Treprostinil-ilo-prost combination therapy

Abstract

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

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 307,919, filed February 8, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application generally relates to compositions comprising prostacyclin and methods of treating diseases using prostacyclin, including compositions comprising treprostine and iloprost and methods of treating diseases using combinations comprising treprostine and iloprost. Summary of the Invention

[0004] One implementation is a method for treating pulmonary hypertension, which includes administering iloprost or a pharmaceutically acceptable salt thereof and treprostone or a pharmaceutically acceptable salt thereof to a subject in need by inhalation.

[0005] Another implementation is a method for treating pulmonary hypertension, comprising administering by inhalation, in a single-event dose, a composition comprising (i) iloprost or a pharmaceutically acceptable salt thereof and (ii) treprostene or a pharmaceutically acceptable salt thereof, wherein the dose of iloprost or a pharmaceutically acceptable salt thereof delivered to the subject is at least 2.5 μg and the dose of treprostene or a pharmaceutically acceptable salt thereof delivered to the subject is at least 5 μg. Attached Figure Description

[0006] The figure shows chromatograms of iloprost-soluble solutions at different pH levels (any units and minutes). Detailed Implementation

[0007] As used herein and in the claims, the singular forms “a,” “an,” and “the” include the plural unless the context clearly indicates otherwise. Throughout the specification, “comprising,” “including,” and “containing” are used inclusively rather than exclusively unless otherwise stated, so a specified integer or group of integers may include one or more other unspecified integers or groups of integers. The term “or” is inclusive unless modified, for example, by “any.” Thus, unless the context clearly indicates otherwise, the word “or” refers to any one member of a particular list and also includes any combination of members in that list. “Constitutes of” should refer to trace elements and substantial method steps excluding other ingredients. Each of these transitional terms defines an embodiment that is within the scope of this technology. When an embodiment is defined by one of these terms (such as “comprising”), it should be understood that this disclosure also includes alternative embodiments, such as “consistently constitutes the embodiment” and “composes of the embodiment.”

[0008] All numerical specifications, such as amounts, times, and concentrations, including ranges, are approximate values, varying in increments of 0.05%, 1%, 2%, 5%, 10%, or 20% (+) or (-). It should be understood that, although not always explicitly stated, all numerical specifications are preceded by the term "approximately".

[0009] "Subject" means an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experimentation. Unless otherwise stated, "subject" and "patient" may be used interchangeably. The methods described herein can be used for human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0010] Where a numerical range is provided, unless the context explicitly specifies otherwise, every value intermediate between the upper and lower limits of the range (one-tenth of a unit of the lower limit), as well as any other specified value or intermediate value within the specified range, is included in this technique. The upper and lower limits of these smaller ranges may be independently included within the smaller range and also within this technique, but are subject to any explicitly excluded limits within the specified range. When the specified range includes one or both limits, the range excluding one or both of those limits is also included in this technique.

[0011] “Pulmonary hypertension” (“PH”) refers to all forms of pulmonary hypertension, including all pulmonary hypertension included in WHO Groups 1–5, unless otherwise stated or obvious to a person skilled in the art. Pulmonary hypertension (PH) is a condition characterized by elevated pulmonary artery blood pressure. Symptoms of PH may include one or more of the following: shortness of breath, syncope, fatigue, chest pain, leg swelling, and rapid heartbeat. “Pulmonary hypertension” includes all forms of pulmonary arterial hypertension (“PAH”) (Group 1), including idiopathic and hereditary PAH. Pulmonary hypertension includes patients with symptoms of NYHA functional classification III. “Pulmonary hypertension” includes pulmonary hypertension caused by left ventricular disease (Group 2). “Pulmonary hypertension” includes pulmonary hypertension caused by 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 anemia, chronic hemolytic anemia, splenectomy, and certain metabolic disorders (Group 5). Generally, the treatment methods described in this article are most suitable for PAH (Group 1) and pulmonary hypertension in Group 3, including PH-ILD.

[0012] One embodiment is a method for treating pulmonary hypertension, which involves administering a combination of iloprost and treprostene to a subject (preferably someone with pulmonary hypertension) via inhalation. As an alternative to or supplement to treprostene or iloprost, a pharmaceutically acceptable salt, ester, or prodrug may be administered. For example, sodium salts of iloprost and treprostene may be administered to treat pulmonary hypertension. Unless otherwise stated, references to treprostene and iloprost herein include pharmaceutically acceptable salts, esters, and prodrugs of these compounds.

[0013] Iloprost (brand name: Ilomedine is used to treat pulmonary arterial hypertension (PAH), scleroderma, Raynaud's phenomenon, and other conditions involving vasoconstriction and impaired blood flow to tissues. Developed by Schering AG, it is marketed in Europe by Bayer Schering Pharma AG and in the United States by Actelion Pharmaceuticals. Ilomedine is a synthetic analogue of prostacyclin PGI2 and has the following structure:

[0014]

[0015] In the United States, iloprost The solution is approved for inhalation via I-Neb AAD or Prodose AAD delivery systems. In Europe, iloprost as Ventavis is approved for use with two compressed air nebulizers (Halolite and Prodose) with AAD delivery systems, as well as two ultrasonic nebulizers, Ventaneb and I-Neb.

[0016] Treprostrenil can also be used to treat pulmonary hypertension. Treprostrenil is a synthetic analogue of prostacyclin (PGI2) and has the following structure:

[0017]

[0018] (Trprostine) Injection, (treprostinil) inhalation solution and The active ingredient treprostrine in sustained-release tablets has been described in U.S. Patent No. 4,306,075. For example, 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. Methods for preparing treprostone and other prostacyclin derivatives are described in U.S. Patent Application Publications 2012-0197041, 2013-0331593, 2014-0024856, 2015-0299091, 2015-0376106, 2016-0107973, 2015-0315114, 2016-0152548 and 2016-0175319; and PCT Publications WO2016 / 0055819 and WO2016 / 081658.

[0019] For example, U.S. Patent 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, 8,410,169, 8,232,316, 8,609,728, 8,350,079, and 8,349,892 7,999,007, 8,658,694, 8,653,137, 9,029,607, 8,765,813, 9,050,311, 9,199,908, 9,278,901, 8,747,897, 9,358,240, 9,339,507, 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, 2014-0275262, 2013-0184295, 2014-0323567, 2016-0030371, 2016-0051505, 2016-0030355, 2016-0143 Various other uses and / or forms of triprostene are disclosed in patents 868, 2015-0328232, 2015-0148414, 2016-0045470, 2016-0129087, 2017-0095432; 2018-0153847; 2021-0330621 and PCT publications WO00 / 57701, WO20160105538, WO2016038532, WO2018 / 058124; WO2021 / 211916.

[0020] A "prodrug" of treprostinil refers to a compound that is converted in vivo into treprostinil or its pharmaceutically active derivatives, or PCT Publication No. WO2005 / 007081; US ​​Patent Nos. 7,384,978, 7,417,070, 7,544,713, 8,252,839, 8,410,169, 8,536,363, 9,050,311, 9,199,900. 8, 9,278,901, 9,422,223; 9,624,156, 9,878,972, 9,371,264, 9,394,227, 9,505,737, 9,758,465, 9,643,911, 9,701,616, 9,776,982, 9,845,305, 9,957,200, 10,494,327 10,053,414, 10,246,403, 10,344,012, 10,450,290, 10,464,877, 10,464,878, 10,703,706, 10,752,733, 9,255,064, 9,469,600, 10,010,518, 10,343,979, 10,526,274; The compounds described in U.S. Patent Application Publication Nos. 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, the entire contents of each of which are incorporated herein by reference.

[0021] "Pharmaceutically acceptable salts" are physiologically acceptable salts of treprostine, treprostine prodrug, or iloprost, as well as non-physiologically acceptable salts of treprostine, treprostine prodrug, or iloprost. Pharmaceutically acceptable salts of treprostine, treprostine prodrug, or iloprost fall within the scope of this technology, including base addition salts that retain the desired pharmacological activity and are biologically non-undesirable (e.g., the salt is not excessively toxic, allergenic, or irritating, and is bioavailable). Treprostine, treprostine prodrug, or iloprost has at least one acidic group, such as a carboxylic acid group. Therefore, treprostine, treprostine prodrug, or iloprost can react with metals such as alkali metals or alkaline earth metals (e.g., Na). + Li + K + Ca 2+ Mg 2+ Zn 2+Salts can be formed from ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, tromethamine) or basic amino acids (such as arginine, lysine, histidine, and ornithine). These salts can be prepared in situ during the separation and purification of the compound, or the purified free acid form of the compound can be reacted with a suitable base, and the resulting salt can be isolated.

[0022] Treatment can improve one or more physiological parameters associated with PH, or alleviate or reduce one or more symptoms associated with PH. For example, in some embodiments, treatment can lower pulmonary artery pressure. In other embodiments, treatment can improve exercise capacity, such as improving the distance covered in a six-minute walk test (6MWT). In some embodiments, treatment can alleviate or reduce more than one symptom of PH, such as reducing shortness of breath or syncope.

[0023] In some implementations, the combination of iloprost and treprostone can be administered via inhalation to treat pulmonary arterial hypertension (PAH). PAH is characterized by thickening (narrowing) 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 pressure can cause the heart to lose its ability to pump enough blood through the lungs to meet the needs of the rest of the body.

[0024] In some implementations, the combination of iloprost and treprostone can be administered by inhalation to treat pulmonary hypertension, WHO Group 3, which is pulmonary hypertension caused by conditions 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).

[0025] Chronic lung diseases can include obstructive lung diseases, in which the airways in the lungs are narrowed and it is difficult to exhale, such as chronic obstructive pulmonary disease (COPD) and emphysema; restrictive lung diseases, in which the lungs are difficult to expand during inhalation, such as interstitial lung disease or pulmonary fibrosis; sleep apnea; long-term living in high-altitude areas; and various combinations of the above conditions.

[0026] In some implementations, 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 pneumonia, occupational lung disease, pulmonary fibrosis, emphysema, connective tissue disease, or any combination of the above conditions.

[0027] Treprostrin or a pharmaceutically acceptable salt thereof and iloprost or a pharmaceutically acceptable salt thereof may be administered in a therapeutically effective amount, which may be an amount effective for the treatment of pulmonary hypertension.

[0028] While not bound by any theory, treprostrenil is effective for pulmonary hypertension (such as pulmonary arterial hypertension or pulmonary hypertension associated with interstitial lung disease) at least in part due to its beneficial vasodilatory effect on pulmonary vessels and / or its ability to induce pulmonary vascular remodeling. Iloprostol has a shorter half-life than treprostrenil. Because of its shorter half-life, iloprostol is generally administered more frequently. However, iloprostol has a more substantial inotropic effect than treprostrenil, which is beneficial to cardiac function. Combining the pulmonary vascular effects of treprostrenil and / or iloprostol with the relatively transient but substantial inotropic effect of iloprostol on the right ventricle can provide additional benefits to some patients with pulmonary hypertension that are not provided when either drug is administered as a monotherapy. For example, a combination of treprostrenil and iloprostol can be administered as needed (i.e., as required) to patients presenting with at least one undesirable symptom of pulmonary hypertension, such as dyspnea or tachypnea. The iloprost in this combination can provide a relatively short but substantial muscle-strengthening effect, which can alleviate or improve at least one undesirable symptom of pulmonary hypertension, such as shortness of breath or rapid breathing.

[0029] In some embodiments, the iloprost administered by inhalation in combination with treprostol can be iloprost as a free acid or iloprost tromethamine. In some embodiments, the treprostol administered by inhalation in combination with iloprostol can be treprostol as a free acid or treprostol sodium.

[0030] In some implementations, iloprost and treprostene can be administered simultaneously. For example, a patient may use any suitable delivery device, such as a nebulizer or dry powder inhaler, to administer both iloprost and treprostene. Simultaneous delivery can also be achieved using a composition containing treprostene and iloprost. A skilled technician can select the relative amounts of treprostene and iloprost based on the desired dosage, which will be discussed in more detail below. In some implementations, simultaneous administration is achieved using a rescue inhaler-type device that delivers a fixed amount of medication or sets an upper limit on the deliverable dose.

[0031] In other embodiments, iloprost and treprostene can be administered separately. These embodiments can be used to adjust the relative dosage of the drugs. For example, treprostene can be administered before or after iloprost. The drugs can be administered using the same or different delivery devices. 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 another drug can be administered using a dry powder inhaler. When iloprost and treprostene are administered separately, the administration can be immediate, for example, iloprost is administered immediately after treprostene (or vice versa), or separated in time, for example, iloprost is administered after treprostene (or vice versa). For example, the administration of iloprost and treprostene can be spaced approximately 2 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, or 4 hours apart. In some embodiments, the drugs are administered at different frequencies. For example, treprostene can be administered once, twice, three or four times daily, and iloprost can be administered four, five, six or more times daily. In some implementations, one of the drugs (such as iloprost) is administered as needed, while the other drug is administered according to a fixed dosage regimen, such as once, twice, three or four times daily.

[0032] In some embodiments, administration of iloprost and treprostone 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 shall 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 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 inhalation).

[0033] The number of single administration events per day for treprostrin, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug, administered 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 two, such as 2 to 5 events per day or 2 to 3 events per day.

[0034] In a single administration event, the dose or amount of treprostrin, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug, administered by inhalation, may vary. In some embodiments, the single administration event dose of treprostrin may be at least 5 μg or at least 6 μg. In some embodiments, the single administration event dose of treprostrin 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, or 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.

[0035] In a single administration event, the dose or amount of iloprost or its pharmaceutically acceptable salt administered by inhalation 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 from 2 μg to 10 μg, or from 2 μg to 9 μg, or from 2.5 μg to 5 μg, or any value or subrange within these ranges. In some embodiments, the daily dose of iloprost administered in all administration events of a single day may be less than 15 μg, or not greater than or less than 14 μg, or not greater than or less than 13 μg, or not greater than or less than 12 μg, or not greater than or less than 11 μg, or not greater than or less than 10 μg, or not greater than or less than 9 μg, or not greater than or less than 8 μg, or not greater than or less than 7 μg, or not greater than or less than 6 μg, or not greater than or less than 5 μg.

[0036] In some implementations, iloprost and treprostol can be administered via a single inhalation device, such as a nebulizer or dry powder inhaler, which may contain two separate compositions, one containing iloprost and the other containing treprostol.

[0037] In some embodiments, iloprost and treprostene can be administered in a single composition comprising (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostene, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug. While not bound by any particular theory, the inventors have found that treprostene, when combined with iloprost in the same composition, provides stability compared to the stability of iloprost in the composition when not combined with treprostene. In some embodiments, such a single composition can be a solution comprising (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostene, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug. The concentration of treprostene in such a solution can vary. In some embodiments, the treprostol concentration can be from 200 μg / ml to 2000 μg / ml, or from 300 μg / ml to 1500 μg / ml, or from 400 μg / ml to 1200 μg / ml, or any value or subrange within these ranges. For example, in one embodiment, the treprostol concentration can be 600 μg / ml. The concentration of iloprost in this solution can vary. In some embodiments, the iloprost concentration can be from 5 μg / ml to 50 μg / ml, or from 5 μg / ml to 40 μg / ml, or from 5 μg / ml to 30 μg / ml, or any value or subrange within these ranges. For example, in one embodiment, the iloprost concentration can be 10 μg / ml or 20 μg / ml.

[0038] In some embodiments, a composition comprising (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostyl, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug may be administered via oral or nasal inhalation. In some embodiments, a composition comprising (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostyl, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug may be administered via an inhalation device, such as a nebulizer. In some embodiments, a composition comprising (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostyl, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug may be administered, for example, via a pulse inhalation device, such as a metered inhaler and / or a pulse 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 entire contents of each of which are incorporated herein by reference.

[0039] In some embodiments, a composition comprising (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostyl, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a prodrug thereof may be administered as a dry powder composition. The dry powder composition may be administered via a dry powder inhaler, which may be a pulse 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 Publication WO2019237028, each of which is incorporated herein by reference.

[0040] In some embodiments, the dry powder inhaler may include a filter containing a dry powder composition, and the filter may be a replaceable filter. In some embodiments, the dry powder inhaler may be a respiratory-driven inhaler, which may be compact, reusable, or disposable. Dry powder inhalers can come in many different shapes and sizes and may include an airflow duct access system for effectively and rapidly delivering powdered medications to the lungs and / or systemic circulation.

[0041] In some embodiments, in addition to (a) iloprost or a pharmaceutically acceptable salt thereof and (b) treprostyl, its prodrug, its pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof, the dry powder composition may further comprise diketopiperazine, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)aminobutyl]-2,5-diketopiperazine (FDKP).

[0042] Patients treated using the methods described herein may receive additional therapies. In some implementations, subjects will receive background therapy for PH, in addition to which a combination of treprostol and iloprost will be added. For example, the combination of iloprost and treprostol may be added to existing therapy to address acute symptoms, such as exercise-induced symptoms. Background therapy may include phosphodiesterase-5 inhibitors (such as sildenafil and tadalafil), soluble guanylate cyclase stimulators (sGCS) (such as riociguat), endothelin receptor antagonists (ERA) (such as bosentan and ambesentan), or other prostacyclins.

[0043] In some embodiments, iloprost and treprostol 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 administered by inhalation.

[0044] The concentration of treprostol in pharmaceutical formulations (such as liquid pharmaceutical formulations) can vary. In some embodiments, the treprostol concentration can be from 200 μg / ml to 2000 μg / ml, or from 300 μg / ml to 1500 μg / ml, or from 400 μg / ml to 1200 μg / ml, or any value or subrange within these ranges. For example, in one embodiment, the treprostol concentration can be 600 μg / ml. The concentration of iloprost in pharmaceutical formulations (such as liquid pharmaceutical formulations) can vary. In some embodiments, the iloprostol concentration can be from 5 μg / ml to 50 μg / ml, or from 5 μg / ml to 40 μg / ml, or from 5 μg / ml to 30 μg / ml, or any value or subrange within these ranges. For example, in one embodiment, the iloprostol concentration can be 10 μg / ml or 20 μg / ml.

[0045] In some embodiments, in addition to iloprost and treprost, the pharmaceutical formulation (such as a liquid pharmaceutical formulation) may also include a buffer solution. In some embodiments, the buffer solution 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.

[0046] In some embodiments, the pharmaceutical formulation (such as a liquid pharmaceutical formulation) may also include a salt. For example, the salt may be an alkali metal halide, such as sodium chloride or sodium iodide. For example, in some embodiments, the formulation may include 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.

[0047] In some implementations, the pharmaceutical preparation (such as a liquid pharmaceutical preparation) may be an isotonic solution.

[0048] 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 about 6.9, or about 6.2 to about 6.8, or about 6.5.

[0049] In some embodiments, the pharmaceutical formulation (such as a liquid pharmaceutical formulation) may have an osmotic pressure 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.

[0050] In some embodiments, the pharmaceutical formulation (such as a liquid pharmaceutical formulation) may include ilorpost itself or a pharmaceutically acceptable salt thereof, such as tromethamine salt. In some embodiments, the pharmaceutical formulation (such as a liquid pharmaceutical formulation) may include treprostrin or a pharmaceutically acceptable salt thereof, such as a sodium salt, as a free base.

[0051] Pharmaceutical formulations (such as liquid formulations) can be administered to a subject (e.g., a human) for the treatment of pulmonary hypertension. In some embodiments, pharmaceutical formulations, such as liquid formulations, can be administered by inhalation. In some embodiments, pulmonary hypertension can be pulmonary arterial hypertension. In some embodiments, pulmonary hypertension can be pulmonary hypertension associated with interstitial lung disease.

[0052] In some embodiments, administration of the pharmaceutical formulation (such as a 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 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 inhalation).

[0053] In some implementations, a single administration of a pharmaceutical preparation (such as a liquid pharmaceutical preparation) may take less than about 10, 7, 5, 3, 2 or 1 minute.

[0054] The number of single administration events per day for a drug formulation (such as a liquid drug formulation) administered via 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 two, such as 2 to 5 times per day or 2 to 3 times per day.

[0055] In some embodiments, pharmaceutical formulations (such as liquid pharmaceutical formulations) can be administered, for example, via a pulse inhalation device, such as a metered-dose inhaler and / or a pulse nebulizer. Pulsed inhalation devices are disclosed, for example, in U.S. Patent Application Publication No. 20080200449, U.S. Patents 9,358,240, 9,339,507; 10,376,525; and 10,716,793, the entire contents of each of which are incorporated herein by reference.

[0056] In a single administration event of a pharmaceutical formulation (such as a liquid pharmaceutical formulation), the dose or amount of iloprost or its pharmaceutically acceptable salt administered by inhalation 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 from 2 μg to 10 μg, or from 2 μg to 9 μg, or from 2.5 μg to 5 μg, or any value or subrange within these ranges. In some embodiments, the daily dose of iloprost administered in all administration events throughout a day may be less than 15 μg, or not greater than or less than 14 μg, or not greater than or less than 13 μg, or not greater than or less than 12 μg, or not greater than or less than 11 μg, or not greater than or less than 10 μg, or not greater than or less than 9 μg, or not greater than or less than 8 μg, or not greater than or less than 7 μg, or not greater than or less than 6 μg, or not greater than or less than 5 μg.

[0057] In a single administration event of a pharmaceutical formulation (such as a liquid pharmaceutical formulation), the dose or amount of treprostene, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug, administered by inhalation, may vary. In some embodiments, the dose of treprostene in a single administration event may be at least 5 μg or at least 6 μg. In some embodiments, the dose of treprostene 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, or 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.

[0058] In some implementations, the pharmaceutical preparation (such as a liquid pharmaceutical preparation) may be administered as needed (i.e., as required) to a patient with at least one undesirable symptom of pulmonary hypertension (such as dyspnea or shortness of breath).

[0059] Iloprost stability in pharmaceutical formulations containing both iloprost and treprostene (such as liquid formulations) may be higher than that in other identical iloprost formulations that do not contain treprostene.

[0060] Pharmaceutical formulations containing both iloprost and treprostene (such as liquid formulations) can be storage-stable formulations and can be freshly prepared. Preferably, the formulation can be stored or be stored for at least 18 months, more preferably at least 24 months. In some embodiments, the formulation can be stored or be stored for at least two weeks, or at least one month, or at least six weeks, or at least two months, or at least ten weeks, or at least three months, or two weeks to three months, or one month to three months, or one month to two months. In some embodiments, preferably, the amount of iloprost in the formulation after storage is 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 can be carried out without cooling the formulation to a temperature below, for example, about 20°C. For example, in some embodiments, storage can be carried out at temperatures from about 20°C to about 50°C, or from about 22°C to about 45°C, or from about 25°C to about 40°C.

[0061] In some embodiments, pharmaceutical preparations (such as liquid pharmaceutical preparations) 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 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 is equipped with a removable cap that can be opened and closed, such as a rubber sealing cap attached to a glass container.

[0062] Dosage forms of pharmaceutical preparations (such as liquid pharmaceutical preparations) in containers are also provided. In some embodiments, the dosage form may be an inhalation dosage form. In some embodiments, the container may be a resealable container. In some embodiments, the container may be a vial or 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 pharmaceutical preparation (such as liquid pharmaceutical preparation) 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 liquid pharmaceutical preparation.

[0063] The implementation schemes described herein are further illustrated by the following working examples, but are not limited thereto.

[0064] Example

[0065] Example 1

[0066] Development of iloprost and treprostol formulations

[0067] The purpose of this embodiment is to describe the formulation development of an inhaled formulation of iloprost and treprostene. An isotonic formulation with a pH of 6.5 was developed.

[0068] Table 1. Definitions

[0069] the term definition ACN Acetonitrile HPLC High performance liquid chromatography <![CDATA[H3PO4]]> Phosphoric acid NaCl Sodium chloride UV Ultraviolet rays

[0070] program

[0071] Solubility assessment

[0072] 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 1 mg / mL iloprost was prepared in ethanol. The stock solution was diluted 10-fold in each buffer and thoroughly mixed. The buffer solutions were visually inspected for precipitation. The buffer solutions were filtered through a 0.45 μm nylon filter before HPLC analysis. The buffer solutions and associated pH values ​​are shown in Table 2. The HPLC conditions used for solubility analysis are shown in Table 3.

[0073] Table 2. Buffer solutions and associated pH values.

[0074] buffer solution Measured pH 10mM citrate 2.89 10mM acetate 5 10mM phosphate 6.23 10mM phosphate 7.27 10mM phosphonate 8.60

[0075] Table 3. HPLC conditions for soluble analysis.

[0076]

[0077] Formulation development

[0078] Development of iloprost formulations

[0079] Iloprost formulations were prepared at 10 μg / mL using two different NaCl concentrations. A 5 mg / mL iloprost stock solution was prepared in ethanol and diluted 500-fold in the formulation. The formulation was 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 osmolarity of the formulation was evaluated.

[0080] Development of iloprost and treprostol formulations

[0081] Two formulations of iloprost and treprostene were prepared, with iloprost at 10 μg / mL and treprostene at 600 μg / mL. A 5 mg / mL iloprost stock solution was prepared in ethanol and diluted 500-fold in the formulation. Treprostene was quantitatively weighed into the formulation. The formulation was buffered with two different NaCl concentrations (115 mM and 125 mM) in 10 mM sodium phosphate buffer. After adding treprostene, 3–4 drops of 1N NaOH were added to dissolve treprostene in the buffer. The pH was further adjusted to bring the pH of the formulation within 0.5 of the target pH of 6.5. The osmolarity of the formulation was evaluated.

[0082] Two formulations of iloprost and treprostene were prepared, with iloprost at 20 μg / mL and treprostene at 600 μg / mL. A 5 mg / mL iloprost stock solution was prepared in ethanol and diluted 250-fold in the formulation. Treprostene was quantitatively weighed into the formulation. The formulation was buffered with two different NaCl concentrations (115 mM and 125 mM) of 10 mM sodium phosphate buffer. After adding treprostene, 3–4 drops of 1N NaOH were added to dissolve treprostene in the buffer. The pH was further adjusted to bring the pH of the formulation within 0.5 of the target 6.5. The osmolarity of the formulation was evaluated.

[0083] Results and Discussion

[0084] Solubility assessment

[0085] No visible solubility issues were found. Visible observations and pH values ​​are shown in Table 4. The figure shows chromatograms of five different buffer solutions containing 100 μg / mL iloprost. Although no visible particles were found, chromatographic analysis suggests potential solubility issues below pH 6.

[0086] Table 4. Physical observations and pH of iloprost buffer solution.

[0087] buffer solution initial pH Final pH observe 10mM citrate 2.89 2.99 Colorless, with no visible particulate matter. 10mM Acetate 5.00 5.08 Colorless, with no visible particulate matter. 10mM phosphate 6.23 6.36 Colorless, with no visible particulate matter. 10mM phosphate 7.27 7.42 Colorless, with no visible particulate matter. 10mM phosphate 8.60 8.59 Colorless, with no visible particulate matter.

[0088] Formulation development

[0089] Development of iloprost formulations

[0090] Both 115 mM and 125 mM salt concentrations are within the isotonic range. The 125 mM formulation is closer to the target of 290 mOsm / kg. Table 5 summarizes the formulations and osmotic pressures.

[0091] Table 5. Iloprost preparations and osmotic pressure.

[0092] preparation Measured pH Measured osmotic pressure (mOsm / kg) 10 μg / mL iloprost, pH 6.5, 115 mM NaCl 6.45 272 10 μg / mL iloprost, pH 6.5, 125 mM NaCl 6.45 290

[0093] Development of Iloprost and Treprostinil Formulations

[0094] Treprostinil requires the addition of a base to dissolve in the formulation buffer. Additional pH adjustment results in an increase in the ions present. The 125 mM salt level in the second formulation (10 μg / mL iloprost and 600 μg / mL treprostinil) combined with the additional pH adjustment results in an osmotic pressure approaching the upper limit of the isotonic range. The 115 mM salt level is most suitable for maintaining the formulation in the middle of the isotonic solution range. Table 6 summarizes the formulations and osmotic pressures.

[0095] Table 6. Iloprost and Treprostinil Formulations and Osmotic Pressures.

[0096]

[0097] Conclusion

[0098] A 10 μg / mL iloprost formulation was developed in 10 mM sodium phosphate buffer at pH 6.5 containing 125 mM NaCl. Two formulations containing iloprost (10 and 20 μg / mL) and 600 μg / mL treprostinil were developed in 10 mM sodium phosphate buffer at pH 6.5 containing 115 mM NaCl.

[0099] Example 2

[0100] [[ID=二十一]]Stability Testing of Iloprost Formulations

[0101] Table 7: Summary of Stability Testing of 10 μg / mL Iloprost, pH 6.5, 125 mM NaCl, at 25 ± 2°C / 60 ± 5% RH, 5 mL Glass Vial, Sample Orientation: Inverted

[0102]

[0103] 1 Results were confirmed by reinjection and repackaging into vials.

[0104] Table 8: Summary of Single Impurities of 10 μg / mL Iloprost, pH 6.5, 125 mM NaCl, at 25 ± 2°C / 60 ± 5% RH, 5 mL Glass Vial

[0105]

[0106] Report the percentage of adjusted area of all impurities with RRT and ≥ 0.05% adjusted area

[0107] ND = Not Detected (< LOD). LOD represents "Limit of Detection".

[0108] ]>NR = Not Reported (≥ LOD and < 0.05%)

[0109] NT = Untested

[0110] Table 9: Summary of stability test results for 10 μg / mL iloprost, pH 6.5, 125 mM NaCl, at 40 ± 2℃ / 75 ± 5% RH, 5 mL glass vial, sample orientation: inverted.

[0111]

[0112] Table 10: Summary of single impurities in 10 μg / mL iloprost, pH 6.5, 125 mM NaCl, at 40 ± 2℃ / 75 ± 5% RH, 5 mL glass vials

[0113]

[0114] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0115] ND = Not detected ( <LOD)

[0116] NR = Not reported (≥LOD and <0.05%)

[0117] NT = Untested

[0118] Table 11: Summary of stability tests for 10 μg / mL iloprost, pH 6.5, 125 mM NaCl, at 25 ± 2℃ / 60 ± 5% RH, in 3 mL LDPE ampoules.

[0119]

[0120] 1 The difference between the two injected samples was approximately 4%.

[0121] Table 12: Summary of single impurities in 10 μg / mL iloprost, pH 6.5, 125 mM NaCl, at 25 ± 2℃ / 60 ± 5% RH, 3 mL LDPE ampoules

[0122]

[0123] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0124] ND = Not detected ( <LOD)

[0125] NR = Not reported (≥LOD and <0.05%)

[0126] NT = Untested

[0127] Table 13: Summary of stability tests for 10 μg / mL iloprost, pH 6.5, 125 mM NaCl, at 40 ± 2℃ / 75 ± 5% RH, in 3 mL LDPE ampoules.

[0128]

[0129] Table 14: Summary of single impurities in 10 μg / mL iloprost, pH 6.5, 125 mM NaCl, at 40 ± 2℃ / 75 ± 5% RH, 3 mL LDPE ampoules

[0130]

[0131] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0132] ND = Not detected ( <LOD)

[0133] NR = Not reported (≥LOD and <0.05%)

[0134] NT = Untested

[0135] Example 3

[0136] Stability testing of iloprost / treprostol formulation 1

[0137] Table 15: Summary of stability tests for 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25 ± 2℃ / 60 ± 5% RH, 5 mL glass vials. Sample orientation inverted.

[0138]

[0139] Table 16A: Summary of iloprost impurities in 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25 ± 2℃ / 60 ± 5% RH, 5 mL glass vials

[0140]

[0141] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0142] ND = Not detected ( <LOD)

[0143] NR = Not reported (≥LOD and <0.05%)

[0144] NT = Untested

[0145] Table 16B: Summary of treprost impurities in 10 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 25 ± 2℃ / 60 ± 5% RH, 5 mL glass vials

[0146]

[0147] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0148] ND = Not detected ( <LOD)

[0149] NR = Not reported (≥LOD and <0.05%)

[0150] NT = Untested

[0151] Table 17: Summary of stability tests for 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 5 mL glass vials, sample orientation: inverted.

[0152]

[0153] Table 18A: Summary of iloprost impurities in 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40 ± 2℃ / 75 ± 5% RH, 5 mL glass vials

[0154]

[0155] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0156] ND = Not detected ( <LOD)

[0157] NR = Not reported (≥LOD and <0.05%)

[0158] NT = Untested

[0159] Table 18B: Summary of treprost impurities in 10 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 5 mL glass vials

[0160]

[0161] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0162] ND = Not detected ( <LOD)

[0163] NR = Not reported (≥LOD and <0.05%)

[0164] NT = Untested

[0165] Table 19: Summary of stability tests for 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25±2℃ / 60±5% RH, in 3 mL LDPE ampoules.

[0166]

[0167] Table 20A: Summary of iloprost impurities in 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25±2℃ / 60±5% RH, 3 mL LDPE ampoules

[0168]

[0169] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0170] ND = Not detected ( <LOD)

[0171] NR = Not reported (≥LOD and <0.05%)

[0172] NT = Untested

[0173] Table 20B: Summary of treprost impurities in 10 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 25±2℃ / 60±5% RH, 3 mL LDPE ampoules

[0174]

[0175] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0176] ND = Not detected ( <LOD)

[0177] NR = Not reported (≥LOD and <0.05%)

[0178] NT = Untested

[0179] Table 21: Summary of stability tests for 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, in 3 mL LDPE ampoules.

[0180]

[0181]

[0182] Table 22A: Summary of iloprost impurities in 10 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 3 mL LDPE ampoules

[0183]

[0184] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0185] ND = Not detected ( <LOD)

[0186] NR = Not reported (≥LOD and <0.05%)

[0187] NT = Untested

[0188] Table 22B: Summary of treprost impurities in 10 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 3 mL LDPE ampoules

[0189]

[0190] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0191] ND = Not detected ( <LOD)

[0192] NR = Not reported (≥LOD and <0.05%)

[0193] NT = Untested

[0194] Example 4

[0195] Stability testing of iloprost / treprostol formulation 2

[0196] Table 23: Summary of stability tests for 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25±2℃ / 60±5% RH, 5 mL glass vials, sample orientation: inverted.

[0197]

[0198] Table 24A: Summary of iloprost impurities in 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25±2℃ / 60±5% RH, 5 mL glass vials

[0199]

[0200] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0201] ND = Not detected ( <LOD)

[0202] NR = Not reported (≥LOD and <0.05%)

[0203] NT = Untested

[0204] Table 24B: Summary of treprost impurities in 20 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 25 ± 2℃ / 60 ± 5% RH, 5 mL glass vials

[0205]

[0206] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0207] ND = Not detected ( <LOD)

[0208] NR = Not reported (≥LOD and <0.05%)

[0209] NT = Untested

[0210] Table 25: Summary of stability tests for 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 5 mL glass vials, sample orientation: inverted.

[0211]

[0212] Table 26A: Summary of iloprost impurities in 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 5 mL glass vials

[0213]

[0214] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0215] ND = Not detected ( <LOD)

[0216] NR = Not reported (≥LOD and <0.05%)

[0217] NT = Untested

[0218] Table 26B: Summary of treprost impurities in 20 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 40 ± 2℃ / 75 ± 5% RH, 5 mL glass vials

[0219]

[0220] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0221] ND = Not detected ( <LOD)

[0222] NR = Not reported (≥LOD and <0.05%)

[0223] NT = Untested

[0224] Table 27: Summary of stability tests for 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25 ± 2℃ / 60 ± 5% RH, in 3 mL LDPE ampoules.

[0225]

[0226] Table 28A: Summary of iloprost impurities in 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 25±2℃ / 60±5% RH, 3 mL LDPE ampoules

[0227]

[0228] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0229] ND = Not detected ( <LOD)

[0230] NR = Not reported (≥LOD and <0.05%)

[0231] NT = Untested

[0232] Table 28B: Summary of treprost impurities in 20 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 25±2℃ / 60±5% RH, 3 mL LDPE ampoules

[0233]

[0234] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0235] ND = Not detected ( <LOD)

[0236] NR = Not reported (≥LOD and <0.05%)

[0237] NT = Untested

[0238] Table 29: Summary of stability tests for 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, in 3 mL LDPE ampoules.

[0239]

[0240] Table 30A: Summary of iloprost impurities in 20 μg / mL iloprost and 600 μg / mL treprostone, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 3 mL LDPE ampoules

[0241]

[0242]

[0243] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0244] ND = Not detected ( <LOD)

[0245] NR = Not reported (≥LOD and <0.05%)

[0246] NT = Untested

[0247] Table 30B: Summary of treprost impurities in 20 μg / mL iloprost and 600 μg / mL treprost, pH 6.5, 115 mM NaCl, at 40±2℃ / 75±5% RH, 3 mL LDPE ampoules

[0248]

[0249] Report the RRT and the percentage of adjusted area for all impurities with an adjusted area of ​​≥0.05%.

[0250] ND = Not detected ( <LOD)

[0251] NR = Not reported (≥LOD and <0.05%)

[0252] NT = Untested

[0253] in conclusion

[0254] The stability test results in Examples 2-4 were surprisingly positive, showing that the iloprost in formulations 1 and 2 of Examples 3 and 4, which contained treprostyl, exhibited higher stability compared to the formulation of Example 2, which did not contain treprostyl. Without being constrained by any theoretical framework, these results may indicate that in formulations 1 and 2 of Examples 3 and 4, the iloprost molecules may attach to the treprostyl molecules.

[0255] ***

[0256] Although the foregoing describes specific preferred embodiments, it is understood that the present invention is not limited thereto. Various modifications can be made to the disclosed embodiments by those skilled in the art, and all such modifications are within the scope of the present invention.

[0257] All publications, patent applications and patents cited in this specification are incorporated herein by reference in their entirety.

Claims

1. Use of a composition comprising iloprost or a pharmaceutically acceptable salt thereof and treprostene or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pulmonary hypertension, wherein the concentration of iloprost or a pharmaceutically acceptable salt thereof in the composition is from 5 μg / ml to 30 μg / ml, wherein the concentration of treprostene or a pharmaceutically acceptable salt thereof in the composition is from 400 μg / ml to 1200 μg / ml, wherein the composition is a liquid composition.

2. The use according to claim 1, wherein the composition is administered in a single dose event.

3. The use according to claim 1, wherein the composition is applied in one minute or less.

4. The use according to claim 2, wherein the composition is applied in one minute or less.

5. The use according to any one of claims 1-4, wherein iloprost or a pharmaceutically acceptable salt thereof is iloprost or an tromethamine salt of iloprost.

6. The use according to any one of claims 1-4, wherein treprostene or a pharmaceutically acceptable salt thereof is treprostene or a sodium salt of treprostene.

7. The use according to any one of claims 1-4, wherein iloprost or a pharmaceutically acceptable salt thereof is administered at a dose of at least 2.5 µg.

8. The use according to claim 7, wherein iloprost or a pharmaceutically acceptable salt thereof is administered in doses of 2.5 µg to 5 µg.

9. The use according to any one of claims 1-4, wherein treprostinil or a pharmaceutically acceptable salt thereof is administered at a dose of at least 5 µg.

10. The use according to claim 9, wherein treprostinil or a pharmaceutically acceptable salt thereof is administered in doses from 6 µg to 96 µg.

11. The use according to claim 9, wherein treprostinil or a pharmaceutically acceptable salt thereof is administered in doses from 5 µg to 120 µg.

12. The use according to claim 9, wherein treprostinil or a pharmaceutically acceptable salt thereof is administered at a dose of 18 µg to 120 µg.

13. The use according to any one of claims 1-4, wherein the composition is applied at least twice a day.

14. The use according to any one of claims 1-4, wherein the composition is applied at least three times a day.

15. The use according to any one of claims 1-4, wherein a single event of administering the composition is three or fewer breaths.

16. The use according to any one of claims 1-4, wherein the composition is applied as needed.

17. The use according to claim 16, wherein the administration is performed when the subject experiences at least one undesirable symptom of pulmonary hypertension.

18. The use according to claim 17, wherein the administration is performed when the subject experiences respiratory distress.

19. The use according to any one of claims 1-4, wherein the pulmonary hypertension is pulmonary arterial hypertension.

20. The use according to any one of claims 1-4, wherein the pulmonary hypertension is pulmonary hypertension associated with interstitial lung disease.

21. The use according to any one of claims 1-4, wherein the composition further comprises a buffer solution.

22. The use according to claim 21, wherein the buffer solution comprises sodium phosphate buffer.

23. The use according to any one of claims 1-4, wherein the composition further comprises 10 mM sodium phosphate buffer.

24. The use according to any one of claims 1-4, wherein the composition is an isotonic solution.

25. The use according to any one of claims 1-4, wherein the osmotic pressure of said composition is from 250 mOsm / kg to 400 mOsm / kg.

26. The use according to claim 25, wherein the osmotic pressure is from 270 mOsm / kg to 340 mOsm / kg.

27. Use of a composition comprising (i) iloprost or a pharmaceutically acceptable salt thereof and (ii) treprostene or a pharmaceutically acceptable salt thereof in a method of preparing a medicament for treating pulmonary hypertension, wherein the method comprises administering the composition to a subject in need by inhalation at a single-event dose, wherein the dose of iloprost or a pharmaceutically acceptable salt thereof delivered to the subject is at least 2.5 μg, and wherein the dose of treprostene or a pharmaceutically acceptable salt thereof delivered to the subject is at least 5 μg, wherein the concentration of iloprost or a pharmaceutically acceptable salt thereof in the composition is from 5 μg / ml to 30 μg / ml, wherein the concentration of treprostene or a pharmaceutically acceptable salt thereof in the composition is from 400 μg / ml to 1200 μg / ml, wherein the composition is a liquid composition.

28. The use according to claim 27, wherein the application is performed using an atomizer.

29. The use according to claim 27 or 28, wherein the single-event dose is administered over three or fewer breaths.

30. The use according to claim 27 or 28, wherein the application is performed within 3 minutes.

31. The use according to claim 30, wherein the application is performed in one minute or less.

32. The use according to claim 27 or 28, wherein the administration is performed in a single breath.

33. The use according to claim 27 or 28, wherein the composition comprises (i) iloprost or iloprost tromethamine and (ii) treprostone or treprostone sodium.

34. The use according to claim 27 or 28, wherein the application is performed at least twice a day, each of the at least two application events comprising a single-event dose of the composition.

35. The use according to claim 34, wherein the at least two application events comprise two or three application events per day.

36. The use according to claim 34, wherein the at least two application events comprise two to five application events per day.

37. The use according to claim 27 or 28, wherein the application is performed as needed.

38. The use according to claim 27 or 28, wherein the pulmonary hypertension is pulmonary arterial hypertension.

39. The use according to claim 27 or 28, wherein the pulmonary hypertension is pulmonary hypertension associated with interstitial lung disease.

40. The use according to claim 27 or 28, wherein the composition further comprises a buffer solution.

41. The use according to claim 40, wherein the buffer comprises sodium phosphate buffer.

42. The use according to claim 27 or 28, wherein the composition further comprises 10 mM sodium phosphate buffer.

43. The use according to claim 27 or 28, wherein the composition is an isotonic solution.

44. The use according to claim 27 or 28, wherein the osmotic pressure of the composition is from 250 mOsm / kg to 400 mOsm / kg.

45. The use according to claim 44, wherein the osmotic pressure is from 270 mOsm / kg to 340 mOsm / kg.

46. ​​A pharmaceutical formulation comprising iloprost or a pharmaceutically acceptable salt thereof and treprostene or a pharmaceutically acceptable salt thereof, wherein the concentration of iloprost or a pharmaceutically acceptable salt thereof in the formulation is from 5 μg / ml to 30 μg / ml, and wherein the concentration of treprostene or a pharmaceutically acceptable salt thereof in the formulation is from 400 μg / ml to 1200 μg / ml, wherein the pharmaceutical formulation is a liquid formulation.

47. The pharmaceutical preparation according to claim 46, wherein it is an inhalable preparation.

48. The pharmaceutical formulation according to claim 46 or 47, wherein the concentration of iloprost is from 10 μg / ml to 20 μg / ml.

49. The pharmaceutical formulation according to claim 46 or 47, wherein the concentration of treprostinil is 600 μg / ml.

50. The pharmaceutical formulation according to claim 46 or 47, wherein the formulation further comprises a buffer solution.

51. The pharmaceutical formulation of claim 50, wherein the buffer solution comprises sodium phosphate buffer.

52. The pharmaceutical formulation according to claim 46 or 47, wherein the formulation further comprises 10 mM sodium phosphate buffer.

53. The pharmaceutical formulation according to claim 46 or 47, wherein the formulation further comprises a salt.

54. The pharmaceutical preparation according to claim 53, wherein the salt is sodium chloride.

55. The pharmaceutical formulation according to claim 46 or 47, wherein the formulation further comprises 100 mM to 150 mM sodium chloride.

56. The pharmaceutical formulation of claim 55, wherein the formulation comprises 115 mM to 125 mM sodium chloride.

57. The pharmaceutical preparation according to claim 46 or 47, wherein the preparation is an isotonic solution.

58. The pharmaceutical preparation according to claim 46 or 47, wherein the pH is 6.0 to 7.

0.

59. The pharmaceutical preparation according to claim 58, wherein the pH is 6.

5.

60. The pharmaceutical formulation according to claim 46 or 47, wherein the osmotic pressure of the formulation is from 250 mOsm / kg to 400 mOsm / kg.

61. The pharmaceutical formulation of claim 60, wherein the osmotic pressure is from 270 mOsm / kg to 340 mOsm / kg.

62. The pharmaceutical formulation according to claim 46 or 47, wherein iloprost or a pharmaceutically acceptable salt thereof is iloprost or an iloprost tromethamine salt.

63. The pharmaceutical formulation of claim 46 or 47, wherein the treprostene or a pharmaceutically acceptable salt thereof is treprostene or a sodium salt of treprostene.

64. Use of the pharmaceutical preparation according to any one of claims 46-63 in a medicament prepared for use in a method of treating pulmonary hypertension, wherein the method comprises administering the pharmaceutical preparation to a subject in need by inhalation.

65. The use according to claim 64, wherein the single application event is performed in one minute or less.

66. The use according to claim 64, wherein the application is performed using an atomizer.

67. The use according to any one of claims 64-66, wherein iloprost or a pharmaceutically acceptable salt thereof is administered at a dose of at least 2.5 μg.

68. The use according to claim 67, wherein iloprost or a pharmaceutically acceptable salt thereof is administered in doses of 2.5 μg to 5 μg.

69. The use according to any one of claims 64-66, wherein treprostrin or a pharmaceutically acceptable salt thereof is administered at a dose of at least 5 μg.

70. The use according to claim 69, wherein treprostinil or a pharmaceutically acceptable salt thereof is administered in doses from 6 μg to 96 μg.

71. The use according to claim 69, wherein treprostinil or a pharmaceutically acceptable salt thereof is administered in doses from 5 μg to 120 μg.

72. The use according to claim 69, wherein treprostinil or a pharmaceutically acceptable salt thereof is administered at a dose of 18 μg to 120 μg.

73. The use according to any one of claims 64-66, wherein the application is performed at least twice a day.

74. The use according to any one of claims 64-66, wherein the application is performed at least three times per day.

75. The use according to any one of claims 64-66, wherein the single event of application is three or fewer breaths.

76. The use according to any one of claims 64-66, wherein the application is performed as needed.

77. The use according to claim 76, wherein the administration is performed when the subject experiences at least one undesirable symptom of pulmonary hypertension.

78. The use according to claim 77, wherein the administration is performed when the subject experiences respiratory distress.

79. The use according to any one of claims 64-66, wherein the pulmonary hypertension is pulmonary arterial hypertension.

80. The use according to any one of claims 64-66, wherein the pulmonary hypertension is pulmonary hypertension associated with interstitial lung disease.

81. A dosage form comprising a dosing container and a pharmaceutical preparation in said container according to any one of claims 46-63.

82. The dosage form according to claim 81, wherein the container is a glass container.

83. The dosage form according to claim 81, wherein the container is a plastic container.

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