847;No. 2021-0330621, and PCT International Publication Nos. WO 00 / 57701, WO 20160105538, WO 2016038532, WO 2018 / 058124, and WO 2021 / 211916.

[0019] A "prodrug" of treprostinil refers to a compound that is a treprostinil or a pharma- ceutically active derivative thereof, or is a compound that is a pharma-ceutically active derivative thereof, as described in PCT Publication WO 2005 / 007081; U.S. Pat. Nos. 7,384,978; 7,417,070; 7,544,713; 8,252,839; 8,410,169; 8,536,363; and 9,0 Specification No. 50,311, Specification No. 9,199,908, Specification No. 9,278,901, Specification No. 9,422,223; Specification No. 9,624,156, Specification No. 9,878,972, Specification No. 9,371,264, Specification No. 9,394,227, Specification No. 9,505,737, Specification No. 9,758,465, Specification No. 9,643,911, Specification No. 9,701,616, Specification No. 9,776,982, Specification No. 9,845,305 Specification, Specification No. 9,957,200, Specification No. 10,494,327, Specification No. 10,053,414, Specification No. 10,246,403, Specification No. 10,344,012, Specification No. 10,450,290, No. 1 Specification No. 0,464,877, Specification No. 10,464,878, Specification No. 10,703,706, Specification No. 10,752,733, Specification No. 9,255,064, Specification No. 9,469,600, Specification No. 10,010,5 No. 18, 10,343,979, 10,526,274; U.S. Patent Application Publication No. 2018-0153847; 2021-0054009; 2021-0378996; U.S. Patent Application No. 17 / 549,573, filed December 13, 2021; and U.S. Provisional Patent Application No. 63 / 156,110, filed March 3, 2021.

[0020] "Pharmaceutically acceptable salts" refer to physiologically acceptable salts of treprostinil, treprostinil prodrugs, or iloprost, as well as non-physiologically acceptable salts of treprostinil, treprostinil prodrugs, or iloprost. Pharmaceutically acceptable salts of treprostinil, treprostinil prodrugs, or iloprost are within the scope of the technology of the present invention and include base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salts are not excessively toxic, allergenic, or irritating and are bioavailable). Treprostinil, treprostinil prodrugs, or iloprost have at least one acidic group, such as a carboxylic acid group. Thus, treprostinil, treprostinil prodrugs, or iloprost can be prepared by the addition of a metal, such as an alkali metal or an alkaline earth metal (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine), or basic amino acids (e.g., arginine, lysine, histidine, and ornithine). Such salts may be prepared in situ during the isolation and purification of the compounds, or by separately reacting the compounds purified in their free acid form with appropriate bases, respectively, and isolating the salts so formed.

[0021] The treatment can improve one or more physiological indicators associated with PH, or can alleviate or reduce one or more symptoms associated with PH. For example, in some embodiments, the treatment can reduce pulmonary artery pressure. In other embodiments, the treatment can result in improved exercise capacity, for example improved distance in the 6-minute walk test (6MWT). In some embodiments, the treatment can result in alleviation or reduction of one or more symptoms of PH, such as reduced shortness of breath or fainting.

[0022] In some embodiments, the combination of iloprost and treprostinil may be administered by inhalation to treat pulmonary arterial hypertension (PAH). PAH is characterized by thickening (narrowing of the lumen) and hardening of the pulmonary arteries. As a result, the right side of the heart may have to work harder to push blood through these narrowed arteries. This extra stress may cause the heart to lose its ability to pump enough blood through the lungs to meet the demands of the rest of the body.

[0023] In some embodiments, the combination of iloprost and treprostinil may be administered by inhalation to treat pulmonary hypertension, WHO Group 3, i.e., pulmonary hypertension due to a condition selected from chronic lung disease and / or hypoxia (low oxygen levels). Group 3 PH can be pulmonary hypertension associated with interstitial lung disease (PH-ILD).

[0024] Chronic lung diseases can include obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD) and emphysema, which narrow the lung airways and make it difficult to breathe out; restrictive lung diseases, such as interstitial lung disease or pulmonary fibrosis, which make it difficult for the lungs to expand when inhaling; sleep apnea; living in high altitude areas for extended periods of time; and various combinations of the above conditions.

[0025] In some embodiments, the chronic lung disease may include idiopathic interstitial pneumonia, such as idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis (e.g., respiratory bronchiolitis associated with interstitial lung disease), desquamative interstitial pneumonia, acute interstitial pneumonia; chronic hypersensitivity pneumonitis, occupational lung disease, pulmonary fibrosis, emphysema, connective tissue disease, or any combination of the above conditions.

[0026] Treprostinil, or a pharma- ceutically acceptable salt thereof, and iloprost, or a pharma- ceutically acceptable salt thereof, may be administered in a therapeutically effective amount, which may be an amount effective to treat pulmonary hypertension.

[0027] Although the present invention is not bound by any theory, treprostinil is effective against pulmonary hypertension (such as pulmonary arterial hypertension or pulmonary hypertension with interstitial lung disease) due at least in part to its beneficial vasodilatory effect on the pulmonary vasculature and / or its ability to induce remodeling of the pulmonary vasculature. Iloprost has a shorter half-life than treprostinil. Iloprost is also generally administered more frequently due to its shorter half-life. However, iloprost has a more substantial inotropic effect than treprostinil, which can be beneficial to cardiac function. The pulmonary vasculature effect of combined treprostinil and / or iloprost, with a relatively short life but substantial inotropic boost to the right heart from iloprost, may provide additional benefits to some pulmonary hypertension patients that would not be obtained if either drug was administered as monotherapy. For example, a combination of treprostinil and iloprost may be administered on an ad-hoc basis (i.e., as needed) to a patient who experiences at least one undesirable symptom of pulmonary hypertension, such as dyspnea or shortness of breath. The iloprost in the combination can provide a relatively short-lived but substantial inotropic boost, which can reduce or alleviate at least one undesirable symptom of pulmonary hypertension, such as dyspnea or shortness of breath.

[0028] In some embodiments, the iloprost administered by inhalation in combination with treprostinil may be iloprost as a free acid or iloprost tromethamine. In some embodiments, the treprostinil administered by inhalation in combination with iloprost may be treprostinil as a free acid or treprostinil sodium.

[0029] In some embodiments, iloprost and treprostinil can be administered simultaneously.For example, a patient can be administered both iloprost and treprostinil using any suitable delivery mechanism, such as a nebulizer or dry powder inhaler.Simultaneous delivery can be administered using a composition that includes both treprostinil and iloprost.The relative amounts of treprostinil and iloprost can be selected by those skilled in the art based on the desired dosage, which will be discussed in more detail below.In some embodiments, simultaneous administration is achieved using a rescue inhaler type device that delivers a fixed amount of drug or imposes an upper limit on the dosage that can be delivered.

[0030] In other embodiments, iloprost and treprostinil can be administered separately. These embodiments may be useful for adjusting the relative dosage of the drugs. For example, iloprost can be administered before or after treprostinil. The drugs can be administered using the same or different delivery mechanisms. The drugs can be administered using the same or different inhalation devices. For example, in some embodiments, one drug can be administered using a nebulizer and the other can be administered using a dry powder inhaler. When iloprost and treprostinil are administered separately, the administration can be immediate, for example, iloprost is administered immediately after administration of treprostinil (or vice versa), or can be administered separately in time, for example, iloprost is administered after administration of treprostinil (or vice versa). For example, administration of iloprost and treprostinil can be spaced apart by about 2 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, or 4 hours. In some embodiments, the drugs are administered at different frequencies. For example, treprostinil can be administered 1, 2, 3, or 4 times daily, and iloprost can be administered 4, 5, 6, or more than 6 times daily. In some embodiments, one of the drugs, such as iloprost, is administered as needed, and the other drug is administered on a fixed dosing regimen, for example, 1, 2, 3, or 4 times daily.

[0031] In some embodiments, the administration of iloprost and treprostinil may be performed in a single administration event or in a single dose event. In some embodiments, the number of breaths in a single administration event or single dose event may not exceed 20 breaths (or inhalations) or 19 breaths (or inhalations) or 18 breaths (or inhalations) or 17 breaths (or inhalations) or 16 breaths (or inhalations) or 15 breaths (or inhalations) or 14 breaths (or inhalations) or 13 breaths (or inhalations) or 12 breaths (or inhalations) or 11 breaths (or inhalations) or 10 breaths (or inhalations) or 9 breaths (or breaths (or inhalations) inhalations) or 8 breaths (or inhalations) or 7 breaths (or inhalations) or 6 breaths (or inhalations) or 5 breaths (or inhalations) or 4 breaths (or inhalations) or 3 breaths (or inhalations) or 2 breaths (or inhalations) or 1 breath (or inhalations).

[0032] The number of single-dosing events per day for administering Treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug pharmaceutically acceptable salt, administered by inhalation, can vary.For example, the number of single-dosing events per day can be 1, 2, 3, 4, 5, or 6 times per day.In some embodiments, the number of single-dosing events per day can be at least 2 times, for example 2 to 5 events per day, or 2 to 3 events per day.

[0033] The dose or amount of Treprostinil, its prodrug, its pharma- ceutically acceptable salt, or its prodrug's pharma- ceutically acceptable salt administered by inhalation in a single administration event may vary. In some embodiments, the single administration event dose of Treprostinil may be at least 5 μg or at least 6 μg. In some embodiments, the single administration event dose of Treprostinil may be 5 μg to 120 μg, or 18 μg to 120 μg, or 6 μg to 96 μg, or 7.5 μg to 100 μg, or 10 μg to 100 μg, or 15 μg to 100 μg, 15 μg to 90 μg, or 15 μg to 75 μg, or 30 μg to 75 μg, or any value or subrange within these ranges.

[0034] The dose or amount of iloprost or its pharma- ceutically acceptable salt administered by inhalation in a single-dose event may vary.In some embodiments, the single-dose event dose of iloprost may be at least 2 μg or at least 2.5 μg.In some embodiments, the single-dose event dose of iloprost may be 2 μg to 10 μg or 2 μg to 9 μg or 2.5 μg to 5 μg or any value or subrange within these ranges. In some embodiments, the daily dose of iloprost administered across all daily administration events may be less than or equal to 15 μg, or less than or equal to 14 μg, or less than or equal to 13 μg, or less than or equal to 12 μg, or less than or equal to 11 μg, or less than or equal to 10 μg, or less than or equal to 9 μg, or less than or equal to 8 μg, or less than or equal to 7 μg, or less than or equal to 6 μg, or less than or equal to 5 μg.

[0035] In some embodiments, iloprost and treprostinil may be administered by a single inhalation device, such as a nebulizer or dry powder inhaler, which may contain two separate compositions, one containing iloprost and one containing treprostinil.

[0036] Furthermore, in some embodiments, iloprost and treprostinil may be administered in a single composition comprising (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug's pharmaceutically acceptable salt.Although the present invention is not bound by any theory, the inventors have found that treprostinil may exert a stabilizing effect when combined in a composition with iloprost, compared to the stability of iloprost when not combined with treprostinil in the same composition.In some embodiments, such a single composition may be a solution comprising (a) iloprost or a pharmaceutically acceptable salt thereof, and (b) treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug's pharmaceutically acceptable salt.The concentration of treprostinil in such a solution may vary. In some embodiments, the treprostinil concentration may be 200μg / ml to 2000μg / ml, or 300μg / ml to 1500μg / ml, or 400μg / ml to 1200μg / ml, or any value or subrange within these ranges. For example, in certain embodiments, the treprostinil concentration may be 600μg / ml. The concentration of iloprost in such solutions may vary. In some embodiments, the iloprost concentration may be 5μg / ml to 50μg / ml, or 5μg / ml to 40μg / ml, or 5μg / ml to 30μg / ml, or any value or subrange within these ranges. For example, in certain embodiments, the iloprost concentration may be 10μg / ml or 20μg / ml.

[0037] In some embodiments, the composition comprising (a) iloprost or a pharma- ceutically acceptable salt thereof, and (b) treprostinil, its prodrug, its pharma- ceutically acceptable salt, or its prodrug's pharma- ceutically acceptable salt may be administered by oral inhalation or nasal inhalation.In some embodiments, the composition comprising (a) iloprost or a pharma- ceutically acceptable salt thereof, and (b) treprostinil, its prodrug, its pharma- ceutically acceptable salt, or its prodrug's pharma- ceutically acceptable salt may be administered by an inhalation device such as a nebulizer.In some embodiments, the composition comprising (a) iloprost or a pharma- ceutically acceptable salt thereof, and (b) treprostinil, its prodrug, its pharma- ceutically acceptable salt, or its prodrug's pharma- ceutically acceptable salt may be administered by a pulsed inhalation device such as a metered dose inhaler and / or a pulsed nebulizer. Pulsed inhalation devices are disclosed, for example, in U.S. Patent Application Publication No. 20080200449, U.S. Patent Nos. 9,358,240; 9,339,507; 10,376,525; and 10,716,793, the contents of each of which are incorporated by reference in their entirety.

[0038] In some embodiments, the composition comprising (a) iloprost or a pharma- ceutically acceptable salt thereof, and (b) treprostinil, its prodrug, its pharma- ceutically acceptable salt, or its prodrug's pharma- ceutically acceptable salt may be administered as a dry powder composition.The dry powder composition may be administered by a dry powder inhaler, which may be a pulsed dry powder inhaler.Dry powder inhalers are disclosed, for example, in U.S. Patent Nos. 7,305,986, 7,464,706, 8,499,757, and 8,636,001, and PCT International Publication No. WO2019237028, each of which is incorporated by reference.

[0039] In some embodiments, the dry powder inhaler may include a cartridge, which may be a replaceable cartridge, containing the dry powder composition. In some embodiments, the dry powder inhaler may be a compact, reusable, or disposable breath-actuated inhaler. The dry powder inhaler may have a number of different shapes and sizes and may include a system of airflow conduit pathways for effective and rapid delivery of the powdered medicament to the lungs and / or systemic circulation.

[0040] In some embodiments, in addition to a) iloprost or a pharma- ceutically acceptable salt thereof, and (b) treprostinil, a prodrug thereof, a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt of a prodrug thereof, the dry powder composition may further comprise a diketopiperazine, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP).

[0041] The patient treated using the method described herein may be treated with other therapies.In some embodiments, the subject will receive basal therapy for PH and will also receive a combination of treprostinil and iloprost.For example, a combination of iloprost and treprostinil may be added to existing therapy to address acute symptoms such as exercise-induced symptoms.Basal therapy may include phosphodiesterase-5 inhibitors (e.g., sildenafil and tadalafil), soluble guanylate cyclase stimulators (sGCS) (e.g., riociguat), endothelin receptor antagonists (ERA) (e.g., bosentan and ambrisentan), or other prostacyclins.

[0042] In some embodiments, iloprost and treprostinil may be in a single pharmaceutical formulation.In some embodiments, the pharmaceutical formulation may be a liquid formulation.In some embodiments, the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may be an inhalable pharmaceutical formulation, i.e., a formulation that is administered by inhalation.

[0043] The concentration of treprostinil in a pharmaceutical formulation, such as a liquid pharmaceutical formulation, may vary. In some embodiments, the treprostinil concentration may be 200 μg / ml to 2000 μg / ml, or 300 μg / ml to 1500 μg / ml, or 400 μg / ml to 1200 μg / ml, or any value or subrange within these ranges. For example, in certain embodiments, the treprostinil concentration may be 600 μg / ml. The concentration of iloprost in a pharmaceutical formulation, such as a liquid pharmaceutical formulation, may vary. In some embodiments, the iloprost concentration may be 5 μg / ml to 50 μg / ml, or 5 μg / ml to 40 μg / ml, or 5 μg / ml to 30 μg / ml, or any value or subrange within these ranges. For example, in certain embodiments, the iloprost concentration may be 10 μg / ml or 20 μg / ml.

[0044] In some embodiments, in addition to iloprost and treprostinil, the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may also include a buffer. In some embodiments, the buffer may be a phosphate buffer, such as sodium phosphate buffer. For example, in some embodiments, the formulation may include about 5-15 mM sodium phosphate buffer, more preferably about 9-11 mM sodium phosphate buffer, and most preferably about 10 mM sodium phosphate buffer.

[0045] In some embodiments, the pharmaceutical formulation, such as the liquid pharmaceutical formulation, may also contain a salt. The salt may be, for example, an alkali metal halide, such as sodium chloride or sodium iodide. For example, in some embodiments, the formulation may contain about 20 mM to 1000 mM, or about 50 mM to about 500 mM, or about 100 mM to about 200 mM, or about 115 mM to about 125 mM.

[0046] In some embodiments, the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may be an isotonic solution.

[0047] In some embodiments, the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may have a pH of about 5.8 to about 7.2, or about 5.9 to about 7.1, or about 6.0 to about 7.0, or about 6.1 to 6.9, or about 6.2 to about 6.8, or about 6.5.

[0048] In some embodiments, a pharmaceutical formulation, such as a liquid pharmaceutical formulation, may have an osmolality of about 200 mOsm / kg to about 500 mOsm / kg, or about 250 mOsm / kg to about 400 mOsm / kg, or about 270 mOsm / kg to about 340 mOsm / kg.

[0049] In some embodiments, the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may contain iloprost itself or a pharma- ceutical acceptable salt thereof, such as the tromethamine salt. In some embodiments, the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may contain treprostinil as a free base or a pharma- ceutical acceptable salt thereof, such as the sodium salt.

[0050] The pharmaceutical formulation, such as a liquid pharmaceutical formulation, may be used to treat pulmonary hypertension by administration to a subject, such as a human. In some embodiments, administering the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may be performed by inhalation. In some embodiments, the pulmonary hypertension may be pulmonary arterial hypertension. Additionally, in some embodiments, the pulmonary hypertension may be pulmonary hypertension associated with interstitial lung disease.

[0051] In some embodiments, administering the pharmaceutical formulation, such as the liquid pharmaceutical formulation, may be performed in a single administration event or a single dose event. In some embodiments, the number of breaths in a single administration event or a single dose event may not exceed 20 breaths (or inhalations) or 19 breaths (or inhalations) or 18 breaths (or inhalations) or 17 breaths (or inhalations) or 16 breaths (or inhalations) or 15 breaths (or inhalations) or 14 breaths (or inhalations) or 13 breaths (or inhalations) or 12 breaths (or inhalations) or 11 breaths (or inhalations) or 10 breaths (or inhalations) or 9 breaths (or breaths (or inhalations) inhalations) or 8 breaths (or inhalations) or 7 breaths (or inhalations) or 6 breaths (or inhalations) or 5 breaths (or inhalations) or 4 breaths (or inhalations) or 3 breaths (or inhalations) or 2 breaths (or inhalations) or 1 breath (or inhalations).

[0052] In some embodiments, a single event of administering a pharmaceutical formulation, such as a liquid pharmaceutical formulation, may be less than about 10, 7, 5, 3, 2, or 1 minute.

[0053] The number of single administration events per day for administering pharmaceutical formulations, such as liquid pharmaceutical formulations, by inhalation can vary.For example, the number of single administration events per day can be 1, 2, 3, 4, 5 or 6 times per day.In some embodiments, the number of single administration events per day can be at least 2 times, for example 2 to 5 events per day, or 2 to 3 events per day.

[0054] In some embodiments, pharmaceutical formulations, such as liquid pharmaceutical formulations, may be administered by pulsed inhalation devices, such as metered dose inhalers and / or pulsed nebulizers. Pulsed inhalation devices are disclosed, for example, in U.S. Patent Application Publication No. 20080200449, U.S. Patent Nos. 9,358,240; 9,339,507; 10,376,525; and 10,716,793, the contents of each of which are incorporated herein by reference in their entirety.

[0055] The dose or amount of iloprost or its pharmaceutically acceptable salt administered by inhalation in a single administration event of pharmaceutical formulation such as liquid pharmaceutical formulation may vary.In some embodiments, the dose of iloprost in a single administration event may be at least 2 μg or at least 2.5 μg.In some embodiments, the dose of iloprost in a single administration event may be 2 μg to 10 μg or 2 μg to 9 μg or 2.5 μg to 5 μg, or any value or subrange within these ranges. In some embodiments, the daily dose of iloprost administered across all daily administration events may be less than or equal to 15 μg, or less than or equal to 14 μg, or less than or equal to 13 μg, or less than or equal to 12 μg, or less than or equal to 11 μg, or less than or equal to 10 μg, or less than or equal to 9 μg, or less than or equal to 8 μg, or less than or equal to 7 μg, or less than or equal to 6 μg, or less than or equal to 5 μg.

[0056] The dose or amount of Treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug's pharmaceutically acceptable salt administered by inhalation in a single administration event of a pharmaceutical formulation, such as a liquid pharmaceutical formulation, may vary. In some embodiments, the dose of Treprostinil in a single administration event may be at least 5 μg or at least 6 μg. In some embodiments, the dose of Treprostinil in a single administration event may be 5 μg to 120 μg, or 18 μg to 120 μg, or 6 μg to 96 μg, or 7.5 μg to 100 μg, or 10 μg to 100 μg, or 15 μg to 100 μg, 15 μg to 90 μg, or 15 μg to 75 μg, or 30 μg to 75 μg, or any value or subrange within these ranges.

[0057] In some embodiments, a pharmaceutical formulation, such as a liquid pharmaceutical formulation, may be administered on an ad-hoc basis (i.e., as needed) to a patient experiencing at least one undesirable symptom of pulmonary hypertension, such as dyspnea or shortness of breath.

[0058] A pharmaceutical formulation, such as a liquid pharmaceutical formulation, that contains both iloprost and treprostinil may have greater stability of iloprost than an otherwise identical iloprost formulation that does not contain treprostinil.

[0059] Pharmaceutical formulations, such as liquid pharmaceutical formulations containing both iloprost and treprostinil, may be such that the formulation, which may be a freshly prepared formulation, is storage stable. Preferably, the formulation can be or is stored for at least 18 months, more preferably at least 24 months. In some embodiments, the formulation can be or is stored for at least 2 weeks, or at least 1 month, or at least 6 weeks, or at least 2 months, or at least 10 weeks, or at least 3 months, or 2 weeks to 3 months, or 1 month to 3 months, or 1 month to 2 months. In some embodiments, preferably, the amount of iloprost in the formulation after storage can be at least 90% or at least 91% or at least 92% or at least 93% or at least 94% of the amount of iloprost in the formulation before storage. In some embodiments, such storage may be performed without cooling the formulation below a temperature such as about 20°C. For example, in some embodiments, storage may be performed at a temperature of about 20°C to about 50°C, or about 22°C to about 45°C, or about 25°C to about 40°C.

[0060] In some embodiments, the pharmaceutical formulation, such as a liquid pharmaceutical formulation, may be stored in a container. In some embodiments, the container may be a sealed container. In some embodiments, the container may be a vial or an ampoule. In some embodiments, the container may be a glass container, i.e., a container made of glass. In some embodiments, the container may be a plastic container, i.e., a container made of plastic. Non-limiting examples of plastics include polyolefins, such as polypropylene, and polyethylene, such as low density polyethylene (LDPE). In some embodiments, the container comprises a removable cap that can be opened and closed, such as a rubber sealing cap attached to the glass container.

[0061] A dosage form of the pharmaceutical formulation, such as a liquid pharmaceutical formulation, is also provided in the container. In some embodiments, the dosage form may be a dosage form for inhalation. In some embodiments, the container may be a sealed container. In some embodiments, the container may be a vial or an ampoule. In some embodiments, the container may be a glass container, i.e. a container made of glass. In some embodiments, the container may be a plastic container, i.e. a container made of plastic. Non-limiting examples of plastics include polyolefins, such as polypropylene, and polyethylene, such as low density polyethylene (LDPE). The amount of the pharmaceutical formulation, such as a liquid pharmaceutical formulation, in the container may vary. In some embodiments, the container may contain 0.5 ml to 50 ml, or 1 ml to 30 ml, or 2 ml to 20 ml of the liquid pharmaceutical formulation.

[0062] The embodiments described herein are further illustrated, but in no way limited, by the following examples. EXAMPLES

[0063] [Example 1] Development of iloprost and treprostinil formulations The purpose of this example is to describe the formulation development work for inhaled formulations of iloprost and treprostinil. An isotonic formulation was developed with a target pH of 6.5.

[0064] [Table 1]

[0065] procedure Solubility evaluation The solubility of iloprost at 100 μg / mL was evaluated at five different pH levels by visual inspection and HPLC-UV analysis. A stock solution of iloprost was prepared in ethanol at 1 mg / mL. The stock solution was diluted 10-fold with each buffer and mixed thoroughly. The buffer solutions were visually inspected for any precipitation. The buffer solutions were filtered through a 0.45 μm nylon filter and then analyzed by HPLC. The buffers and associated pH are shown in Table 2. The HPLC conditions for the solubility analysis are shown in Table 3.

[0066] [Table 2]

[0067] [Table 3]

[0068] Formulation Development Iloprost formulation development Iloprost formulations were prepared at 10 μg / mL with two different NaCl concentrations. A stock iloprost solution of 5 mg / mL was prepared in ethanol and diluted 500-fold into the formulation. The formulations were buffered with 10 mM sodium phosphate buffer at pH 6.5. NaCl was added to final salt concentrations of 115 mM and 125 mM. The osmolality of the formulations was evaluated.

[0069] Iloprost and Treprostinil Formulation Development Two formulations of iloprost and treprostinil were prepared with 10 μg / mL iloprost and 600 μg / mL treprostinil. A stock iloprost solution of 5 mg / mL was prepared in ethanol and diluted 500-fold into the formulation. Treprostinil was quantitatively weighed into the formulation. The formulations were buffered with 10 mM sodium phosphate buffer at two different NaCl concentrations, 115 and 125 mM. After addition of treprostinil, 3-4 drops of 1N NaOH were added to solubilize the treprostinil in the buffer. Further pH adjustments were made to bring the formulation pH within 0.5 of the target 6.5. The osmolality of the formulations was evaluated.

[0070] Two formulations of iloprost and treprostinil were prepared with 20 μg / mL iloprost and 600 μg / mL treprostinil. A stock iloprost solution of 5 mg / mL was prepared in ethanol and diluted 250-fold into the formulation. Treprostinil was quantitatively weighed into the formulation. The formulations were buffered with 10 mM sodium phosphate buffer at two different NaCl concentrations, 115 and 125 mM. After addition of treprostinil, 3-4 drops of 1N NaOH were added to solubilize the treprostinil in the buffer. Further pH adjustments were made to bring the formulation pH within 0.5 of the target 6.5. The osmolality of the formulations was evaluated.

[0071] Results and Discussion Solubility evaluation No visible solubility issues were noted. Visual observations and pH are shown in Table 4. Chromatograms of five different buffer solutions containing 100 μg / mL of iloprost are shown in the figure. Although no visible particles were noted, chromatographic analysis indicates potential solubility issues below pH 6.

[0072] [Table 4]

[0073] Formulation Development Iloprost formulation development Both the 115 and 125 mM salt concentrations were within the isotonic range. The 125 mM formulation was closer to the target of 290 mOsm / kg. The formulations and osmolalities are summarized in Table 5.

[0074] [Table 5]

[0075] Iloprost and Treprostinil Formulation Development Treprostinil required the addition of base to solubilize in the formulation buffer. Additional pH adjustment causes an increase in the ions present. The 125 mM salt level of the second formulation (20 μg / mL iloprost and 600 μg / mL treprostinil) combined with additional pH adjustment results in an osmolality near the upper isotonic range. A salt level of 115 mM is best suited to keep the formulation toward the center of the isotonic solution range. The formulations and osmolality are summarized in Table 6.

[0076] [Table 6]

[0077] conclusion A formulation was developed for iloprost at 10 μg / mL in 10 mM sodium phosphate buffer with 125 mM NaCl at pH 6.5. Two formulations were developed containing iloprost (10 and 20 μg / mL) and treprostinil at 600 μg / mL in 10 mM sodium phosphate buffer with 115 mM NaCl at pH 6.5.

[0078] [Example 2] Stability test of iloprost formulation

[0079] [Table 7]

[0080] [Table 8]

[0081] [Table 9]

[0082] [Table 10]

[0083] [Table 11]

[0084] [Table 12]

[0085] [Table 13]

[0086] [Table 14]

[0087] [Example 3] Stability study of iloprost / treprostinil formulation 1

[0088] [Table 15]

[0089] [Table 16]

[0090] [Table 17]

[0091] [Table 18]

[0092] [Table 19]

[0093] [Table 20]

[0094] [Table 21]

[0095] [Table 22]

[0096] [Table 23]

[0097] [Table 24]

[0098] [Table 25]

[0099] [Table 26]

[0100] [Example 4] Stability study of iloprost / treprostinil formulation 2

[0101] [Table 27]

[0102]

Table 28

[0103]

Table 29

[0104]

Table 30

[0105]

Table 31

[0106]

Table 32

[0107]

Table 33

[0108]

Table 34

[0109]

Table 35

[0110]

Table 36

[0111]

Table 37

[0112] [Table 38]

[0113] conclusion The results of the stability tests of Examples 2-4 show that iloprost is unexpectedly more stable in treprostinil-containing formulations 1 and 2 of Examples 3 and 4 compared to the formulation of Example 2 that did not contain treprostinil. Without being bound by any theory, these results may indicate that iloprost molecules may be bound to treprostinil molecules in formulations 1 and 2 of Examples 3 and 4.

[0114] While the foregoing refers to certain preferred embodiments, it will be understood that the invention is not so limited. Various modifications to the disclosed embodiments may occur to those skilled in the art that are intended to fall within the scope of the invention.

[0115] All publications, patent applications, and patents cited herein are hereby incorporated by reference in their entirety.

Claims

1. A pharmaceutical composition comprising iloprost or a pharmaceutically acceptable salt thereof and treprostinil or a pharmaceutically acceptable salt thereof for treating pulmonary hypertension, comprising administering by inhalation to a subject in need thereof.

2. 10. The pharmaceutical composition of claim 1, wherein the composition is a dry powder composition.

3. 2. The pharmaceutical composition of claim 1, wherein the iloprost or a pharmaceutically acceptable salt thereof is iloprost or the tromethamine salt of iloprost.

4. 2. The pharmaceutical composition of claim 1, wherein the treprostinil or a pharmaceutically acceptable salt thereof is treprostinil or a sodium salt of treprostinil.

5. 10. The pharmaceutical composition of claim 1, wherein the iloprost or a pharmaceutically acceptable salt thereof is administered in a dose of at least 2.5 μg.

6. 6. The pharmaceutical composition of claim 5, wherein the iloprost or a pharmaceutically acceptable salt thereof is administered at a dose of 2.5 μg to 5 μg.

7. 10. The pharmaceutical composition of claim 1, wherein the treprostinil or a pharmaceutically acceptable salt thereof is administered in a dose of at least 5 μg.

8. 8. The pharmaceutical composition of claim 7, wherein the treprostinil or pharmaceutically acceptable salt is administered at a dose of 6 μg to 96 μg.

9. 8. The pharmaceutical composition of claim 7, wherein the treprostinil or a pharmaceutically acceptable salt thereof is administered at a dose of 5 μg to 120 μg.

10. 8. The pharmaceutical composition of claim 7, wherein the treprostinil or a pharmaceutically acceptable salt thereof is administered at a dose of 18 μg to 120 μg.

11. 10. The pharmaceutical composition of claim 1, wherein the administration occurs in at least two administration events per day.

12. 10. The pharmaceutical composition of claim 1, wherein the administration occurs in at least three administration events per day.

13. 10. The pharmaceutical composition of claim 1, wherein the single event of administering is three or fewer breaths.

14. The pharmaceutical composition of claim 1 , wherein the administration is as needed.

15. 15. The pharmaceutical composition of claim 14, wherein said administering is in response to said subject experiencing at least one undesirable symptom of said pulmonary hypertension.

16. 16. The pharmaceutical composition of claim 15, wherein the administration occurs in response to the subject experiencing respiratory distress.

17. The pharmaceutical composition of claim 1, wherein the pulmonary hypertension is pulmonary arterial hypertension.

18. The pharmaceutical composition according to claim 1, wherein the pulmonary hypertension is pulmonary hypertension associated with interstitial lung disease.

19. 1. A pharmaceutical composition for treating pulmonary hypertension, comprising administering by inhalation to a subject in need thereof a composition comprising (i) iloprost or a pharmaceutically acceptable salt thereof and (ii) treprostinil or a pharmaceutically acceptable salt thereof in a single event dose, wherein the dosage of iloprost or a pharmaceutically acceptable salt thereof delivered to the subject is at least 2.5 μg, and the dosage of treprostinil or a pharmaceutically acceptable salt thereof delivered to the subject is at least 5 μg.

20. 20. The pharmaceutical composition of claim 19, wherein the composition is a dry powder.

21. 221. The pharmaceutical composition of claim 19 or 220, wherein the administration is performed using a dry powder inhaler.

22. 20. The pharmaceutical composition of claim 19, wherein the administration is performed using a nebulizer.

23. 20. The pharmaceutical composition of claim 19, wherein the single event dose is administered in three or fewer breaths.

24. 20. The pharmaceutical composition of claim 19, wherein the administration occurs within 3 minutes.

25. 25. The pharmaceutical composition of claim 24, wherein the administration occurs in 1 minute or less.

26. 20. The pharmaceutical composition of claim 19, wherein the administration is in a single breath.

27. 20. The pharmaceutical composition of claim 19, wherein the composition comprises (i) iloprost or iloprost tromethamine and (ii) treprostinil or treprostinil sodium.

28. 20. The pharmaceutical composition of claim 19, wherein the administering is effected in at least two administration events per day, each of the at least two administration events comprising administering a single event dose of the composition.

29. 29. The pharmaceutical composition of claim 28, wherein the at least two administration events comprises two or three administration events per day.

30. 30. The pharmaceutical composition of claim 28, wherein the at least two administration events comprises two to five administration events per day.

31. 20. The pharmaceutical composition of claim 19, wherein the administration is as needed.

32. 20. The pharmaceutical composition of claim 19, wherein the pulmonary hypertension is pulmonary arterial hypertension.

33. 20. The pharmaceutical composition of claim 19, wherein the pulmonary hypertension is pulmonary hypertension associated with interstitial lung disease.

34. A pharmaceutical formulation comprising iloprost or a pharmaceutically acceptable salt thereof and treprostinil or a pharmaceutically acceptable salt thereof.

35. 35. The pharmaceutical formulation of claim 34, which is a liquid formulation.

36. 336. The pharmaceutical formulation of claim 334 or 335, which is an inhalable formulation.

37. 35. The pharmaceutical formulation of claim 34, wherein the concentration of iloprost in the formulation is from 5 μg / ml to 50 μg / ml.

38. 38. The pharmaceutical formulation of claim 37, wherein the concentration of iloprost is from 10 μg / ml to 20 μg / ml.

39. 35. The pharmaceutical formulation of claim 34, wherein the concentration of treprostinil in the formulation is from 200 μg / ml to 2000 μg / ml.

40. 40. The pharmaceutical formulation of claim 39, wherein the concentration of treprostinil is about 600 μg / ml.

41. 35. The pharmaceutical formulation of claim 34, wherein the formulation further comprises a buffering agent.

42. 42. The pharmaceutical formulation of claim 41, wherein the buffer comprises a sodium phosphate buffer.

43. 35. The pharmaceutical formulation of claim 34, wherein the formulation further comprises about 10 mM sodium phosphate buffer.

44. 35. The pharmaceutical formulation of claim 34, wherein the formulation further comprises a salt.

45. 45. The pharmaceutical formulation of claim 44, wherein the salt is sodium chloride.

46. 35. The pharmaceutical formulation of claim 34, wherein the formulation further comprises about 100 mM to 150 mM sodium chloride.

47. 47. The pharmaceutical formulation of claim 46, wherein the formulation comprises 115 mM to 125 mM sodium chloride.

48. 35. The pharmaceutical formulation of claim 34, wherein the formulation is an isotonic solution.

49. 35. The pharmaceutical formulation of claim 34, having a pH of about 6.0 to 7.

0.

50. 50. The pharmaceutical formulation of claim 49, having a pH of about 6.

5.

51. 35. The pharmaceutical formulation of claim 34, wherein the formulation has an osmolality of 250 mOsm / kg to 400 mOsm / kg.

52. 52. The pharmaceutical formulation of claim 51, wherein the osmolality is from 270 mOsm / kg to 340 mOsm / kg.

53. 35. The pharmaceutical formulation of claim 34, wherein the iloprost or a pharmaceutically acceptable salt thereof is iloprost or the tromethamine salt of iloprost.

54. 35. The pharmaceutical formulation of claim 34, wherein the treprostinil or a pharmaceutically acceptable salt thereof is treprostinil or a sodium salt of treprostinil.

55. 35. A pharmaceutical formulation for treating pulmonary hypertension, comprising administering by inhalation to a subject in need thereof the pharmaceutical formulation of claim 34.

56. 56. The pharmaceutical formulation of claim 55, wherein the single administering event occurs in 1 minute or less.

57. 57. The pharmaceutical formulation of claim 55 or 56, wherein the administration is performed using a nebulizer.

58. 56. The pharmaceutical formulation of claim 55, wherein the iloprost or a pharmaceutically acceptable salt thereof is administered in a dose of at least 2.5 μg.

59. 59. The pharmaceutical formulation of claim 58, wherein the iloprost or a pharmaceutically acceptable salt thereof is administered at a dose of 2.5 μg to 5 μg.

60. 56. The pharmaceutical formulation of claim 55, wherein the treprostinil or a pharmaceutically acceptable salt thereof is administered in a dose of at least 5 μg.

61. 61. The pharmaceutical formulation of claim 60, wherein the treprostinil or a pharmaceutically acceptable salt thereof is administered at a dose of 6 μg to 96 μg.

62. 61. The pharmaceutical formulation of claim 60, wherein the treprostinil or a pharmaceutically acceptable salt thereof is administered in a dose of 5 μg to 120 μg.

63. 61. The pharmaceutical formulation of claim 60, wherein the treprostinil or a pharmaceutically acceptable salt thereof is administered at a dose of 18 μg to 120 μg.

64. 56. The pharmaceutical formulation of claim 55, wherein the administration occurs in at least two administration events per day.

65. 56. The pharmaceutical formulation of claim 55, wherein the administration occurs in at least three administration events per day.

66. 56. The pharmaceutical formulation of claim 55, wherein the single administering event is three or fewer breaths.

67. 56. The pharmaceutical formulation of claim 55, wherein the administration is as needed.

68. 68. The pharmaceutical formulation of claim 67, wherein the administration is in response to a subject experiencing at least one undesirable symptom of pulmonary hypertension.

69. 69. The pharmaceutical formulation of claim 68, wherein the administration is in response to a subject experiencing respiratory distress.

70. 56. The pharmaceutical preparation of claim 55, wherein the pulmonary hypertension is pulmonary arterial hypertension.

71. 56. The pharmaceutical preparation of claim 55, wherein the pulmonary hypertension is pulmonary hypertension associated with interstitial lung disease.

72. 35. A dosage form comprising a dosing container and the pharmaceutical formulation of claim 34 within said container.

73. 73. The dosage form of claim 72, wherein the container is a glass container.

74. 73. The dosage form of claim 72, wherein the container is a plastic container.

Images