Injectable pharmaceutical composition for treating pulmonary hypertension

Abstract

The present invention relates to a pharmaceutical composition use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension. The pharmaceutical composition is administered at a time interval of 1 to 8 weeks, and comprises calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate or hydrate or solvate thereof in the form of an aqueous suspension. In particular, such suspension is an aqueous suspension comprising microparticles of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate or hydrate or solvate thereof; and further comprising a surfactant and / or wetting agent, a buffer and / or pH adjusting agent; and a pharmaceutically acceptable aqueous carrier.

Description

[0001] ACT6055USPSP4 INJECTABLE PHARMACEUTICAL COMPOSITION FOR TREATING PULMONARY HYPERTENSION Field of the Invention The present invention relates to an injectable pharmaceutical composition comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I) Formula (I) for treating pulmonary hypertension. The compound of formula (I) is the calcium salt of the metabolite of selexipag (calcium salt of JNJ-68006861), and has the formula Ca(C25H28N3O3)2, i.e., C50H56N6O6Ca (MW: 877.109). In the present invention, the terms “calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate”, “calcium;2-[4- [(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy]acetate”, “calcium;2-[4-[(5,6- diphenylpyrazin-2-yl)-isopropyl-amino]butoxy]acetate”, “calcium;2-[4-[(5,6- diphenylpyrazin-2-yl)- (propan-2-yl)-amino]butoxy]acetate”, “calcium salt of {4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetic acid”; “calcium salt of {4-[(5,6- diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid”; “calcium salt of 2-(4-((5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino)butoxy)acetic acid”; “calcium salt of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid”; “bis[[2-[4-[(5,6-diphenylpyrazin- 2-yl)-isopropyl-amino]butoxy]acetyl]oxy]calcium)” and calcium salt of the metabolite of selexipag (calcium salt of JNJ-68006861) are used synonymously. Selexipag (INN) is 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N- (methanesulfonyl)acetamide (ACT-293987, NS-304, CAS: 475086-01-2; 2-{4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide), also known as UPTRAVI™. The metabolite of selexipag is 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (MRE-269, ACT-333679, JNJ-68006861, 2-{4- [(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy}acetic acid; {4-[(5,6-diphenylpyrazin- 2-yl)(isopropyl)amino]butoxy}acetic acid; {4-[(5,6-diphenylpyrazin-2-yl)-(propan-2- yl)amino]butoxy}acetic acid; CAS: 475085-57-5 (MW 419.52)). Salts of selexipag metabolite are described in JP 2019-149945 and WO2021 / 033702. The present pharmaceutical composition in the form of an aqueous suspension is suitable for subcutaneous or intramuscular injection. It may also by filled as a solid product into vials or cartridges or lyophilized and reconstituted to give the respective aqueous suspension. Moreover, the present invention relates to the use of pharmaceutical compositions for the treatment or prevention of specific diseases, such as pulmonary hypertension, and, in particular, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), and a process to produce it. Background of the Invention The preparation and the medicinal use of selexipag and its active metabolite 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid is described in WO2002 / 088084; WO2009 / 157396; WO2009 / 107736; WO2009 / 154246; WO2009 / 157397; WO2009 / 157398; WO2010 / 150865; WO2011 / 024874; Nakamura et al., Bioorg Med Chem (2007), 15, 7720-7725; Kuwano et al., J Pharmacol Exp Ther (2007), 322(3), 1181- 1188; Kuwano et al., J Pharmacol Exp Ther (2008), 326(3), 691-699; O. Sitbon et al., N Engl J Med (2015), 373, 2522-33; Asaki et al., Bioorg Med Chem (2007), 15, 6692-6704; Asaki et al., J. Med. Chem. (2015), 58, 7128−7137. Intravenous formulations of selexipag are disclosed in WO2018 / 162527. Salts of selexipag metabolites are described in JP2019-149945. US20190022004 describes liposome compositions comprising weak acid drugs and uses thereof. EP3718537 describes stealth liposomes having a prostaglandin I2 receptor agonist encapsulated therein. Selexipag was shown to be beneficial in the treatment of pulmonary arterial hypertension. In a phase III clinical trial, among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower among patients who received selexipag than among those who received placebo. Selexipag received market approval e.g., in the US and is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. So far, standard film-coated tablet formulations of selexipag intended for twice daily oral administration have been used, wherein excipients comprise D-mannitol, corn starch, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and magnesium stearate; the tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxides. Moreover, a safety study of the switch from oral selexipag to intravenous selexipag in patients with PAH has been conducted (NCT03187678), whereby selexipag was administered twice daily as an infusion of approximately 87 minutes. The dose was individualized for each patient to correspond to his / her current oral dose of selexipag. Selexipag is thought to function as a prodrug (while retaining some agonistic activity on the prostacyclin receptor (IP receptor) on its own) which can exert long-lasting selective IP receptor agonist activity of the active metabolite 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid in mammals, especially humans. The in vivo metabolism of selexipag effectively may act as a kind of ‘slow-release mechanism’ that potentially both prolongs activity and reduces typical adverse effects associated with high concentrations of PGI2 agonists (Kuwano et al., J Pharmacol Exp Ther (2007), 322(3), 1181-1188). In certain instances, the use of an oral formulation of selexipag may be inappropriate or impossible, e.g., in urgent care, or in case a patient is for some reasons unable to swallow a tablet. Moreover, in general, it is desirable to reduce the drug burden, particularly for treatment regimens that may last several months or longer. The number and / or volume of dosage forms that need to be administered are commonly referred to as "drug burden". A high drug burden is undesirable for many reasons, such as the frequency of administration, often combined with the inconvenience of having to swallow large dosage forms, as well as the need to store and transport a large number or volume of pharmaceutical formulations. A high drug burden increases the risk of patients not taking their entire dose, thereby failing to comply with the prescribed dosage regimen. Therefore, there is a need to develop a pharmaceutical composition or formulation, whose pharmaceutical effect is maintained, for example, for one week or longer, or one month or longer, whereby it only has to be administered at long time intervals such as one week or longer, or even one month or longer (a long-acting formulation), e.g., three months. Long-acting injectable (LAI) drug formulations that permit less frequent dosing, on the order of a week or longer, even a month or longer, are an option to address patient compliance challenges and are more convenient for the patient. Moreover, more stable drug levels in blood improve efficacy, safety, and tolerability. However, suboptimal physicochemical properties of the drugs often limit their formulation as conventional drug suspensions, causing problems such as stability of the suspension, as well as insufficient maintenance of therapeutically effective plasma concentrations. A long-acting formulation of selexipag metabolite for treating PAH or CTEPH is described in WO2022 / 162158, incorporated by reference herein, which includes an aqueous suspension of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate having a Dv50 particle size of 1 to 50 µm. Nonetheless, improvements for a long-acting formulation are desirable. Summary of the Invention It is an object of the present invention to provide a long-acting formulation of selexipag metabolite, 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid. The inventors of the investigational drug product described herein were tasked with creating an investigational drug product that was safe for testing in humans to eventually assess whether the investigational drug product was safe, tolerated, and effective to treat diseases modulated by the IP receptor, notably pulmonary hypertension and in particular PAH or CTEPH. For example, considering the long term treatment of PAH or CTEPH, the inventors were not only charged with determining a specific and stable formulation of the investigational drug product including 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid but they were also tasked with ensuring that this formulation would release 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid to the PAH or CTEPH patient in need thereof for a period of at least 14 days, without exhibiting a significant burst release in the first hours / days after administration and at the same time providing over the whole release period a therapeutically effective dosage of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid to the patient. Thus, they have now found that selexipag metabolite can advantageously be formulated into a long-acting formulation by using a calcium salt of selexipag metabolite or hydrate or solvate thereof, i.e., calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate, in a micronized form either in suspension or in solid form. Therefore, the present invention relates to a pharmaceutical composition suitable for administration by subcutaneous or intramuscular injection, comprising calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate or hydrate or solvate thereof in the form of an aqueous suspension. In particular, a pharmaceutical composition is disclosed for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension, wherein the pharmaceutical composition is administered at a time interval of one week to eight weeks and comprises about eq.1 mg to about eq.160 mg of the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof, having a Dv50 particle size of 1 to 50 µm; a surfactant and / or wetting agent; a buffer and / or pH adjusting agent; and a pharmaceutically acceptable aqueous carrier, wherein the pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C, and the concentration of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is from eq.25 mg / mL to eq.100 mg / mL. In other embodiments, the pharmaceutical composition for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension further comprises a flocculating agent. The long-acting profile of the formulation avoids frequent plasma peak and trough levels and achieves minimal toxic concentration and longer therapeutic duration. Moreover, the number of prostacyclin-associated adverse events was lower after single-dose subcutaneous administration of the long-acting formulation of the calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate compared to multiple oral doses of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid. In another embodiment, the disclosure relates to a method of transitioning a patient being treated with an oral dosage form of selexipag to a long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof for treating and / or prevention of pulmonary hypertension, wherein the long acting injectable is a pharmaceutical composition in the form of an aqueous suspension comprising: (a) about eq.1 mg to about eq.160 mg of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I) having a Dv50 particle size of 1 to 50 µm; (b) a surfactant and / or wetting agent; (c) a buffer and / or pH adjusting agent; and (d) a pharmaceutically acceptable aqueous carrier; wherein the pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C; wherein the concentration of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate is from eq.25 mg / mL to eq.100 mg / mL; wherein the oral dosage form of selexipag is administered at an individual maximum tolerated dose (iMTD), where administration of said iMTD of selexipag provides to thepatient an individual average plasma concentration CiMTDavg of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861), the oral dosage form is discontinued, and the pharmaceutical composition is administered at a time interval of one week to eight weeks at a dosage of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof selected to provide to the patient an average plasma concentration of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is about equal to or higher than CiMTDavg. Description of the Figures Fig.1 shows the plasma concentrations of the different studied formulations containing selexipag, selexipag metabolite (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)- butoxy)acetic acid; JNJ-68006861; ACT-333679), and the calcium salt of selexipag metabolite (calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate; Ca- slat of JNJ-68006861; Ca-salt of ACT-333679) in function of time. Fig.2 and Fig.3 show PK rat profiles with different particle sizes (Dv50 of 2, 5, 8 µm (micrometer)) of calcium salt of selexipag metabolite and different surfactants / wetting agents (polysorbate 20 and poloxamer 338). Fig.4 shows resulting particle size distributions of the differently formulated drug products (calcium salt of selexipag metabolite) with different particle size. Fig.5 shows resulting particle size distributions of the differently formulated drug products (calcium salt of selexipag metabolite) with different surfactants / wetting agents. Fig.6 shows resulting particle size distribution with calcium salt of selexipag metabolite at a concentration of 200 mg / mL. Fig.7 shows resulting particle size distributions of the differently formulated drug products (calcium salt of selexipag metabolite) with different amounts of resuspending agent. Fig.8 shows the results of zeta potential as function of pH of suspension. Fig.9 shows plasma concentration of selexipag metabolite over a period of 12 hours when injected at different concentrations in healthy volunteers. Fig.10 shows a general scheme for the Example 18 PK study of a long acting injectable. Fig.11 shows the plasma concentrations of different formulations of selexipag metabolite from Example 18. Fig.12 shows the plasma concentrations of different formulations of selexipag metabolite from Example 18. Fig.13 shows a general scheme for the Example 19 PK study of a long acting injectable. Fig.14 shows the plasma concentrations of different formulations of selexipag metabolite from Example 20. Fig.15 shows the plasma concentrations of different formulations of selexipag metabolite from Example 20. Detailed Description of the Invention The present invention is concerned with a pharmaceutical composition in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I). The present invention is concerned with a pharmaceutical composition for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension, wherein the pharmaceutical composition is administered at a time interval of one week to eight weeks , wherein the pharmaceutical composition is in the form of an aqueous suspension comprising: (a) about eq.1 mg to about eq.160 mg of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I) having a Dv50 particle size of 1 to 50 µm; (b) a surfactant and / or wetting agent; (c) a buffer and / or pH adjusting agent; and (d) a pharmaceutically acceptable aqueous carrier; wherein the pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C; wherein the concentration of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate is from eq.25 mg / mL to eq.100 mg / mL. In some embodiments, the present invention is concerned with a pharmaceutical composition in the form of an aqueous suspension comprising (a) calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I) having a Dv50 particle size of 1 to 50 µm; (b) a surfactant and / or wetting agent; (c) a flocculating agent; (d) optionally, a resuspending agent; and (e) a pharmaceutically acceptable aqueous carrier; wherein the pharmaceutical composition has a pH in the range of 6 to 9 at 20-25 °C, and in particular in the range of 6 to 8.5. The present pharmaceutical composition is a suspension, by which we mean that the active ingredient calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is suspended in the pharmaceutically acceptable aqueous carrier. Thereby, pharmaceutical compositions in the form of an aqueous suspension are suitable for intramuscular and / or subcutaneous injection, in particular to a human patient in need thereof. In some embodiments, the pharmaceutical composition is in the form of an intramuscular injection. In some embodiments, the pharmaceutical composition is in the form of a subcutaneous injection. Calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, having the structure of formula (I) as indicated above, may be in anhydrous form, or in a hydrate form or a pharmaceutically acceptable solvate form. The term "pharmaceutically acceptable solvate" refers to solvates that retain the desired biological activity of the compound and exhibit minimal undesired toxicological effects. Preferred is an anhydrous form or a hydrate form. Calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate may be in a hydrate form. The hydrate form may be from about 0.1 to about 1 water molecules per calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate molecule. In some embodiments, the molar ratio of water to calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate ranges from about 0.1 to about 1, such as about 0.1 to about 0.15, about 0.15 to about 0.2, about 0.2 to about 0.25, about 0.25, to about 0.3, about 0.3 to about 0.35, about 0.35 to about 0.4, about 0.4 to about 0.45, about 0.45 to about 0.5, about 0.5 to about 0.55, about 0.55 to about 0.6, about 0.6 to about 0.65, about 0.65 to about 0.7, about 0.7 to about 0.75, about 0.75 to about 0.8, about 0.8 to about 0.85, about 0.85 to about 0.9, about 0.9 to about 0.95, about 0.95 to about 1. The molar ratio of water in the hydrate form may change based on storage conditions of the compound, the method of formation of the compound, and the crystal structure of the compound. In some embodiments, calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or hydrate or solvate thereof is provided in a micronized form, i.e., in particles having a Dv50 particle size of 1 to 50 µm (micrometer), or 1 to 40 µm (micrometer), or 1 to 30 µm (micrometer), or 1 to 20 µm (micrometer), or 1 to 18 µm (micrometer), or 1 to 15 µm (micrometer), or 2 to 50 µm (micrometer), or 2 to 40 µm (micrometer), or 2 to 30 µm (micrometer), or 2 to 20 µm (micrometer), or 2 to 18 µm (micrometer), or 2 to 15 µm (micrometer), or 3 to 50 µm (micrometer), or 3 to 40 µm (micrometer), or 3 to 30 µm (micrometer), or 3 to 20 µm (micrometer), or 3 to 18 µm (micrometer), or 3 to 15 µm (micrometer), or 4 to 50 µm (micrometer), or 4 to 40 µm (micrometer), or 4 to 30 µm (micrometer), or 4 to 20 µm (micrometer), or 4 to 18 µm (micrometer), or 4 to 15 µm (micrometer), or 5 to 50 µm (micrometer), or 5 to 40 µm (micrometer), or 5 to 30 µm (micrometer), or 5 to 20 µm (micrometer), or 5 to 18 µm (micrometer), or 5 to 15 µm (micrometer). In some embodiments, the Dv50 particle size is 5 µm (micrometer) ±10%, or 5 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 6 µm (micrometer) ±10%, or 6 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 7 µm (micrometer) ±10%, or 7 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 8 µm (micrometer) ±10%, or 8 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 9 µm (micrometer) ±10%, or 9 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 10 µm (micrometer) ±10%, or 10 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 11 µm (micrometer) ±10%, or 11 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 12 µm (micrometer) ±10%, or 12 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 13 µm (micrometer) ±10%, or 13 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 14 µm (micrometer) ±10%, or 14 µm (micrometer) ±5%; in some embodiments, the Dv50 particle size is 15 µm (micrometer) ±10%, or 15 µm (micrometer) ±5%. The particles used herein are micro-particles, and the aqueous suspension is termed a micro-suspension, i.e., an aqueous micro-suspension. Particle size is defined herein as Dv50, also known as the median diameter. Median values are defined as the value where half of the population resides above this point, and half resides below this point. For particle size distributions (PSD) the median is called the D50 (or x50 when following certain ISO guidelines). The D50 is the size in microns (micrometer, µm) that splits the distribution with half above and half below this diameter. The Dv50 (or Dv0.5) is the median for a volume distribution. The volume distribution is the primary result from laser diffraction. Herein, PSD is given in volume distribution. PSD can be measured by well-known methods in the art, for example, laser diffraction, sedimentation field flow fractionation, photon correlation spectroscopy or disk centrifugation. Thereby, laser diffraction (LD) measures particle size distribution by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. Larger particles scatter light more intense than smaller particles and will be more intensively presented in the output of the LD analysis, the volumetric size distribution. The angular scattering intensity data is then analysed to calculate the size of the particles responsible for creating the scattering pattern. In the present application, PSD was measured with a Malvern Mastersizer 3000 apparatus from Malvern Panalytical using the laser diffraction measurement method and the Mie theory. The results of the laser diffraction analyses are reported based on the particle size volume distribution as the cumulative undersize values Dv50. The measurement method is disclosed in the experimental part. Preferably, calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, having the structure of formula (I) as indicated above, is used in crystalline form. In some embodiments, the pharmaceutical composition comprises a surfactant and / or wetting agent, or a mixture of surfactants and / or wetting agents. A “surfactant and / or wetting agent” (surfactant / wetting agent) as used herein is pharmaceutically acceptable and able to stabilise the aqueous suspension. The surfactant and / or wetting agent may be non-ionic or ionic. Surfactants and / or wetting agents are well known in the art. Representative examples of surfactants and / or wetting agents include gelatin, casein, lecithin, salts of negatively charged phospholipids or the acid form thereof (such as phosphatidyl glycerol, phosphatidyl inosite, phosphatidyl serine, phosphatic acid, and their salts such as alkali metal salts, e.g., their sodium salts, for example egg phosphatidyl glycerol sodium, such as the product available under the tradename Lipoid™ EPG), gum acacia, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives such as polyoxyl 35 castor oil (CREMOPHORTMEL) or polyoxyl 40 hydrogenated castor oil (CREMOPHORTMRH40); polyoxyethylene stearates, colloidal silicon dioxide, sodium dodecylsulfate, carboxymethylcellulose sodium, bile salts such as sodium taurocholate, sodium desoxytaurocholate, sodium desoxycholate, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminate silicate, polyvinyl alcohol (PVA), poloxamers (which are block copolymers of ethylene oxide and propylene oxide), such as poloxamer 188, poloxamer 338 and poloxamer 407 (tradenames are Pluronic™ F68, F108 and F127); tyloxapol; d-α-tocopheryl polyethylene glycol succinate (TPGS), in particular α-tocopheryl polyethylene glycol 1000 succinate; poloxamines, such as Tetronic™ 908 (T908) which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine; dextran; lecithin; dioctyl ester of sodium sulfosuccinic acid such as the products sold under the tradename Aerosol OT™ (AOT); sodium lauryl sulphate (Duponol™ P); alkyl aryl polyether sulfonate available under the tradename Triton™ X- 200; polyoxyethylene sorbitan fatty acid esters or polysorbates (such as polysorbate 20, 40, 60 and 80, known also as TWEEN®20, 40, 60 and 80); sorbitan esters of fatty acids (Span™ 20, 40, 60 and 80 or ARLACEL™ 20, 40, 60 and 80); sucrose stearate and sucrose distearate mixtures such as the product available under the tradename CRODESTA™ F110 or CRODESTA™ SL-40; hexadecyl trimethyl ammonium chloride (HTAC); polyvinylpyrrolidone (PVP), sodium dodecyl sulphate (SDS), docusate sodium, sodium deoxycholate, macrogol 15 hydroxystearate (SOLUTOLTMHS 15), octoxynol (octoxynol-9, octoxynol-10), or simethicone. If desired, two or more surfactants and or wetting agents can be used in combination. In one embodiment, the surfactants / wetting agents may be selected from one or more of a polysorbate, a poloxamer, an α-tocopheryl polyethylene glycol succinate, a salt of a negatively charged phospholipid (e.g., egg phosphatidylglycerols), lecithin, polyvinylpyrrolidone (PVP), docusate sodium, sodium deoxycholate, sodium dodecyl sulphate (SDS), polyoxyethylene castor oil derivatives, macrogol 15 hydroxystearate, or mixtures thereof. Preferred surfactants / wetting agents are polysorbates, poloxamers and α-tocopheryl polyethylene glycol succinates, for example polysorbate 20, polysorbate 80, poloxamer 188, poloxamer 338, poloxamer 407, TPGS, egg phosphatidylglycerol (Egg PG), and mixtures thereof. Particularly preferred surfactants / wetting agents are polysorbate 20, poloxamer 338, TPGS, or mixtures thereof; for instance polysorbate 20 and / or poloxamer 338. Polysorbates are polyoxyethylene sorbitan fatty acid esters. Polyoxyethylene sorbitan fatty acid esters / polysorbates is the nonprorietary name, and several grades thereof are available, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. Polysorbates are derived from ethoxylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Examples for polysorbates are Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The different types of polysorbate differ in the fatty acid, the average number of polyoxyethylene units in the molecule and the degree of esterification. The two-digit number of the name of each polysorbate follows a certain scheme: The first number stands for the mainly esterified fatty acid: 2 = lauric acid, 4 = palmitic acid, 6 = stearic acid, 8 = oleic acid, 12 = isostearic acid. The second digit indicates the type of esterification: 0 for a monoester with 20 polyoxyethylene units, 1 for a monoester with 4 or 5 polyoxyethylene units and the number 5 stands for a triester with 20 polyoxyethylene units. The preferred polysorbate 20 (CAS No 9005-64-5, E 432) is for instance sold under the brand name TWEEN®20. Poloxamers are non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), i.e., they are polyoxypropylene-polyoxyethylene copolymers. Preferred poloxamers are poloxamer 188, poloxamer 338, and poloxamer 407, in particular poloxamer 338. α-Tocopheryl polyethylene glycol succinate as used herein refers to TPGS, i.e., d-α- tocopheryl polyethylene glycol 1000 succinate, also referred to as tocophersolan (INCI), CAS No.9002-96-4. Lecithins are phosphatidylcholines. Herein, lecithin refers to any of a group of phospholipids, occurring in animal and plant tissues and egg yolk, composed of elements of choline, phosphoric acid, fatty acids, and glycerol. Salts of a negatively charged phospholipid or the acid form thereof, are for example phosphatidyl glycerol, phosphatidyl inosite, phosphatidyl serine, phosphatic acid, and their salts such as alkali metal salts, e.g., their sodium salts, for example egg phosphatidyl glycerol sodium, such as the product available under the tradename Lipoid™ EPG). Polyvinylpyrrolidone (povidone, PVP) has the molecular formula of (C6H9NO)n. United States Pharmacopeia (USP) 32 describes povidone as a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of polymerization of which results in polymers of various molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, in the range 10–120. The K-value is calculated using Fikentscher’s equation. Several are available, such as PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90 or PVP K120. Preferred is PVP K17. The optimal relative amount of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate, in relation to the surfactant / wetting agent depends on the surfactant / wetting agent selected, the specific surface area of the drug suspension which is determined by the average effective particle size and the drug concentration, the critical micelle concentration of the surfactant / wetting agent if it forms micelles, etc. The relative amount (w / w) of drug to the surfactant / wetting agent preferably is in the range 20:1 to 2:1, in particular in the range of 18:1 to 4:1. The pharmaceutical composition optionally comprises a resuspending agent. A resuspending agent as used herein is pharmaceutically acceptable and able to stabilise the aqueous suspension in order to avoid caking during shelf-life, or needle clogging, or to facilitate resuspending the formulation after storage. The resuspending agent is selected from the group consisting of polyethylene glycol (PEG) of various polymerization grades, carmellose sodium, and poloxamers, or a mixture thereof; preferably polyethylene glycol (PEG) of various polymerization grades, and carmellose sodium, or a mixture thereof. Preferred resuspending agents are selected from the group consisting of PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, and carmellose sodium, or a mixture thereof; in particular PEG 4000. It may be noted that poloxamers can function as surfactants / wetting agents, but also as resuspending agents, because they contribute to some viscosity in the suspension. In one embodiment, the resuspending agent is selected from the group consisting of PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, carmellose sodium, Poloxamer 338, and Poloxamer 407, or a mixture thereof. Preferred resuspending agents are selected from the group consisting of PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, and carmellose sodium, or a mixture thereof, in particular polyethylene glycol 4000 (PEG 4000). Polyethylene glycol (PEG) exists in various polymerization grades. The structure of PEG is commonly expressed as H−(O−CH2−CH2)n−OH. Polyethylene glycols (PEGs) are available in various grades, which is indicated as a number, for instance PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000 or PEG 20000. The number is indicative for the average molecular weight of the polymer. Carmellose sodium (carboxymethylcellulose sodium) has a viscosity of 27-63 mPa.s, such as 34-50 mPa.s, 34-64 mPa.s, 30-56 mPa.s, and 27-50 mPa.s (Viscosity 2%), 0.65 to 0.90 degree of substitution and 7.0-8.8% Na content (calculated vs DS). The product conforms to the monograph for carmellose sodium in the current European Pharmacopeia. The optimal relative amount (w / w) of the drug, i.e., calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate, in relation to the resuspending agent depends on the resuspending agent selected, and is preferably in the range of 2:1 to 1:3, in particular 2:1 to 1:1. It is to be noted that each indicated surfactant / wetting agent described above may be combined with each resuspending agent mentioned herein. Particularly preferred combinations are polysorbate 20 with PEG 4000, poloxamer 338 with PEG 4000, TPGS with PEG 4000, poloxamer 338 and carmellose sodium, polysorbate 80 and carmellose sodium, and poloxamer 338 and TPGS. The pharmaceutical composition comprises a pharmaceutically acceptable aqueous carrier. Said aqueous carrier comprises sterile water, i.e., water suitable for injection, optionally in admixture with other pharmaceutically acceptable ingredients. These ingredients may be selected from one or more of a buffering agent, a pH adjusting agent, a preservative or an isotonifying agent. The aqueous carrier has a pH in the range of 6 to 8.5. Further pH ranges are from 7 to 8.5, or pH 8, i.e., pH 8 ±1 / 2, or pH 7.5, i.e., 7.5 ±1 / 2. In some embodiments, the composition comprises one or more buffering and / or pH adjusting agent(s), rendering the pH of the pharmaceutical composition in the range of 6 to 8.5; 7 to 8.5, or pH 8, i.e., pH 8 ±1 / 2, or pH 7.5, i.e., 7.5 ±1 / 2. The pH is measured at a temperature of 20-25 °C. In some embodiments, the buffering and / or pH adjusting agent(s) is / are selected from the group consisting of tris(hydroxymethyl)aminomethane (TRIS), histidine, HCl and NaOH, or a mixture thereof. Thereby, the buffering agents are tris(hydroxymethyl)aminomethane (TRIS) and histidine; and the pH-adjusting agents are HCl or NaOH, preferably in aqueous solution. In particular, the buffering and / or pH adjusting agent(s) is / are selected from the group consisting of tris(hydroxymethyl)aminomethane (TRIS), HCl and NaOH, or a mixture thereof. Thereby, the buffering agent is tris(hydroxymethyl)aminomethane (TRIS); and the pH-adjusting agents are HCl or NaOH, preferably in aqueous solution. In some embodiments, the buffering agent comprises histidine. In some embodiments, the buffering agent comprises tris(hydroxymethyl)aminomethane (TRIS). In some embodiments, the buffering agent comprises histidine and tris(hydroxymethyl)aminomethane (TRIS). The use of histidine, for example, allows the formulation to be worked with at elevated temperatures, such as to sterilize by autoclavation. A preferred pH of the pharmaceutical composition is pH 7.5 ±1 / 2. Micro-suspensions may be formulated with TRIS buffer. The buffering agent or buffer is able to provide stability to the formulation, i.e., to prevent dissociation into the free from of the metabolite of selexipag, i.e., the free acetic acid derivative. The buffer strength ranges from 5 to 100 millimolar (mM), or from 10 to 50 mM. In some embodiments, the composition comprises one or more flocculating agents. The flocculating agent allows the formation of loose and porous aggregates which are more easily redispersed by agitation. In some embodiments, the flocculating agent is a Ca2+containing agent. In some embodiments, the flocculating agent is selected from calcium chloride, calcium chloride dihydrate, calcium acetate, calcium saccharate, calcium hydroxide, calcium citrate, calcium disodium edetate, calcium saccharin, calcium lactate, or mixtures thereof. In some embodiments, the pharmaceutical composition comprises from 1 to 30 mg / mL of the flocculating agent, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg / mL and ranges within those amounts. In some embodiments, the pharmaceutical composition comprises from 1 to 8 mg / mL of the flocculating agent, such as 1, 2, 3, 4, 5, 6, 7, or 8 mg / mL and ranges within those amounts. In some embodiments, the flocculating agent comprises calcium chloride or calcium chloride dihydrate. In some embodiments, the pharmaceutical composition comprises from 1 to 8 mg / mL of the calcium chloride or calcium chloride dihydrate flocculating agent, such as 1, 2, 3, 4, 5, 6, 7, or 8 mg / mL and ranges within those amounts. In some embodiments, the flocculating agent comprises calcium chloride or calcium chloride dihydrate and the buffering and / or pH adjusting agent comprises tris(hydroxymethyl)aminomethane. In some embodiments, calcium chloride dihydrate may replace calcium chloride. Suitable optional preservatives for the pharmaceutical compositions comprise antimicrobials and antioxidants which can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, a gallate, a hydroxybenzoate, ethylenediaminetetraacetic acid (EDTA) or edetate, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ- piccolinium chloride, phenylmercuric acetate and thimerosal. Radical scavengers include BHA, BHT, Vitamin E and ascorbyl palmitate, and mixtures thereof. Oxygen scavengers include sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, acetone sodium bisulfite, isoacorbic acid, hydroxypropyl cyclodextrin. Chelating agents include sodium citrate, sodium EDTA and malic acid. In one embodiment, the composition does not contain a perseverative. An isotonifying agent or isotonifier may be present to ensure isotonicity of the pharmaceutical composition, and includes sugars such as mannitol, glucose, dextrose, sucrose, fructose, trehalose, lactose; polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol. Alternatively, sodium chloride, sodium sulphate, or other appropriate inorganic salts may be used to render the solutions isotonic. These isotonifiers can be used alone or in combination. The aqueous suspensions conveniently comprise from 0 to 10% (w / v), in particular 0 to 6% of isotonifying agent. Of interest are non-ionic isotonifiers, e.g., glucose, as electrolytes may affect colloidal stability. In one embodiment, the composition contains an isotonifying agent or isotonifier, which, in a further embodiment is a non-ionic isotonifier, such as a suitable sugar such as mannitol. A desirable feature for a pharmaceutical composition relates to the ease of administration. The viscosity of the pharmaceutical composition should be sufficiently low to allow administration by injection, and sufficiently high to maintain slow sedimentation and good resuspendability. In particular it should be designed so that it can be taken up easily in a syringe (e.g., from a vial), injected through a fine needle (e.g., a 19 G to 25 G needle) in not too long a time span. In one embodiment the viscosity of the composition is from 1mPa·s to 75 mPa·s at 200 s-1, or from 5 mPa·s to 40 mPa·s at 200 s-1.Ideally, the aqueous suspension will comprise as much calcium;{4-[(5,6-diphenylpyrazin- 2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof, as can be tolerated so as to keep the injection volume to a minimum, in particular 1% to 50% (w / v), or from 1% to 45% (w / v), or from 1% to 40% (w / v), or from 1% to 35% (w / v), or from 1% to 30% (w / v), or from 1% to 25% (w / v), or from 1% to 20% (w / v), or from 1% to 15% (w / v), notably 2% to 50% (w / v), or from 2% to 45% (w / v), or from 2% to 40% (w / v), or from 2% to 35% (w / v), or from 2% to 30% (w / v), or from 2% to 25% (w / v), or from 2% to 20% (w / v), or from 2% to 15% (w / v), and in particular from 2.5% to 10% (w / v). Ideally, the amount of surfactant / wetting agent is selected as low as possible but effective and robust, in particular from 0.5% to 20% (w / v), or from 0.5% to 15% (w / v), or from 0.5% to 12% (w / v) or from 0.5% to 10% (w / v), or from 0.5% to 8% (w / v), or from 0.5% to 7% (w / v), or from 0.5% to 6% (w / v), or from 0.5% to 5% (w / v), or from 0.5% to 4% (w / v), or from 0.5% to 3% (w / v), or from 0.5% to 2% (w / v), of a surfactant / wetting agent, or a mixture of surfactants / wetting agents. In some embodiments, there is 0.125% to 20% (w / v), or from 0.125% to 15% (w / v), or from 0.125% to 12% (w / v) or from 0.125% to 10% (w / v), or from 0.125% to 8% (w / v), or from 0.125% to 7% (w / v), or from 0.125% to 6% (w / v), or from 0.125% to 5% (w / v), or from 0.125% to 4% (w / v), or from 0.125% to 3% (w / v), or from 0.125% to 2% (w / v), of a surfactant / wetting agent, or a mixture of surfactants / wetting agents. In some embodiments, there is 0.1% to 20% (w / v), or from 0.1% to 15% (w / v), or from 0.1% to 12% (w / v) or from 0.1% to 10% (w / v), or from 0.1% to 8% (w / v), or from 0.1% to 7% (w / v), or from 0.1% to 6% (w / v), or from 0.1% to 5% (w / v), or from 0.1% to 4% (w / v), or from 0.1% to 3% (w / v), or from 0.1% to 2% (w / v), of a surfactant / wetting agent, or a mixture of surfactants / wetting agents. In some embodiments, there is 0.25% to 20% (w / v), or from 0.25% to 15% (w / v), or from 0.25% to 12% (w / v) or from 0.25% to 10% (w / v), or from 0.25% to 8% (w / v), or from 0.25% to 7% (w / v), or from 0.25% to 6% (w / v), or from 0.25% to 5% (w / v), or from 0.25% to 4% (w / v), or from 0.25% to 3% (w / v), or from 0.25% to 2% (w / v), of a surfactant / wetting agent, or a mixture of surfactants / wetting agents. Ideally, the amount of resuspending agent is selected as low as possible but effective, in particular from 0% to 30% (w / v), or from 1% to 30% (w / v), or from 1% to 25%, or from 1% to 20% (w / v), or from 1 to 15% (w / v), or from 3 to 10% (w / v) of a resuspending agent or a mixture of resuspending agents. Ideally, the amount of buffering agent is selected as low as possible but effective, in particular from 0 to 100 mM, or from 5 to 100 mM, or from 5 to 50 mM, or from 10 to 50 mM of a buffering agent, or a mixture of buffering agents. In one embodiment, the pharmaceutical composition comprises by weight based on the total volume of composition (a) from 1% to 50% (w / v), or from 2% to 50% (w / v), or from 2% to 30% (w / v), or from 2% to 15% (w / v) or from 2.5% to 10% (w / v) of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate (or a pharmaceutically acceptable hydrate or solvate thereof; but where the w / v is calculated on the basis of its anhydrous form); (b) from 0.5% to 20% (w / v), or from 0.5% to 15% (w / v), or from 0.5% to 12% (w / v), or 0.5% to 10%, or from 0.5% to 8% (w / v), or from 0.5% to 7% (w / v), or from 0.5% to 6% (w / v), or from 0.5% to 5% (w / v), or from 0.5% to 4% (w / v), or from 0.5% to 3% (w / v), of a surfactant / wetting agent or a mixture of surfactants / wetting agents; alternatively from 0.1% to 20% (w / v), or from 0.1% to 15% (w / v), or from 0.1% to 12% (w / v) or from 0.1% to 10% (w / v), or from 0.1% to 8% (w / v), or from 0.1% to 7% (w / v), or from 0.1% to 6% (w / v), or from 0.1% to 5% (w / v), or from 0.1% to 4% (w / v), or from 0.1% to 3% (w / v), or from 0.1% to 2% (w / v), of a surfactant / wetting agent, or a mixture of surfactants / wetting agents; (c) from 0% to 30% (w / v), or from 1% to 30% (w / v), or from 1% to 20% (w / v), or from 1 to 15% (w / v) or from 3 to 10% (w / v) of a resuspending agent or a mixture of resuspending agents; and (d) from 0 to 100 mM, or from 5 to 50 mM, or from 10 to 50 mM of a buffering agent, or mixtures thereof; (e) optionally from 1 to 30 mg / mL of a flocculating agent (f) water for injection q.s. ad 100%. In one embodiment, the pharmaceutical composition comprises by weight based on the total volume of composition (a) from 2% to 15% (w / v) or from 2.5% to 10% (w / v) of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate (or a pharmaceutically acceptable hydrate or solvate thereof; but where the w / v is calculated on the basis of its anhydrous form); (b) from 0.5% to 12% (w / v), or 0.5% to 10%, or from 0.5% to 8% (w / v), or from 0.5% to 7% (w / v), or from 0.5% to 6% (w / v), or from 0.5% to 5% (w / v), or from 0.5% to 4% (w / v), or from 0.5% to 3% (w / v), of a surfactant / wetting agent or a mixture of surfactants / wetting agents; alternatively from 0.1% to 20% (w / v), or from 0.1% to 15% (w / v), or from 0.1% to 12% (w / v) or from 0.1% to 10% (w / v), or from 0.1% to 8% (w / v), or from 0.1% to 7% (w / v), or from 0.1% to 6% (w / v), or from 0.1% to 5% (w / v), or from 0.1% to 4% (w / v), or from 0.1% to 3% (w / v), or from 0.1% to 2% (w / v), of a surfactant / wetting agent, or a mixture of surfactants / wetting agents; (c) from 0 to 15% (w / v), or from 1 to 15% (w / v) or from 3 to 10% (w / v) of a resuspending agent or a mixture of resuspending agents; and (d) from 5 to 50 mM, or from 10 to 50 mM of a buffering agent, or mixtures thereof; (e) optionally from 1 to 30 mg / mL of a flocculating agent (f) water for injection q.s. ad 100%. Thereby, the surfactant / wetting agent, the optional resuspending agent, and buffering agents, as well as mixtures thereof, are as described above. Calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate can be prepared as described in the example part. The pharmaceutical compositions as described herein may be in a container, notably in a vial or cartridge or in a syringe; especially in a syringe. In some embodiments, a pharmaceutical composition as described herein can be prepared by a process comprising the steps of: (a) adding calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof, to a liquid medium comprising a surfactant and / or wetting agent at a pH in the range of 6 to 8.5, optionally a resuspending agent; a flocculating agent; and a pharmaceutically acceptable aqueous carrier, to form a premix / predispersion; and (b) subjecting the premix to mechanical means in the presence of a grinding medium to reduce the average effective particle size. The particle size of the micro-particles can be prepared by mechanical means known in the art. In one embodiment a method is used comprising the steps of dispersing calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof (drug) in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug to an average effective particle size of 50 µm (micrometer) or less, in particular to the desired Dv50 particle size as indicated above. The grinding media for the particle size reduction step can be selected from rigid media preferably spherical or particulate in form having an average size less than 3 mm and, more preferably, less than 2 mm, such as 1 mm ±10%, or 1 mm ±5%. Examples of grinding media are ZrO2such as 95% ZrO2stabilized with magnesia or stabilized with yttrium, zirconium silicate, glass grinding media, polymeric beads, stainless steel, titania, alumina and the like. Preferred grinding media have a density greater than 2.5 g / cm3and include 95% ZrO2stabilized with magnesia and polymeric beads. The particles should be reduced in size at a temperature that does not significantly degrade the drug. Processing temperatures of less than 30 to 40 °C are ordinarily preferred. If desired, the processing equipment may be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures, which are safe and effective for the milling process. The liquid medium for milling comprises a surfactant / wetting agent, optionally a resuspending agent; and a pharmaceutically acceptable aqueous carrier at a pH in the range of 6 to 8.5, to form a premix / predispersion. The surfactant / wetting agent, the optional resuspending agent, and the pharmaceutically acceptable aqueous carrier, including buffering and pH adjusting agents are preferably those described above. Preferably, the premix / predispersion is over-concentrated, and subsequently diluted to final volume directly before filling. The final formulation is separated from the grinding media by adequate separation methods known in the field. The calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate can be sterilized using gamma irradiation, and used for aseptically manufacturing final drug product. The final drug product can be sterilized using gamma irradiation or heat sterilization, e.g., autoclaving (steam sterilising) at elevated temperatures. Suitable conditions for autoclavation (steam sterilisation) are 15 min at 121-124 °C (± 2 °C). A pressure is built up to allow for the desired temperature. Conditions relating to validation as prescribed in the Pharmacopeia, e.g., “US Pharmacopeia”, or “The International Pharmacopoeia, Ninth Edition 2019”, etc. should be taken into account. Suitable conditions for gamma irradiation are achieved by exposure to ionizing radiation in the form of gamma radiation from a suitable radioisotopic source such as60Co (cobalt 60) or of electrons energized by a suitable electron accelerator. Suitable conditions are radiation levels of 5 to 60 kGy, for instance 5 kGy, 25 kGy, 40 kGy, 50 kGy, or 60 kGy. Conditions relating to validation as prescribed in the Pharmacopeia, e.g., “US Pharmacopeia”, or “The International Pharmacopoeia, Ninth Edition 2019”, etc. should be taken into account. Hence, the present invention further relates to a process for preparing a sterile pharmaceutical composition as described above, wherein the pharmaceutical composition is sterilized with autoclavation (steam sterilisation), or with gamma-irradiation; or wherein calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is sterilised with gamma-irradiation and which is then used for aseptically preparing the pharmaceutical composition. A sterile pharmaceutical composition is obtainable by said process. The bioindicator strain proposed for validation of autoclavation (steam sterilisation) process is: spores of Bacillus stearothermophilus (e.g., ATCC 7953 or CIP 52.81) for which the D-value (i.e., 90% reduction of the microbial population) is 1.5-2 minutes at 121 °C, using about 106 spores per indicator. The bioindicator strains proposed for validation of gamma-irradiation sterilisation process in general are: spores of Bacillus pumilus (e.g., ATCC 27142 or CIP 77.25) with 25 kGy (2.5 Mrad) for which the D-value is about 3 kGy (0.3 Mrad) using 107-108 spores per indicator; for higher doses, spores of Bacillus cereus (e.g., SSI C 1 / 1) or Bacillus sphaericus (e.g., SSl C1A) are used. The pharmaceutical compositions as described herein can further be lyophilized, i.e., freeze-dried, and a lyophilized injectable composition will be obtained. The pharmaceutical composition will, prior to freeze drying, preferably be filled into containers (unit dose or multi-dose containers such as vials or cartridges) suitable for storage of the lyophilized cake, and suitable for the later reconstitution of the pharmaceutical composition. Such containers may be filled under an inert gas atmosphere (such as notably a nitrogen atmosphere). Such inert gas atmosphere may reduce oxidative degradation of the active ingredient. A further embodiment thus relates to a container such as for example a vial, a cartridge, an ampoule, a syringe, a coupled chamber device, a pen device, or an autoinjector device, especially a vial or a cartridge, filled with a pharmaceutical composition as described above. The steps for lyophilisation / freeze-drying of the pharmaceutical composition in the form of an aqueous suspension as described herein comprise a step of freezing the pharmaceutical composition in a container and drying it by applying a vacuum. The freezing temperature is in the range from -55 °C to -35 °C, preferably from -50 °C to -35 °C, preferably from -45 °C to -35 °C; for instance, -40 °C ± 3 °C. The drying temperature is in the range from -55 °C to +30 °C, preferably from -50 °C to 28 °C, preferably from -45 °C to 28 °C. The freezing and the drying temperature may be applied as a fixed temperature, or as a temperature ramp. Preferably, the end temperatures of each procedural step are reached via a temperature ramp. During freeze-drying, a vacuum is applied to the pharmaceutical composition. Preferably, a vacuum of 0.05 to 1.5 mbar is applied, for instance 0.1 mbar. The vacuum is applied after the freezing step, and during drying. The drying procedure may be divided into several steps, for instance a primary drying step, and a secondary drying step, whereby each step may be followed by a holding step, i.e., holding the pharmaceutical composition at the temperature and pressure reached at the end of the preceding drying step. Moreover, the container can be stoppered after the freeze-drying procedure. Stoppering the container may further include a step of capping the container. The method of freeze-drying preferably comprises the following steps: a) preparing an aqueous pharmaceutical composition as described above; and b) freeze-drying said aqueous pharmaceutical composition to form a cake using a method comprising the steps of: (i) freezing the aqueous pharmaceutical composition at a first temperature for a period sufficient to transform the liquid formulation into solid state, wherein said first temperature is in the range from -55 °C to -35 °C, preferably from -50 °C to - 35 °C, preferably from -45 °C to -35 °C; for instance to -40 °C ± 3 °C; (ii) optionally holding the frozen composition at the temperature of step (i); (iii) applying a primary drying step by subjecting the frozen composition at the temperature of step (i) or (ii) to a vacuum (preferably a vacuum of 0.05 to 1.5 mbar), and applying a temperature ramp in the range from -55 °C to -25 °C; preferably from -50 °C to -25 °C, preferably from -45 °C to -25 °C, for instance from -40 °C ± 3 °C to -20 °C ± 3 °C; (iv) optionally holding the frozen composition at the end temperature of step (iii) under vacuum (preferably a vacuum of 0.05 to 1.5 mbar); (v) applying a secondary drying step by subjecting the composition of step (iii) or (iv) to a vacuum (preferably a vacuum of 0.05 to 1.5 mbar), and applying a temperature ramp, starting with the end-temperature of step (iii) or step (iv) and proceeding to a temperature in a range from 15 °C to 30 °C, preferably from 20 °C to 28 °C, for instance 25 °C ± 3 °C; (vi) optionally holding the end-temperature of step (v) and the vacuum; (vii) releasing the vacuum. This method may be applied to an aqueous composition as described above, contained in a container, whereby the container is stoppered, and optionally capped, after releasing of the vacuum. The term “cake” refers to a dry solid material that results when a liquid formulation has been lyophilized or freeze dried. The pharmaceutical compositions as described herein can be in the form of a lyophilised pharmaceutical composition. In particular, it can be a lyophilised pharmaceutical composition obtainable by the lyophilisation process described above, e.g., by freezing the pharmaceutical composition in a container, and drying it by applying a vacuum. Moreover, the lyophilised pharmaceutical composition as described herein may be reconstituted by adding at least one diluent to said lyophilised pharmaceutical composition to provide a reconstituted pharmaceutical composition. Suitable diluents to reconstitute said pharmaceutical composition include any diluent that is a safe, stable and pharmaceutically acceptable carrier. Preferred is water for injection (WFI) such as especially sterile water for injection (SWFI) or bacteriostatic water for injection (BWFI), optionally containing a tonicity modifier, or mixtures of several tonicity modifiers, such as aqueous (preferably physiological) saline. One embodiment relates to a pharmaceutical composition as described herein for use in the treatment and / or prevention of a disease and / or disorder selected from the group consisting of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pressure ulcer (bedsore), hypertension, pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion / restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), transient ischemic attack (TIA), diabetic neuropathy, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, allergy, bronchial asthma, restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., renal diseases such as tubulointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia, (idiopathic) pulmonary fibrosis, chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g., myocardial fibrosis), bone and articular diseases (e.g., bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g., cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis, type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostate, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti- inflammatory agent and symptoms associated with lumbar spinal canal stenosis. Preferred disease and / or disorders are selected from the group consisting of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance, connective tissue disease, chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved, and respiratory diseases. In certain embodiments, the pharmaceutical compositions described herein are for use in the treatment and / or prevention of pulmonary hypertension, in particular, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis. Particularly preferred is pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). The pharmaceutical compositions described herein, in particular for the treatment of the above-indicated diseases and / or disorders, is preferably in the form of a subcutaneous or intramuscular injectable. Thereby, the injectable is a long-acting injectable (LAI). The term "long-acting injectable" is used herein for an administration interval of one week to three months, or 1 week to two months, or 1 week to one month, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks. In some embodiments, the pharmaceutical composition is administered at a time interval of 1 week to 8 weeks, such as a time interval of 1 week, a time interval of 2 weeks, a time interval of 3 weeks, a time interval of 4 weeks, a time interval of 5 weeks, a time interval of 6 weeks, a time interval of 7 weeks, or a time interval of 8 weeks. In some embodiments, the pharmaceutical composition is administered at a time interval of 1 week to 4 weeks. When the pharmaceutical composition is administered at a time interval, it is administered once during that period of time and will typically have repeated administrations. For example, in a particular embodiment, the pharmaceutical composition is administered once every 4 weeks. A month is considered to be 4 weeks. In some embodiments, the pharmaceutical composition is administered at a time interval of 4 weeks. The administered dose may range from eq.10 mg to eq.100 mg of the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof. In some embodiments, the pharmaceutical composition is administered at a time interval of 3 weeks. The administered dose may range from eq.5 mg to eq.80 mg of the calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof. In some embodiments, the pharmaceutical composition is administered at a time interval of 2 weeks. The administered dose may range from eq. 2.5 mg to eq.50 mg of the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof. The pharmaceutical compositions described herein provide release of the active ingredient over a prolonged period of time and therefore it can also be referred to as sustained or delayed release composition. After administration, the composition stays in the body and steadily releases 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid or its calcium salt, keeping such levels of this active ingredient in the patient's system for a prolonged period of time, thereby providing, during said period, the appropriate treatment or prevention of the above-given diseases and / or disorders, in particular PAH and CTEPH. Because of the fact that the pharmaceutical compositions described herein facilitate that the active ingredient stay in the body and steadily releases the active ingredient, it can be referred to as pharmaceutical composition suitable as long-acting (or depot) formulations. A long-acting injectable pharmaceutical composition as disclosed herein allows less frequent dosing and more stable drug levels in blood. This improves efficacy, safety, and tolerability. A daily oral dose results in a rapid increase in the drug level in blood which may not be tolerated. In some embodiments, administration of the pharmaceutical composition to a subject in need results in a Cmaxof less than 10 ng / mL within 6 hours. In some embodiments, the Cmaxis less than 10 ng / mL within 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours of administration. In some embodiments, within 6 hours after administration, the Cmaxis less than 20 ng / mL, 15 ng / mL, 10 ng / mL, 8 ng / mL, 6 ng / mL, or 5 ng / mL. A long-acting injectable pharmaceutical composition allows for a more even drug level in the blood. After the blood plasma concentration is at Cmaxthe concentration gradually decreases. In some embodiments, four weeks after administration of the pharmaceutical composition, the blood plasma concentration is greater than 40% of the Cmax. In some embodiments, four weeks after administration of the pharmaceutical composition, the blood plasma concentration is greater than 30%, 35%, 40%, 45%, 50%, or 55% of the Cmax. In some embodiments, the blood plasma concentration is greater than 40% of the Cmax2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration. The Ctroughis the lowest blood plasma concentration. Typically, Ctroughis the blood plasma concentration right before the next administrations of the pharmaceutical composition. In some embodiments, when the pharmaceutical composition is administered once every 4 weeks, the ratio of the Cmaxto Ctroughranges from 4:1 to 1.5:1. In some embodiments, the ratio of the Cmaxto Ctroughranges from 4:1 to 1.5:1, such as 3.5:1 to 1.5:1, 3:1 to 1.5:1, 2.5:1 to 1.5:1, 4:1 to 2:1, 4:1 to 2.5:1, or 4:1 to 3:1. In some embodiments, the ratio of the Cmaxto Ctroughranges from 4:1 to 1.5:1 when the pharmaceutical composition is administered once every 1 to 8 weeks, such as 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. Injection of selexipag metabolite can induce pain, tenderness, erythema / redness, and induration / swelling at the injection site. Novel pharmaceutical compositions have been found that result in less pain, tenderness, erythema / redness, and induration / swelling. It has been found that pharmaceutical compositions with higher concentrations of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof result in less injection site pain, tenderness, erythema / redness, and induration / swelling compared to lower concentrations. In some embodiments, a pharmaceutical composition for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension is disclosed. The pharmaceutical composition is in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I); a surfactant and / or wetting agent; and a buffer and / or pH adjusting agent. The pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C. In some embodiments, the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof has a Dv50 particle size from 2 to 30 µm. The peak plasma concentration (Cmax) and the area under the curve (AUC) within the first 12 hours after injection are believed to impact injection site reactions of pain, tenderness, erythema / redness, and induration / swelling. In some embodiments, within 6 hours of administration the Cmaxis less than 0.5 ng / mL per mg of calcium;{4-[(5,6-diphenylpyrazin- 2-yl)(propan-2-yl)amino]butoxy}acetate administered to the subject. In some embodiments, within 6 hours of administration the Cmaxis less than 0.7 ng / ml per mg of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate administered to the subject, such as 0.7 ng / ml to 0.6 ng / ml, 0.6 ng / ml to 0.5 ng / ml, 0.5 ng / ml to 0.4 ng / ml, 0.4 ng / ml to 0.3 ng / ml, 0.3 ng / ml to 0.2 ng / ml, 0.2 ng / ml to 0.1 ng / ml, and ranges therein. In some embodiments, within 12 hours of administration the Cmaxis less than 6 ng / mL, such as 6 ng / ml to 5 ng / ml, 5 ng / ml to 4 ng / ml, 4 ng / ml to 3 ng / ml, 3 ng / ml to 2 ng / ml, 2 ng / ml to 1 ng / ml, and ranges therein. In some embodiments, the AUC0-12his less than 3.2 ng / mL per mg of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate administered to the subject. In some embodiments, the AUC0-12his less than 3.2 ng / ml per mg of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate administered to the subject, such as 3.2 ng / ml to 3.0 ng / ml, 3.0 ng / ml to 2.8 ng / ml, 2.8 ng / ml to 2.6 ng / ml, 2.6 ng / ml to 2.4 ng / ml, 2.4 ng / ml to 2.2 ng / ml, 2.2 ng / ml to 2.0 ng / ml, and ranges therein. In some embodiments, the AUC0-12his less than 40 ng / mL, such as 40 ng / ml to 38 ng / ml, 38 ng / ml to 36 ng / ml, 36 ng / ml to 34 ng / ml, 34 ng / ml to 32 ng / ml, 32 ng / ml to 30 ng / ml, and ranges therein. Plasma samples may be evaluated at pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, and 12 hours post dosing, such as at pre-dose, 6 hours, and 12 hours. In some embodiments, the pharmaceutical composition for use as a long acting injectable comprises a flocculating agent. In some embodiments, the flocculating agent is a Ca2+containing agent. In some embodiments, the flocculating agent is selected from calcium chloride, calcium chloride dihydrate, calcium acetate, calcium saccharate, calcium hydroxide, calcium citrate, calcium disodium edetate, calcium saccharin, or calcium lactate. In some embodiments, the pharmaceutical composition comprises from 1 to 30 mg / mL of the flocculating agent, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg / mL and ranges within those amounts. In some embodiments, the pharmaceutical composition comprises from 1 to 8 mg / mL of the flocculating agent, such as 1, 2, 3, 4, 5, 6, 7, or 8 mg / mL and ranges within those amounts. In some embodiments, the flocculating agent comprises calcium chloride or calcium chloride dihydrate. In some embodiments, the pharmaceutical composition comprises from 1 to 8 mg / mL of the calcium chloride or calcium chloride dihydrate flocculating agent, such as 1, 2, 3, 4, 5, 6, 7, or 8 mg / mL and ranges within those amounts. In some embodiments, the flocculating agent comprises calcium chloride or calcium chloride dihydrate and the buffering and / or pH adjusting agent comprises tris(hydroxymethyl)aminomethane. In some embodiments, calcium chloride dihydrate may replace calcium chloride. The pharmaceutical composition for use as a long acting injectable comprises a surfactant. Examples of surfactants / wetting agents include a polysorbate, a poloxamer, an α-tocopheryl polyethylene glycol succinate, a salt of a negatively charged phospholipid (e.g., egg phosphatidylglycerols), lecithin, polyvinylpyrrolidone (PVP), docusate sodium, sodium deoxycholate, sodium dodecyl sulphate (SDS), polyoxyethylene castor oil derivatives, macrogol 15 hydroxystearate, or mixtures thereof. In some embodiments, the surfactants / wetting agents comprise polysorbates, poloxamers, α-tocopheryl polyethylene glycol succinates, for example polysorbate 20, polysorbate 80, poloxamer 188, poloxamer 338, poloxamer 407, TPGS, egg phosphatidylglycerol (Egg PG), or mixtures thereof. In some embodiments, the surfactants / wetting agents comprise polysorbate 20, poloxamer 338, TPGS, or a mixture thereof. In some embodiments, the surfactants / wetting agents comprise polysorbate. In some embodiments, the pharmaceutical composition for use as a long acting injectable comprises one or more buffering and / or pH adjusting agent(s), rendering the pH of the pharmaceutical composition in the range of 6 to 8.5. In some embodiments, the buffering and / or pH adjusting agent(s) comprises tris(hydroxymethyl)aminomethane (TRIS), histidine, HCl, NaOH, or a mixture thereof. In some embodiments, the buffering agent is tris(hydroxymethyl)aminomethane (TRIS); and the pH-adjusting agents are HCl or NaOH. In some embodiments, the buffering agent comprises histidine. In some embodiments, the buffering agent comprises tris(hydroxymethyl)aminomethane (TRIS). In some embodiments, the buffering agent comprises histidine and tris(hydroxymethyl)aminomethane (TRIS). In some embodiments, the pharmaceutical composition for use as a long acting injectable comprises about eq.1 mg to about eq.160 mg of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof. In some embodiments, the pharmaceutical composition for use as a long acting injectable has a concentration of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof of from eq.25 mg / mL to eq.100 mg / mL based on the total volume of the pharmaceutical composition; such as eq.25 mg / mL, eq.30 mg / mL, eq.40 mg / mL, eq.50 mg / mL, eq.60 mg / mL, eq.70 mg / mL, eq.80 mg / mL, eq.90 mg / mL, or eq.100 mg / mL. In some embodiments, the pharmaceutical composition has a concentration of eq.25 mg / mL or eq.50 mg / mL. In some embodiments, the pharmaceutical composition for use as a long acting injectable comprises by weight based on the total volume of composition: from 10% to 30% (w / v), or from 10% to 15% (w / v) of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate (or a pharmaceutically acceptable hydrate or solvate thereof; but where the w / v is calculated on the basis of its anhydrous form). Injection site reactions include pain, tenderness, erythema / redness, and induration / swelling. These injection site reactions can be measured by known methods in the art. Example measurement techniques include the toxicity grading scale in the “Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” published by the U.S. Department of Health and Human Services and the F.D.A. on September 2007. Alternatively, pain can be measured by any conventional scale, such as a scale of 1 to 10. The erythema / redness and induration / swelling are measured directly at the injection site. Erythema / redness and induration / swelling can be measured by any conventional test, such as measurement by the greatest diameter of each at the injection site. The injection may be subcutaneous or intramuscular. The injection site reactions typically build over time and can be measured at different time points. In some embodiments, the average erythema / redness at an injection site is reduced for the pharmaceutical composition for use after subcutaneous or intramuscular administration compared to the same pharmaceutical composition having a lower concentration of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate. The erythema / redness may be measured at the 12 hour, 24 hour, or 48 hour time point. In some embodiments, the average induration / swelling at an injection site is reduced for the pharmaceutical composition for use after subcutaneous or intramuscular administration compared to the same pharmaceutical composition having a lower concentration of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate. The induration / swelling may be measured at the 12 hour, 24 hour, or 48 hour time point. In some embodiments, the average pain at an injection site is reduced for the pharmaceutical composition for use after subcutaneous or intramuscular administration compared to the same pharmaceutical composition having a lower concentration of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate. The pain may be measured at the 12 hour, 24 hour, or 48 hour time point. In general, the injection site reactions may be measured from the time of administration to different time points for assessment purposes; for example, at 0 hours, 0.25 hours, 0.5 hours, 1 hour, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours, and up to 264 hours. The pharmaceutical compositions described herein may be applied in the long-term treatment or the long-term prevention of the diseases and / or disorders disclosed herein, in particular PAH and CTEPH. The pharmaceutical compositions as described herein includes the active ingredient, i.e., calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate (or a pharmaceutically acceptable hydrate or solvate thereof) in a therapeutically effective amount. The term “therapeutically effective amount” refers to amounts, or concentrations, of the composition (or amounts / concentrations of active ingredient within such composition) that result in efficacious plasma levels for treating the indicated diseases, in particular PAH and CTEPH. For instance, a therapeutically effective amount may be eq.1 to eq.200 mg, for example eq.2 to eq.150 mg or eq.5 to eq.100 mg, and notably eq.25 mg to eq. 100 mg of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate per month. With “efficacious plasma levels” it is meant those plasma levels of {4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetic acid, that provide effective treatment or effective prevention of the indicated diseases and / or disorders, in particular PAH and CTEPH. The dose (or amount) of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate (or a pharmaceutically acceptable hydrate or solvate thereof) administered also depends on the frequency of the administrations (i.e., the time interval between each administration). Usually, the dose will be higher where administrations are less frequent. In some embodiments, the dose is from 0.1 to 2 mL of a formulation comprising eq.25 mg / mL or eq.50 mg / mL of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate. Example volumes include 0.1 to 1.8 mL, 0.1 to 1.5 mL, or 0.1 to 1.4 mL. When calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate (or a pharmaceutically acceptable hydrate or solvate thereof) is administered at a time interval of 1 to 8 weeks, the dose is about eq.1 mg to about eq.160 mg. Examples doses include: eq.7.5 mg, eq.15 mg, eq.22.5 mg, eq.30 mg, eq.37.5 mg, eq.45 mg, eq.52.5 mg, eq.60 mg, or eq.75 mg. The dose amount and time interval may depend on the individual maximum tolerated dose (iMTD) for each individual patient. In some embodiments, the time interval is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the pharmaceutical composition is administered at a time interval of 1 week to 4 weeks. In some embodiments, the pharmaceutical composition is administered at a time interval of 4 weeks and the dose is selected from: eq.7.5 mg, eq.15 mg, eq.22.5 mg, eq.30 mg, eq.37.5 mg, eq.45 mg, eq.52.5 mg, eq.60 mg, or eq.75 mg. In some embodiments, the time interval is 4 weeks, and the composition comprises tris(hydroxymethyl)aminomethane. In some embodiments, the time interval is 4 weeks, and the composition comprises tris(hydroxymethyl)aminomethane and calcium chloride or calcium chloride dihydrate. In some embodiments, the pharmaceutical composition has a concentration of calcium;{4- [(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof of from eq.25 mg / mL to eq.100 mg / mL based on the total volume of the pharmaceutical composition; such as eq.25 mg / mL, eq.30 mg / mL, eq.40 mg / mL, eq.50 mg / mL, eq.60 mg / mL, eq.70 mg / mL, eq.80 mg / mL, eq.90 mg / mL, or eq.100 mg / mL. In some embodiments, the pharmaceutical composition is administered at a time interval of 1 weeks and the dose is selected from: eq.2.0 mg, eq.4.0 mg, eq.6.0 mg, eq.8.0 mg, eq.10.0 mg, eq.12.0 mg, eq.15.0 mg, eq.18.0 mg, or eq.22.0 mg. In some embodiments, the pharmaceutical composition is administered at a time interval of 2 weeks and the dose is selected from: eq.4.0 mg, eq.7.5 mg, eq.10.0 mg, eq.15.0 mg, eq.20.0 mg, eq.22.5 mg, eq.26.0 mg, eq.30.0 mg, or eq.37.5 mg. In some embodiments, the pharmaceutical composition is administered at a time interval of 3 weeks and the dose is selected from: eq.5.0 mg, eq.10 mg, eq.17.5 mg, eq.22.5 mg, eq.27.5 mg, eq.34.0 mg, eq.40.0 mg, eq.47.5 mg, or eq.60.0. In some embodiments, the pharmaceutical composition is administered at a time interval of 4 weeks and the dose is selected from: eq.7.5 mg, eq.15.0 mg, eq.22.5 mg, eq.30 mg, eq.37.5 mg, eq.45 mg, eq.52.5 mg, eq.60 mg, or eq.75 mg. In some embodiments, the pharmaceutical composition is administered at a time interval of 6 weeks and the dose is selected from: eq.10.0 mg, eq.22.5 mg, eq.30.0 mg, eq.40.0 mg, eq.55.0 mg, eq.65.0 mg, eq.80.0 mg, eq.95.0 mg, or eq.115.0. In some embodiments, the pharmaceutical composition is administered at a time interval of 8 weeks and the dose is selected from: eq.15.0 mg, eq. 60.0 mg, eq.45.0 mg, eq.60.0 mg, eq.75.0 mg, eq.90.0 mg, eq.105.0 mg, eq.120.0 mg, or eq.150.0 mg. The term “subject” in particular relates to a human being. The present invention further concerns a method of treating a subject suffering from the above-indicated diseases and / or disorders, in particular PAH and CTEPH, said method comprising the administration of a therapeutically effective amount of a pharmaceutical composition as described herein to a human subject in need thereof. The administration of the present pharmaceutical composition will be via subcutaneous or intramuscular injection. In particular, the present invention relates to a method for preventing and / or treating ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance, connective tissue disease, chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved, and respiratory diseases, comprising administering the pharmaceutical compositions as described herein to a human subject in need thereof. The present invention also concerns the use of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, in the form of an aqueous suspension. The present invention also concerns calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for use in the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, wherein said calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof, is within an aqueous suspension. The present invention also concerns the use of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, in the form of a lyophilized cake. The present invention also concerns calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for use in the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, wherein said calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof, is in the form of a lyophilized cake. The present invention also concerns the use of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm; a surfactant and / or wetting agent; a buffer and / or pH adjusting agent; and a pharmaceutically acceptable aqueous carrier, in the form of an aqueous suspension, wherein the aqueous suspension has a pH in the range of 6 to 8.5. The present invention also concerns calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for use in the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, wherein said calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm; a surfactant and / or wetting agent; a buffer and / or pH adjusting agent; and a pharmaceutically acceptable aqueous carrier, is within an aqueous suspension, wherein the aqueous suspension has a pH in the range of 6 to 8.5. The present invention also concerns the use of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, in the form of a subcutaneous or intramuscular injectable. The present invention also concerns calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for use in the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, wherein said calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof, is in the form of a subcutaneous or intramuscular injectable. The present invention also concerns the use of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, wherein said medicament is administered at a time interval of one week to three months, preferably one week or one month or three months. The present invention also concerns calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for use in the treatment of the above-indicated diseases and / or disorders, in particular PAH and CTEPH, wherein said calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof, wherein it is administered at a time interval of one week to three months, preferably one week or one month or three months. The present invention further concerns a pharmaceutical composition for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension, wherein the pharmaceutical composition is in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I). In particular, said pharmaceutical composition for use as a long acting injectable will be for the treatment of and / or prevention of pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis. Said pharmaceutical composition for use as a long acting injectable may notably be for use in the treatment and / or prevention of pulmonary arterial hypertension (PAH). Said pharmaceutical composition for use as a long acting injectable may also be for use in the treatment and / or prevention of chronic thromboembolic pulmonary hypertension (CTEPH). Said pharmaceutical composition for the previously mentioned uses may be in the form of a subcutaneous or intramuscular injectable. In particular, said subcutaneous or intramuscular injectable may be administered at a time interval of one week to three months, notably at a time interval of two weeks to one month. The suspended particles of said subcutaneous or intramuscular injectable may have a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm. The present invention further relates to calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof Formula (I) having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm. The present invention further relates to calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof Formula (I) having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm, wherein said particles are suspended in an aqueous medium. Said aqueous medium, in addition to water, may comprise (i) a surfactant and / or wetting agent; and optionally (ii) a resuspending agent. Furthermore, the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5. Moreover, the present invention relates to calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof Formula (I) having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm, wherein said particles are suspended in an aqueous medium, for use in the treatment of a disease and / or disorder selected from the group consisting of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pressure ulcer (bedsore), hypertension, pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion / restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), transient ischemic attack (TIA), diabetic neuropathy, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, allergy, bronchial asthma, restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., renal diseases such as tubulointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia, (idiopathic) pulmonary fibrosis, chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g., myocardial fibrosis), bone and articular diseases (e.g., bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g., cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis, type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostate, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent and symptoms associated with lumbar spinal canal stenosis; in particular pulmonary hypertension and specially a disease and / or disorder selected from the group consisting of PAH and CTEPH. Furthermore, the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5. In particular, the present invention relates to calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof Formula (I) having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm, wherein said particles are suspended in an aqueous medium, for use in the treatment of pulmonary hypertension, especially PAH or CTEPH, wherein said particles suspended in said aqueous medium are for administration by subcutaneous or intramuscular injection. Said aqueous medium, in addition to water, may comprise (i) a surfactant and / or wetting agent; and optionally (ii) a resuspending agent. Furthermore, the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5. In particular, said subcutaneous or intramuscular injection is for administration at a time interval of one week to three months, notably at a time interval of two weeks to one month. The invention also relates to an investigational drug (‘ID’) in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I). The present invention relates to pharmaceutical composition for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension, wherein the pharmaceutical composition is administered at a time interval of one week to eight weeks. The pharmaceutical composition is in the form of an aqueous suspension comprising: about eq.1 mg to about eq.160 mg of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I), having a Dv50 particle size of 1 to 50 µm. The pharmaceutical composition further comprises a surfactant and / or wetting agent; a buffer and / or pH adjusting agent; and a pharmaceutically acceptable aqueous carrier. The pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C. The concentration of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is from eq.25 mg / mL to eq.100 mg / mL. In particular embodiments, the pharmaceutical composition comprises tris(hydroxymethyl)aminomethane as the buffer and / or pH adjusting agent, and, optionally, calcium chloride or calcium chloride dihydrate. By “Investigational New Drug” or “investigational drug (ID)” is meant herein a new drug or biological drug that is used in a clinical investigation. Preferably, the investigational drug will be used in a clinical investigation regarding the treatment of pulmonary hypertension, in particular PAH or CTEPH. According to one embodiment, said ID will be safe and efficacious for the treatment of and / or prevention of pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis, notably for the treatment of pulmonary hypertension and in particular the treatment of PAH or CTEPH. Said ID for the previously mentioned uses may be in the form of a subcutaneous or intramuscular injectable. In particular, said subcutaneous or intramuscular injectable may be administered at a time interval of one week to three months, notably at a time interval of two weeks to one month. The suspended particles of said subcutaneous or intramuscular injectable may have a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm. The present invention further relates to an ID in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof Formula (I) having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm. The present invention further relates to an ID in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof Formula (I). having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm, wherein said particles are suspended in an aqueous medium. Said aqueous suspension, in addition to water, comprises (i) a surfactant and / or wetting agent; and (ii) a buffer and / or pH adjusting agent. Furthermore, the pH of said aqueous suspension may be in the range of 6 to 9, and in particular in the range of 6 to 8.5. In particular, the present invention relates to an ID in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof Formula (I). having a Dv50 particle size of 1 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm, wherein said particles are suspended in an aqueous medium, for use in the treatment of pulmonary hypertension, especially PAH or CTEPH, wherein said particles suspended in said aqueous medium are for administration by subcutaneous or intramuscular injection. Said aqueous suspension, in addition to water, comprises (i) a surfactant and / or wetting agent; and (ii) a buffer and / or pH adjusting agent. Furthermore, the pH of said aqueous suspension may be in the range of 6 to 9, and in particular in the range of 6 to 8.5. In particular, said subcutaneous or intramuscular injection is for administration at a time interval of one week to three months, notably at a time interval of two weeks to one month. In particular, the present invention relates to a pharmaceutical composition in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I) having a Dv50 particle size of 1 to 50 µm; a surfactant and / or wetting agent; buffer and / or pH adjusting agent; and a pharmaceutically acceptable aqueous carrier. The pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25 °C. In certain embodiments, the composition also includes a flocculating agent wherein the flocculating agent comprises calcium chloride or calcium chloride dihydrate, and the buffering and / or pH adjusting agent comprising tris(hydroxymethyl)aminomethane. In other embodiments, the present invention relates to a pharmaceutical composition for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension, wherein the pharmaceutical composition is in the form of an aqueous suspension comprising calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I); a surfactant and / or wetting agent; and a flocculating agent; wherein the pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25 °C. In certain embodiments, the flocculating agent comprises calcium chloride or calcium chloride dihydrate, and the aqueous carrier comprises a buffering and / or pH adjusting agent comprising tris(hydroxymethyl)aminomethane. In certain embodiments, the flocculating agent comprises calcium chloride or calcium chloride dihydrate, and the aqueous carrier comprises a buffering and / or pH adjusting agent comprising tris(hydroxymethyl)aminomethane and 12 hours after injection the Cmaxis less than 0.5 ng / mL per eq.1 mg of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate administered to the subject. Furthermore, the concentration of the calcium chloride or calcium chloride dihydrate may be 1 to 8 mg / mL based on the total volume of the pharmaceutical composition. Furthermore, the calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof has a Dv50 particle size from 2 to 30 µm. Furthermore, the surfactant and / or wetting agent is selected from the group consisting of poloxamer 338, polysorbate 20, and TPGS, or a mixture thereof. In another embodiment, the disclosure relates to transitioning a patient (subject) that is being treated with an oral dosage form of selexipag to a long acting injectable form comprising the calcium salt of selexipag metabolite, that is, calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate. For example, a method of transitioning a patient being treated with an oral dosage form of selexipag to a long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof for treating and / or prevention of pulmonary hypertension, wherein the long acting injectable is a pharmaceutical composition in the form of an aqueous suspension comprising: (a) about eq.1 mg to about eq.160 mg of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof: Formula (I) having a Dv50 particle size of 1 to 50 µm; (b) a surfactant and / or wetting agent; (c) a buffer and / or pH adjusting agent; and (d) a pharmaceutically acceptable aqueous carrier; wherein the pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C; wherein the concentration of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate is from eq.25 mg / mL to eq.100 mg / mL; wherein the oral dosage form of selexipag is administered at an individual maximum tolerated dose (iMTD), where administration of said iMTD of selexipag provides to the patient an individual average plasma concentration CiMTDavgof 2-(4-((5,6-diphenylpyrazin- 2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861), the oral dosage form is discontinued, and the pharmaceutical composition is administered at a time interval of one week to eight weeks at a dosage of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof selected to provide to the patient an average plasma concentration of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is about equal to or higher than CiMTDavg. The expression “about equal to a concentration” or “about equal to an amount” refers to a concentration range or an amount range that is within plus or minus 10%, and preferably plus or minus 5% of the corresponding concentration or amount. In one embodiment, the dosage of the long acting injectable form is selected to provide to the patient an average plasma concentration of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is about equal to CiMTDavg, and in certain embodiments, the dosage of the long acting injectable form is selected to provide to the patient an average plasma concentration of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is higher than CiMTDavg. In certain cases, the oral form of selexipag is administered at a starting dose and is increased to determine the iMTD. The term "iMTD" as used herein refers to the maximum amount of selexipag that may be administered to a patient per day, without resulting in adverse physical and / or pharmacological effects. Thus, the iMTD is typically evaluated for each patient on an independent basis. In some aspects, the starting dose of selexipag is the same as the iMTD. In further aspects, the starting dose of selexipag is lower than the iMTD. A particular embodiment is disclosed in the patient information provided to UPTRAVI patients which is available, for example, at www.accessdata.fda.gov / drugsatfda_docs / label / 2015 / 207947s000lbl.pdf or pdf.hres.ca / dpd_pm / 00065527.PDF. As noted in the patient information, oral treatment with selexipag should be started at 200 micrograms given twice daily. The selexipag dose should be increased in increments of 200 micrograms twice daily at weekly intervals, to the highest tolerated dose up to 1600 micrograms twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose which is then considered to be the iMTD. Based on the iMTD of the oral dosage form of selexipag that is determined, that oral dosage form of selexipag may be discontinued, and the patient may then be transitioned to a long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof at a dosage selected to provide to the patient an average plasma concentration of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is about equal to CiMTDavgwhen administered at a time interval of one week to eight weeks, for example, every 1, 2, 3, 4, 6 or 8 weeks. There would be an option to maintain the administration long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof at a dosage that provides to the patient an average plasma concentration of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is about equal to CiMTDavg, or to increase the dose of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof in the long acting injectable dosage form to provide to the patient an average plasma concentration of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ- 68006861) that is higher than CiMTDavg. For example, the dose of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof may provide to the patient an average plasma concentration of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is 20, 30, or 50% higher than CiMTDavg. An example increase is when the dose of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is increased so the average plasma concentration of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861)is greater than the CiMTDavg2-(4- ((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) corresponding to the administration of the administration of the iMTD of the iMTD of the oral dosage form of selexipag. In particular embodiments, the dose of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is increased to provide to the patient an average plasma concentration of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) at least 20% greater, at least 30% greater, or at least 50% greater than the CiMTDavgof2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) corresponding to the administration of the iMTD of the oral dosage form of selexipag. In certain embodiments, when the iMTD of the oral form of selexipag is 200 µg, 400 µg, 600 µg, 800 µg, 100 µg, 1200 µg, 1400 µg, or 1600 µg twice daily, the corresponding dose of the long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof is eq. 1-5 mg Q2W, eq.2.5-10 mg Q2W, eq.10-30 mg Q4W, eq.22.5-37.5 mg Q4W, eq.30-45 mg Q4W, eq.37.5-52.5 mg Q4W, eq.45-60 mg Q4W, or eq.52.5-75 mg Q4W, respectively, of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate. In particular, Table 36 herein sets forth corresponding doses of oral selexipag (UPTRAVI) and JNJ-68006861 LAI doses. For example, where the iMTD of the oral form of selexipag is 200 µg, 400 µg, 600 µg, 800 µg, 100 µg, 1200 µg, 1400 µg, or 1600 µg twice daily, the corresponding dose of the long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin- 2-yl)(propan-2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof is eq.2.5 mg Q2W, eq.5 mg Q2W, eq.22.5 mg Q4W, eq.30 mg Q4W, eq.37.5 mg Q4W, eq.45 mg Q4W, eq.52.5 mg Q4W, or eq.60 mg Q4W, respectively, of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate. In certain embodiments, the methods of transitioning a patient being treated with an oral dosage form of selexipag to a long acting injectable form of selexipag are for use in the treatment and / or prevention of pulmonary hypertension, in particular, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis. Particularly preferred is pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). In yet another embodiment, the disclosure relates to transitioning a patient (subject) that is being treated with an oral dosage form of selexipag metabolite (2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid or JNJ-68006861) to a long acting injectable form comprising the calcium salt of selexipag metabolite, that is, calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate. All documents cited herein are incorporated by reference in their entirety. The following examples are intended to illustrate the present invention and should not be construed as limiting the invention thereto. EXAMPLES Abbreviations (as used herein and in the description above): ADME absorption, distribution, metabolism, and excretion API Active Pharmaceutical Ingredient aq. aqueous BHA butylated hydroxyanisole BHT butylated hydroxytoluene CTAC hexadecyl trimethyl ammonium chloride CTEPH chronic thromboembolic pulmonary hypertension EDTA ethylenediaminetetraacetic acid HPLC high performance liquid chromatography IM intramuscular iMTD individual maximum tolerated dose INCI international nomenclature of cosmetic ingredients INN international nonproprietary name IP receptor prostacyclin receptor ISO International Organization of Standardization LAI long acting injectable LD laser diffraction min minute(s) mM millimole PAH Pulmonary Arterial Hypertension PEG polyethylene glycol PK pharmacokinetic PSD particle size distribution PVP polyvinylpyrrolidone q.s. quantum satis (as much as is sufficient) q.s. ad quantum satis (as much as is sufficient) to make Q2W every 2 weeks Q4W every 4 weeks RT room temperature SC subcutaneous SDS sodium dodecyl sulphate TEAE Treatment-Emergent Adverse Event TRIS tris(hydroxymethyl)aminomethane UPLC Ultra Performance Liquid Chromatography WFI water for injection WHO World Health Organization w / v weight per volume w / w weight per weight PSD Measurement PSD was measured with a Malvern Mastersizer 3000 apparatus from Malvern Panalytical using the laser diffraction measurement method and the Mie theory. The results of the laser diffraction analysis are reported based on the particle size volume distribution as the cumulative undersize values Dv50. The following settings were used: Particle Type Non-spherical particle mode Yes Is Fraunhofer type No Material properties Material name Mie 1.63 / 0.01 Refractive index 1.630 Absorption index 0.010 Particle density 1.00 g / cm³ Different optical properties in blue No light Dispersant properties Dispersant name Water Refractive index 1.330 Level sensor threshold 100.000 Measurement duration Background measurement 15.00 s duration (red) Sample measurement duration 15.00 s (red) Perform blue light measurement? Yes Background measurement 15.00 s duration (blue) Sample measurement duration 15.00 s (blue) Assess light background stability No Measurement sequence Aliquots 1 Automatic number of No measurements Pre-alignment delay 0.00 s Number of measurements 3 Delay between measurements 0.00 s Pre-measurement delay 60.00 s Close measurement window after No measurement Measurement obscuration settings Auto start measurement No Obscuration low limit 4.00% Obscuration high limit 6.00% Enable obscuration filtering No Measurement alarms Use Background Check No Background Check Limits [1;200]; [20;60] Accessory control settings Accessory name Hydro MV Is accessory dry? No Stirrer speed 1750 rpm Ultrasound percentage 50% Fill Dispersant Source Identifier Manual Manual tank fill? Yes Degas after tank and cell fill Yes Sonicate to stability? No Ultrasound mode None Post-Measurement clean sequence settings Clean sequence type None Sonicate during clean? No Manually Fill Tank During Clean? No Clean Dispersant Source Auto Identifier Clean Dispersant Level Sensor 0 Threshold Degas After Clean? Yes Drain Valve Flush? Yes Tank Overfill? Yes Analysis settings Analysis model General Purpose Single result mode No Number of excluded inner 0 detectors Blue light detectors excluded No Fine powder mode No Analysis sensitivity Normal Analysed as Mastersizer 3000E? No Result Settings Result range is limited No Result Units Volume Extend Result No Result Emulation No User sizes for histograms and tables Use user sizes No Data export output Enabled? No Averaging Averaging enabled? Yes Printing options Printing enabled? No Software used: Mastersizer software v3.81; Malvern Instruments Ltd Examples: Example 1: Preparation of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate: 12 g (28.604 mmol) of {4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetic acid were added to a two piece 400 ml reactor and 145.34 g of acetone / water (95 / 5% w / w) were added. Ramp stirring to a speed of 400 rpm was applied, and the reactor was heated to 50 °C at 1 K / min, and kept at that temperature for 30 min. Then, 15vol% (4.2 ml) of Ca(Oac)2x ½H2O dissolved in water (stock solution containing 2.51 g (15.012 mmol) Ca(Oac)2 x ½H2O in 26.66 g water)) were added over 30 min. The mixture was kept for 8 h. Then, the rest of the stock solution of Ca(Oac)2dissolved in water was added over 2 h. The mixture was stirred for 7.75 h, and the obtained solid was filtered off, washed with 24 g (2g / g) acetone / water 80 / 20% w / w at 50 °C. After drying at 50 °C under vacuum and N2purge, 12.46 g of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]-butoxy}acetate (99.3%) were obtained as crystalline solid. Example 2: Feasibility PK rat study An initial PK rat study was conducted to demonstrate the LAI potential of an aqueous micro-suspension of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate. For this study, aqueous micro-suspensions of selexipag, {4- [(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetic acid and calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate were prepared. An overview of the design of the study can be found in Table 1.

[0002] Table 1. PK rat study design (ADME) to demonstrate LAI feasibility API eq. Particle Group Formulation API concentration size Injection Dose (mg / mL) (Dv50, route (mg / kg) µm) PVP K17 F Citrate buffer Selexipag 125 6.6 IM 50 pH 5 PVP K17 Ca-salt of G Citrate buffer JNJ- 125 3.5 IM 50 pH 8 68006861 PVP K17 H Citrate buffer JNJ- 680125 4.3 IM 50pH 506861Release profiles and mean AUC of the different formulations are depicted in Figure 1. As shown in Figure 1, the study group dosed with the Ca-salt of JNJ-68006861 exhibits significant lower plasma concentrations compared to both other groups, which demonstrates a long-acting release profile up to 336 hours (i.e., 14 days) and the AUC increases up until 720 hours. Selexipag and its metabolite (group F and H) did not demonstrate a long-acting release profile because of their high solubility and dissolution rate. Example 3: PK rat study comparing particle size and surfactants / wetting agents A PK rat study was set up to evaluate the effect of Ca-salt of JNJ-68006861 physical properties (i.e., PSD), surfactant / wetting agent and administration route on the in-vivo drug release rate. Particle size of the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate at Dv50 was varied between 2, 5 and 8 µm. The API concentration of the different studied aqueous suspensions was kept constant at eq.100 mg / mL. Both intramuscular and subcutaneous injection routes were investigated in this rat study. An overview of the studied groups is shown in Table 2. Table 2. Design overview of PK rat study Ex.3 API eq. Particle size Dose Dose Group* Formulation concentration(Dv50, µm)Injectionroute(mg- volume, (mg / mL) eq. / kg) (mL / kg) Immediate Release (IR) 1 solution 10 N / A SC 4.0 0.4 100% PEG 400 Immediate Release (IR) 2 solution 10 N / A IM 4.0 0.4 100% PEG 400 5 mg / mL Polysorbate 20 3 50 mg / mL PEG 4000 100 2 SC 40.0 0.4 50 mmol Tris (pH 8) 5 mg / mL Polysorbate 20 4 50 mg / mL PEG 4000 100 2 IM 40.0 0.4 50 mmol Tris (pH 8) 5 mg / mL Polysorbate 20 5 50 mg / mL PEG 4000 100 5 SC 40.0 0.4 50 mmol Tris (pH 8) 5 mg / mL Polysorbate 20 6 50 mg / mL PEG 4000 100 5 IM 40.0 0.4 50 mmol Tris (pH 8) 5 mg / mL Polysorbate 20 7 50 mg / mL PEG 4000 100 8 SC 40.0 0.4 50 mmol Tris (pH 8) 5 mg / mL Polysorbate 20 8 50 mg / mL PEG 4000 100 8 IM 40.0 0.4 50 mmol Tris (pH 8) 15 mg / mL Poloxamer 338 9 50 mg / mL PEG 4000 100 2 SC 40.0 0.4 50 mmol Tris (pH 8) 15 mg / mL Poloxamer 338 10 50 mg / mL PEG 4000 100 2 IM 40.0 0.4 50 mmol Tris (pH 8) 15 mg / mL Poloxamer 338 11 50 mg / mL PEG 4000 100 5 SC 40.0 0.4 50 mmol Tris (pH 8) 15 mg / mL Poloxamer 338 12 50 mg / mL PEG 4000 100 5 IM 40.0 0.4 50 mmol Tris (pH 8) 15 mg / mL Poloxamer 338 13 50 mg / mL PEG 4000 100 8 SC 40.0 0.4 50 mmol Tris (pH 8) 15 mg / mL Poloxamer 338 14 50 mg / mL PEG 4000 100 8 IM 40.0 0.4 50 mmol Tris (pH 8) *N=4 male rats per group An overview of PK profiles for the different studied groups are visualized in Figure 2 and 3. It can be concluded that long acting extended in vivo release profiles were observed in the whole range from Dv50 from 2 µm to 8 µm. The larger the particle size, the lower the initial release and the longer the duration time was observed. To reach 1-month (or longer) drug release, Dv50 particle size should be equal to or bigger than 8 µm. Example 4: Preparation of formulation examples – particle size Four separate vials (volume = 50 mL) were prepared with varying target particle sizes (Dv50 of 2, 5, 8 and 12 µm (micrometer)). In each vial, 1.568 g (eq.100 mg / mL) of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate was weighed. Next to the active ingredient, 45 g of 1 mm Zirconium beads was added to each vial. In a next step 12 mL of a stock solution of Polysorbate 20, PEG 4000 and buffer was added to each vial. The compositions of the stock solutions were dependent on the experiment. The composition of each stock solution is shown in Table 3 below. Table 3: Composition of the tested Polysorbate 20 / PEG 4000 / buffer (pH 8) stock solutions Ingredient Concentration (mg / mL) Experimental ID n001-00101 n001-00133 TWEEN®20 (polysorbate 20) 5 6.25 PEG 4000 50 93.75 Disodium hydrogen phosphate anhydrous N / A 10.00 Citric acid monohydrate N / A 0.2125 Trometamol (TRIS) 6.056 N / A NaCl 4.7 1N HCl q.s. ad pH 8 Purified water q.s. In a last step, 3 mL of purified water was added to each vial or n001-00133 for which a 125% over concentrated polysorbate 20 / PEG4000 / buffer solution was used. All 4 vials were put on a roller mill with a rotational speed of 300 rpm. To reach different particle sizes (Dv50 of 2, 5, 8 and 12 µm), different milling times were needed. An overview of the different milling times and the resulting particle sizes (obtained with MASTERSIZER®3000) is shown in Table 4. Table 4: Overview of the different milling times and the resulting particle sizes. Experimental Milling Particle size ID time (Dv10, µm) (Dv50, µm) (Dv90, µm) n001-00101 23 hours 0.6 2.2 5.8 90 min. 2.0 5.1 16.3 n001-00133 16 min. 2.9 8.0 26.1 2 min. 3.9 11.3 37.3 Each milled suspension was harvested in 8 mL vials and final particle size was determined with MASTERSIZER®3000. An overlap of the resulting particle size distributions is shown in Figure 4. Example 5: Preparation of formulation examples – surfactant / wetting agent 3 separate vials (volume = 50 mL) were prepared with different surfactants / wetting agents (Polysorbate 20, Poloxamer 338, and TPGS). In each vial, 1.568 g (eq.100 mg / mL) of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate was weighed. Next to the active ingredient, 45 g of 1 mm Zirconium beads was added to each vial. In a next step, 12 mL of a 125% over-concentrated stock solution of surfactant / wetting agent, PEG 4000 and McIlvaine buffer was added to each vial. The composition of the stock solution was dependent on the experiment. The composition of each stock solution is shown in Table 5 below.

[0003] Table 5: Composition of the tested 125% over-concentrated surfactant (and / or wetting agent) / PEG 4000 / McIlvaine buffer (pH 8) stock solutions Ingredient Concentration (mg / mL) Experimental ID n001-00119 Polysorbate 20 6.25 N / A N / A Poloxamer 338 N / A 18.75 N / A TPGS N / A N / A 6.25 PEG 4000 93.75 Disodium hydrogen 34.51 phosphate anhydrous Citric acid monohydrate 0.72 1N HCl q.s. ad pH 8 Purified water q.s. In a last step, 3 mL of purified water was added to each vial. All 3 vials were put on a roller mill with a rotational speed of 300 rpm. To reach a target Dv50 particle size of 8 µm, different milling times were needed for the different surfactants / wetting agents. An overview of the different milling times and the resulting particle sizes (obtained with MASTERSIZER®3000) is shown in Table 6. Table 6: Overview of the different milling times and the resulting particle sizes. Surfactant / wetting Milling Particle size agent time (Dv10, µm) (Dv50, µm) (Dv90, µm) Polysorbate 20 32 min. 2.9 8.0 29.4 Poloxamer 338 27 min. 2.9 8.0 29.6 TPGS 27 min. 2.9 8.1 29.9 Each milled suspension was harvested in both 8 mL vials and pre-filled syringes. Final particle size was determined with MASTERSIZER®3000. An overlap of the resulting particle size distributions is shown in Figure 5. All resulting vials and pre-filled syringes were stored under different conditions. The vials were stored for 12 days at 5, 25 and 40 °C. Pre-filled syringes were stored at 5 °C only. After 12 days of storage, all different concepts (both vials and syringes) were evaluated for resuspendability (time to reach visually homogenous suspension). The results are shown in Table 7. Table 7: Resuspendability after 12 days of storage at different conditions Surfactant / Resuspendability (seconds) wetting agent 5 °C RT 40 °C SC syringes (5 °C) Polysorbate 20 >5<10 >5<10 <5 >15<20 Poloxamer 338 >5<10 >15<20 >5<10 >15<20 TPGS >5<10 >5<10 <5 >10<15 Example 6: Preparation of formulation examples – drug substance concentration One individual vial (volume = 50 mL) was prepared. In this vial, 3.1350 g (eq.200 mg / mL) of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate was weighed. Next to the active ingredient, 45 g of 1 mm Zirconium beads was added to the vial. In a next step 12 mL of a 125% over-concentrated stock solution of Polysorbate 20, PEG 4000 and McIlvaine buffer was added to the vial. The composition of the stock solution is shown in Table 8 below. Table 8: Composition of the tested 125% over-concentrated Polysorbate 20 / PEG 4000 / McIlvaine buffer (pH 8) stock solution Ingredient Concentration (mg / mL) Experimental ID n001-00134 Polysorbate 20 12.50 PEG 4000 93.75 Disodium hydrogen 10.00 phosphate anhydrous Citric acid monohydrate 0.2125 1N HCl q.s. ad pH 8 Purified water q.s. In a last step, 3 mL of purified water was added to the vial. The vial was put on a roller mill with a rotational speed of 300 rpm. To reach a target particle size (i.e., Dv50) of 10 µm, 6 minutes of milling was needed. An overview of the resulting particle size (obtained with MASTERSIZER®3000) is shown in Table 9. Table 9: Overview of the different milling time and the resulting particle size. Experimental Milling Particle size ID time (Dv10, µm) (Dv50, µm) (Dv90, µm) n001-00134 6 min. 3.6 10.3 34.7 The milled suspension was harvested into a 8 mL vial and final particle size was determined with MASTERSIZER®3000. The resulting particle size distribution is shown in Figure 6. Example 7: Preparation of formulation examples – resuspending agent 3 separate vials (volume = 50 mL) were prepared with varying concentrations of PEG 4000 (50, 75 and 100 mg / mL). In each vial, 1.568 g (100 mg / mL eq.) of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate was weighed. Next to the active ingredient, 45 g of 1 mm Zirconium beads was added to each vial. In a next step 12 mL of a stock solution of Polysorbate 20, PEG 4000 and TRIS buffer was added to each vial. The composition of the stock solution was dependent on the experiment. The composition of each stock solution is shown in Table 10 below. Table 10: Composition of the tested Polysorbate 20 / PEG 4000 / TRIS buffer (pH 8) stock solutions Ingredient Concentration (mg / mL) Experimental ID n001-00101 n001-00119 n001-00111 Polysorbate 20 5 PEG 4000 50 93.75 125 Trometamol (TRIS) 6.056 NaCl 4.700 1N HCl q.s. ad pH 8 Purified water q.s. In a last step, 3 mL of purified water was added to each vial. All 3 vials were put on a roller mill with a rotational speed of 300 rpm. To reach a target particle size (i.e., Dv50) of 8 µm, different milling times were needed for each concept. An overview of the different milling times and the resulting particle sizes (obtained with MASTERSIZER®3000) is shown in Table 11. Table 11: Overview of the different milling times and the resulting particle sizes. Experimental Milling Particle size ID time (Dv10, µm) (Dv50, µm) (Dv90, µm) n001-00101 30 min. 2.7 7.5 24.0 n001-00119 30 min. 2.9 8.3 30.7 n001-00111 26 min. 2.84 8.02 29.8 Each milled suspension was harvested in 5 mL vials and final particle size was determined with MASTERSIZER®3000. An overlap of the resulting particle size distributions is shown in Figure 7. Example 8: Characterization of surface charge by measuring Zeta potential A suspension of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate (100 mg / mL) was prepared to a Dv50 particle size of around 1 micrometer. The suspension was diluted 10000 times in water. The pH was adjusted from pH 3.0 to pH 9.0 with either an HCl solution or NaOH solution. Zeta potential was measured using Zetasizer Ultra equipment from Malvern. Figure 8 shows the results of zeta potential as function of pH of suspensions. The Zeta potential is an indicator for the stability of the suspension. Example 9: Lyophilisation of suspension concepts To further improve the stability of the suspensions at room (or higher) temperature, feasibility of lyophilization of 4 suspension concepts were conducted. The suspension formulation components prior to lyophilization and the lyophilization program are shown in tables as below. Table 12 Component Concept 1 Concept 2 Concept 3 Concept 4 (mg / mL) (mg / mL) (mg / mL) (mg / mL) Selexipag metabolite Ca-salt 100 100 100 100 Poloxamer 338 - 15 - 15 Polysorbate 20 5 - 5 - PEG 4000 75 75 75 75 Sodium hydrogen 23.38 23.38 23.38 23.38 phosphate Citric acid monohydrate 3.71 3.71 3.71 3.71 Mannitol - - 50 50 Water for injection q.s. ad 1 mL q.s. ad 1 mL q.s. ad 1 mL q.s. ad 1 mL Table 13: Lyophilization programLyo step T startTendTime Ramping spee Time Vaccum SP (°C)(°C) (min) d (°C / min) (hour)(µbar)Air supplyPre-cooling ofshelvesNot requiredFreezing 20 -40 200 0.3 3.33 Atmospheric Hold at -40 °C -40 -40 500 / 8.33 Atmospheric Primary drying -40 -20 120 0.33 2 100 Sterile compressed Hold at -20 °C -20 -20 2880 / 48 100 air Secondarydrying-20 25 100 0.45 1.67 100Hold at 25 °C 25 25 300 / 5 100Stoppering AtmosphericThe lyophilized concepts were easily reconstituted in water in 30 to 60 seconds by gentle shaking, and the particle size (Dv50) results were comparable before and after lyophilization. No particle aggregation was observed after lyophilization. Table 14: Particle size distribution before and after lyophilization Concept Dv50 before Dv50 after lyo lyo (μm) (μm) 1 8.0 8.1 2 8.1 8.1 3 8.2 7.8 4 8.1 7.8 Example 10: Sterilization of drug substance by gamma-irradiation To evaluate if gamma-irradiation could be used to produce sterile product, different irradiation grades were tested on calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate. In this study, calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate (“COMPOUND”) was irradiated with three different grades (i.e., 5, 25 and 40 kGy). Each irradiation grade was applied on two different COMPOUND vials. One of the two vials for each grade was flushed with nitrogen for 10 seconds. One reference vial containing non-irradiated COMPOUND was included in the assay / purity analysis. All samples were analyzed immediately after irradiation (Table 15) and re- analyzed after 3 months of storage at room temperature. Table 15: Initial Assay / purity results of gamma-irradiated calcium;{4-[(5,6-diphenylpyrazin- 2-yl)(propan-2-yl)amino]butoxy}acetate (“COMPOUND”) Assay, % Impurity, % Sample Name COMPOUND RRT 1.16* RRT 1.32* RRT 1.34* Reference – T0 95.3 < 0.05 < 0.05 0.09 Reference – 3 months 94.4 < 0.05 < 0.05 < 0.05 5 kGy – T0 95.3 0.05 < 0.05 0.09 5 kGy – 3 months 94.0 < 0.05 0.06 < 0.05 5 kGy – T0 (flushed with N2) 94.6 0.05 < 0.05 0.06 5 kGy – 3 months (flushed 94.1 < 0.05 0.06 < 0.05 with N2) 25 kGy – T0 95.1 0.10 0.11 0.06 25 kGy – 3 months 94.2 0.07 0.12 0.06 25 kGy – T0 (flushed with N2) 95.6 < 0.05 0.13 0.09 25 kGy – 3 months (flushed 93.6 < 0.05 0.05 0.08 with N2) 40 kGy – T0 94.3 0.13 0.14 0.06 40 kGy – 3 months 94.3 0.08 0.15 0.10 40 kGy – T0 (flushed with N2) 94.5 0.12 0.15 0.07 40 kGy – 3 months (flushed 92.9 0.08 0.14 0.10 with N2) Relative retention time (RRT) 1.16* is an impurity with a relative retention time of 1.16 min (1-Butanol, 4-[(5,6-diphenyl-2-pyrazinyl)(1-methylethyl)amino]-) RRT 1.35* is an impurity with a relative retention time of 1.31 min RRT 1.34* is an impurity with a relative retention time of 1.34 min (acetic acid, 2-[4-[(5,6- diphenyl-2-pyrazinyl)(1-methylethyl)amino]butoxy]-, ethyl ester) A second study was conducted on calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate where three different irradiation grades were applied (i.e., 5, 25 and 40 kGy). Results are shown in Table 16. Table 16: Initial Assay / purity results of gamma-irradiated calcium;{4-[(5,6-diphenylpyrazin- 2-yl)(propan-2-yl)amino]butoxy}acetate (“COMPOUND”) Irradiation Assay, % Impurity, % grade COMPOUND RRT 1.15* RRT 1.16* RRT 1.32* 5 kGy 104.4 <0.05 <0.05 <0.05 25 kGy 104.3 0.06 0.09 0.07 40 kGy 103.7 0.06 0.12 0.10 RRT 1.15* is an impurity with a relative retention time of 1.15 min (N-isopropyl-5,6- diphenyl-pyrazin-2-amine) RRT 1.16* is an impurity with a relative retention time of 1.16 min (1-Butanol, 4-[(5,6- diphenyl-2-pyrazinyl)(1-methylethyl)amino]-) RRT 1.32* is an impurity with a relative retention time of 1.32 min (N-isopropyl-N-(4- methoxybutyl)-5,6-diphenyl-pyrazin-2-amine) Based on the results in Table 15 and 16, it can be concluded that with increasing irradiation grade, three impurities / degradation products gradually increase. Nevertheless, the chemical stability of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate is considered acceptable, demonstrating the feasibility of sterilization of drug substance using gamma-irradiation. Analytical Method used: The assay and the impurities of calcium salt of selexipag metabolite before (ref) and after gamma irradiation were analysed using reversed phase chromatography. Sample preparation was done by weighing 50 mg of sample in a 500 mL flask. Approximately 100 mL pH7 phosphate buffer:ACN (50:50) was added whereafter the flask was shaken mechanically for at least 30 minutes until complete dissolution. Dilute to volume with pH7 phosphate buffer:ACN (50:50). The resulting solution was diluted 5x by pipetting 5 mL into a 25 mL flask and diluting with the same dilution solvent. The reference solution is made following the same sample preparation, but using calcium salt of selexipag metabolite (“API”). Analysis was performed using a Waters UPLC H-Class equipped with DAD detector, column manager and auto-sampler. Separation was done on a Acquity UPLC BEH C18 (2.1 x 150mm, 1.7µm) analytical column using a column temperature of 60 °C. DAD detector was set on 230nm. A 10mM NH4Ac:ACN:MeOH (950:38:12) solution was used as mobile phase A. A 10mM NH4Ac:ACN:MeOH (50:710:240) solution was used as mobile phase B. A linear gradient program of 26 minutes was applied starting in which the mobile phase B increases from 5% to 100% in 20 minutes. Hereafter the concentration of mobile phase B was brought back to 5% in 1 minute followed by an equilibration time of 5 minutes. The applied flow rate is 0.30 mL / min. An injection volume of 7 µL was used for the analysis. The assay value of the sample is calculated according following formula: % = [API peak responsesamplex concrefx purityrefx 100%] / [peak responserefx concsample] The concentration of an impurity is calculated according following formula: % = [Impurity peak responsesamplex concrefx purityrefx 100%] / [peak responserefx concsample] Example 11: Sterilization of drug product by gamma-irradiation Although feasibility for gamma-irradiation of drug substance is demonstrated, terminal sterilization is still preferred. For this reason, both gamma-irradiation and autoclavation (steam sterilization) of the final drug product need to be investigated. To evaluate the chemical stability of the final drug product during gamma-irradiation, 2 different concepts with calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate having a Dv50 particle size of 8 micrometer were subjected to radiation dose of 40 kGy and 60 kGy. An overview of the study with the associating assay / purity results is shown in Table 17. Table 17: Overview of drug product (i.e., formulation) concepts subjected to gamma- irradiation with the corresponding assay / purity results. Assay, Formulation Impurity, % % g n.iD dn tN radiatio U RRT RRT RRT RRT RRT RRT APIe nSurfactant BufferOn dosepse Pug0.60 0.72 1.11* 1.15 1 sa.16 1.32 M e O R C Ref.tlas105.4 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 -a02CL emt0 kGyea4til / b101.9 <0.05 <0.05 0.45 <0.05 0.06 0 og rbo).12 8 a0mst05ylH 60 kGye 0m4 oPp(et102.0 <0.05 <0.05 0.70 <0.05 <0.05 0.19 g G aE apri P ticRef.xe L-leem / t 101.0 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05Sg8a.q mL 3h3p40 kGye5L7m / rgesomhP 97.4 <0.05 <0.05 0.39 <0.05 0.05 0.12 m / mg5 a1xomlo60 kGy0 P98.3 0.05 0.05 0.65 <0.05 <0.05 0.18 01RRT 0.60* is an impurity with a relative retention time of 0.60 min RRT 0.72* is an impurity with a relative retention time of 0.72 min RRT 1.11* is an impurity with a relative retention time of 1.11 min RRT 1.15* is an impurity with a relative retention time of 1.15 min (N-isopropyl-5,6- diphenyl-pyrazin-2-amine) RRT 1.16* is an impurity with a relative retention time of 1.16 min (1-Butanol, 4-[(5,6- diphenyl-2-pyrazinyl)(1-methylethyl)amino]-) RRT 1.32* is an impurity with a relative retention time of 1.32 min (N-isopropyl-N-(4- methoxybutyl)-5,6-diphenyl-pyrazin-2-amine) Several impurities are formed when the different concepts are subjected to gamma- irradiation. In all gamma-irradiated concepts, RRT 1.11 can be found. Based on identification results, this impurity is an esterification product of PEG 4000 and calcium;{4- [(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate (i.e., PEG adduct). Impurities RRT 1.15 and 1.16 are less present during gamma-irradiation of the formulated drug product, compared with the unformulated drug substance. The assumption is that the radicals present in the drug product have a higher tendency to react with PEG 4000, hence less formation of RRT 1.15. Furthermore, there is an assumption that RRT 1.16 will convert to RRT 1.32 in the drug product. Based on the results in Table 17, it can be concluded that with increasing radiation dose, the impurities / degradation products gradually increase. Nevertheless, the chemical stability of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate in the drug product are considered acceptable, demonstrating the feasibility of sterilization of drug product using gamma-irradiation. Method used: The assay and the impurities of the gamma irradiated and non- gamma irradiated (ref) calcium salt of selexipag metabolite suspension (formulation) were analysed using reversed phase chromatography. Sample preparation was done by weighing 0.5mL suspension in a 500 mL flask. Approximately 200 mL pH7 phosphate buffer:ACN (50:50) was added whereafter the flask was shaken mechanically for at least 30 minutes until complete dissolution. Dilute to volume with pH7 phosphate buffer:ACN (50:50). The resulting solution was diluted 5x by pipetting 5 mL into a 25 mL flask and diluting with the same dilution solvent. The reference solution is made following the same sample preparation, but using calcium salt of Selexipag Metabolite (see example 10). Analysis was performed using a Waters UPLC H-Class equipped with DAD detector, column manager and auto-sampler. Separation was done on a Acquity UPLC BEH C18 (2.1 x 150mm, 1.7µm) analytical column using a column temperature of 60 °C. DAD detector was set on 230nm. A 10mM NH4Ac:ACN:MeOH (950:38:12) solution was used as mobile phase A. a 10mM NH4Ac:ACN:MeOH (50:710:240) solution was used as mobile phase B. A linear gradient program of 26 minutes was applied starting in which the mobile phase B increases from 5% to 100% in 20 minutes. Hereafter the concentration of mobile phase B was brought back to 5% in 1 minute followed by an equilibration time of 5 minutes. The applied flow rate is 0.30 mL / min. An injection volume of 7 µL was used for the analysis. The assay value of the sample is calculated according following formula: % = [API peak responsesamplex concrefx purityrefx 100%] / [peak responserefx concsamplex dose claim] The concentration of an impurity is calculated according following formula: % = [Impurity peak responsesamplex concrefx purityrefx 100%] / [peak responserefx concsamplex dose claim] Example 12: Sterilization of drug product by autoclavation (steam sterilization) In parallel with gamma-irradiation of the final drug product (formulated calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate having a Dv50 particle size of 8 micrometer), autoclavation (steam sterilization ) was evaluated as well. Autoclavability (122 °C, 15 min.) was investigated on 2 different concepts in two separate studies, as shown in Table 18. Table 18: Overview of drug product concepts subjected to autoclavation (steam sterilization) with the corresponding assay / purity results. Formulation Assay, % Impurity, % g tni DpdtNencAPIepnUeSurfactant BufferORRT RRT RRT RRT RRT RRT nosugPaM 0.60 0.72 1.11* 1.15 1.16 1.32 CseO R C 135-1tl5 mg / mL 8a0 97.5 <0.05 <0.05 <0.s0Polysorbate 2005 <0.05 <0.05 <0.05L-a 0H 4p135-2m / CG15 mg / mL etgg aaE 96.1 <0.05 <0.05 <0.05 <0.05 <0.05 <0.PPoloxamer 338rti 05mpi c / 42-50xL5et1 01 elm e / mg / mLgaPolh 103.3 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05Sysorbate 20 p.m sq 5 15 mg / o142-2e 7mL hPoloxamer 338 P97.4 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05RRT 0.60* is an impurity with a relative retention time of 0.60 min RRT 0.72* is an impurity with a relative retention time of 0.72 min RRT 1.11* is an impurity with a relative retention time of 1.11 min RRT 1.15* is an impurity with a relative retention time of 1.15 min (N-isopropyl-5,6-diphenyl- pyrazin-2-amine) RRT 1.16* is an impurity with a relative retention time of 1.16 min (1-Butanol, 4-[(5,6-diphenyl- 2-pyrazinyl)(1-methylethyl)amino]-) RRT 1.32* is an impurity with a relative retention time of 1.32 min (N-isopropyl-N-(4- methoxybutyl)-5,6-diphenyl-pyrazin-2-amine) The same analytical method as in example 11 has been used. Results show that no impurities are formed during autoclavation and hence autoclavation (steam sterilization) does not impact chemical stability of the different studied drug concepts. Not only the effect upon chemical stability, but upon resuspendability was evaluated as well for the process of autoclavation (steam sterilization). The tested samples of experiment 142 were evaluated for resuspendability right after autoclavation (T0) and after 14 days of storage at 5 °C. An overview of the results is shown in Table 19. Time needed for resuspendability was acceptable at both timepoints. Table 19: Resuspendability results of drug product concepts after subjected to autoclavation (steam sterilization) Concept Sampling time Resuspendability (Seconds) 142-5 T0 15 - 2014 days (storage at 5 °C) 15 - 20142-2 T0 15 - 2014 days (storage at 5 °C) 15 - 20Based on the results in Table 18 and 19, it can be concluded that calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is chemically stable in the drug product after the sterilization of drug product using autoclavation (steam sterilization). No aggregation was formed and the drug product can easily be resuspended after autoclavation. Example 13: To guarantee sterility of the final drug product (formulated calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate having a Dv50 particle size of 8 micrometer), feasibility of three potential pathways was studied: gamma-irradiation of drug product and heat sterilization of drug product. To demonstrate feasibility, both physical (i.e., resuspendability and particle size) and chemical stability (i.e., formation of impurities) should be guaranteed, and the results are shown in Table 20. Table 20: ^Summary of assay / impurity results for drug substance (not formulated) and drug product (formulated) sterilized by gamma-irradiation and autoclavation Assay, % Impurity, % Sample Name Concept COMPOUND RRTRRT RRT RRT RRT RRT 0.600.72 1.11 1.15 1.16 1.32 DP - PX338(reference)142-1 101 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05DP - PX338(autoclavation)142-2 97.4 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05DP - PX338 (γ-irradiation / 142-10 97.4 <0.05 <0.05 0.39 <0.05 0.05 0.12 40 kGy) DP - PX338 (γ -irradiation / 142-3 98.3 0.05 0.05 0.65 <0.05 <0.05 0.18 60 kGy) DP - PS 20(reference)142-4 105.4 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05DP - PS 20(autoclavation)142-5 103.3 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05DP - PS 20 (γ-irradiation / 142-12 101.9 <0.05 <0.05 0.45 <0.05 0.06 0.12 40 kGy) DP - PS 20 (γ-irradiation / 142-6 102 <0.05 <0.05 0.7 <0.05 <0.05 0.19 60 kGy) DP: drug product (formulated) DS: drug substance (not formulated) PX338: Poloxamer 338 PS20: polysorbate 20 RRT 0.60* is an impurity with a relative retention time of 0.60 min RRT 0.72* is an impurity with a relative retention time of 0.72 min RRT 1.11* is an impurity with a relative retention time of 1.11 min RRT 1.15* is an impurity with a relative retention time of 1.15 min (N-isopropyl-5,6- diphenyl-pyrazin-2-amine) RRT 1.16* is an impurity with a relative retention time of 1.16 min (1-Butanol, 4-[(5,6- diphenyl-2-pyrazinyl)(1-methylethyl)amino]-) RRT 1.32* is an impurity with a relative retention time of 1.32 min (N-isopropyl-N-(4- methoxybutyl)-5,6-diphenyl-pyrazin-2-amine) The same analytical method as in example 11 has been used. Based on Table 20, calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate is chemically stabile by autoclavation (steam sterilization) of the final drug product. With gamma-irradiation of the drug product, impurity levels are relatively high but still in an acceptable range. Therefore, it can be concluded that the final drug product can be sterilized with both autoclavation (steam sterilization) and gamma irradiation. Example 14: TRIS and CaCl2Resuspendability was evaluated for composition without and with calcium chloride in the compositions shown in table 21. The compositions were filled in 2R vials and 2.25 mL COC syringes (fill volume was 1.9 mL, headspace in syringe was 5 mm) and stored for 2 weeks at 25 °C. Syringes were stored tip-down. Table 21: Material TRIS concept TRIS + CaCl2concept Conc. (mg / mL) Conc. (mg / mL) calcium;{4-[(5,6-diphenylpyrazin-2- 52.25 52.25 yl)(propan-2-yl)amino]butoxy}acetate Polysorbate 20 2.5 2.5 Trometamol 1.21 1.21 HCl 6N q.s. ad pH 7.5 q.s. ad pH 7.5 CaCl2 N / A 3.70 PEG 4000 75.00 75.00 Purified water q.s. ad 1 mL q.s. ad 1 mL Resuspendability was evaluated by shaking with the needle tip of the syringe pointed upwards. Vials were placed between thumb and index finger and shaken vigorously in cycles of 5 seconds. Resuspendability was evaluated in cycles of 5 seconds vigorously shaking. The more cycles required, the worse the resuspendability. Table 22: Formulation Primary container Resuspendability (# 5 s cycles required) Tris Vial 10 COC syringe 4 Tris + CaCl2Vial 2 COC syringe 2 The assay of the supernatant of the suspensions (reflecting the amount of free metabolite) was evaluated as well. The suspension is assayed by centrifugation of the suspension and assaying the supernatant via RP-UPLC (UV). Table 23 Formulation Assay in supernatant (mg / mL) Tris 0.08 Tris + CaCl20.02 Phosphate-citrate buffer 0.76 Example 15: Histidine and CaCl2Resuspendability was evaluated for composition without and with calcium chloride in the compositions shown in the table below. The compositions were filled in 2R vials and 3 mL cartridges (fill volume was 1.9 mL, headspace in cartridge was 5 mm) and stored for 2 weeks at 25 °C. Table 24: Composition Material Histidine concept Histidine + CaCl2 Conc. (mg / mL) concept Conc. (mg / mL) calcium;{4-[(5,6-diphenylpyrazin-2- 52.25 52.25 yl)(propan-2-yl)amino]butoxy}acetate Polysorbate 20 2.5 2.5 L-Histidine 1.55 1.55 HCl 6N q.s. ad pH 7.5 q.s. ad pH 7.5 CaCl2dihydrate N / A 7.948 PEG 4000 75.00 75.00 Purified water q.s. ad 1 mL q.s. ad 1 mL Resuspendability was evaluated in cycles of 5 seconds vigorously shaking. The more cycles required, the worse the resuspendability. Table 25: Formulation SampleResuspendability (# 5 s cyclesrequired)Vial 1 3 Vial 2 3 Vial 3 4 Vial 4 3 Vial 5 3 Histidine Cartridge 1 4 Cartridge 2 4 Cartridge 3 3 Cartridge 4 4 Cartridge 5 4 Vial 1 1 Vial 2 1 Vial 3 1 Vial 4 1 Vial 5 1 Histidine / CaCl2Cartridge 1 2 Cartridge 2 2 Cartridge 3 1 Cartridge 4 1 Cartridge 5 2 Example 16: Phosphate-citrate and CaCl2Resuspendability was evaluated for composition without and with calcium chloride in the compositions shown in table 26. The compositions were filled in four 8R vials and stored for 2 weeks at 25 °C. Table 26: Material Conc. (mg / mL) calcium;{4-[(5,6-diphenylpyrazin-2- 52.25 yl)(propan-2-yl)amino]butoxy}acetate Polysorbate 20 2.5 Disodium hydrogen phosphate anhydrous 23.38 Citric acid monohydrate 3.710 Sodium hydroxide 1.120 (pH = 7.5) CaCl2 dihydrate 7.948 PEG 4000 75.00 Purified water q.s. ad 1 mL After 2 weeks of storage, the suspension was evaluated. Gel formation occurred in all four vials and the composition could not be resuspended. Example 17: PK Study Comparing Concentration of API A PK study was set up to evaluate the effect of the dose and concentration of Ca-salt of JNJ-68006861 using SC administration on the in-vivo drug release rate. The API concentration of the different studied aqueous suspensions was eq.25 mg / mL and eq.50 mg / mL. The formulations are described in table 27. Plasma samples were evaluated pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, and 12 hours post dosing. Mean (+ / - SD) plasma concentrations of selexipag metabolite are shown in Figure 9. Table 27: Material Conc. (mg / mL) Conc. (mg / mL) calcium;{4-[(5,6-diphenylpyrazin-2- 52.25 26.125 yl)(propan-2-yl)amino]butoxy}acetate Polysorbate 20 2.5 1.25 Disodium hydrogen phosphate anhydrous 23.38 23.38 Citric acid monohydrate 3.710 3.710 Sodium hydroxide 1.120 (pH = 7.5) 1.120 (pH = 7.5) PEG 4000 75.00 75.00 Purified water q.s. ad 1 mL q.s. ad 1 mL Injection site reactions, for example pain, tenderness, erythema / redness, and induration / swelling, were measured for sample injections of these formulations. Example measurement techniques include the toxicity grading scale in the “Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” published by the U.S. Department of Health and Human Services and the F.D.A. on September 2007. The erythema / redness and induration / swelling were measured directly at the injection site by their greatest diameter. Example 18: PK Study of Long Acting Injectable This study assessed the safety, tolerability, and PK following multiple doses up-titration of oral JNJ-68006861 (Period 1) and single doses of different LAI JNJ-68006861 formulations (Period 2). In addition, the relative bioavailability between different LAI formulations, mode of administration (SC vs IM), and for LAI vs oral administration was assessed. Figure 10 shows a general scheme. Approximately 88 participants were enrolled in this study. Participants were recruited into up to 6 cohorts (Cohort 1 / n=8, Cohort 2 / n=8, Cohort 3 / n=46, Cohort 4 / n=10, Cohort 5 / n=8, and Cohort 6 / n=6). Cohorts have 2 study periods: • Study Period 1: an Oral Treatment Period and • Study Period 2: an LAI Treatment Period. Each cohort was initiated with titration of oral JNJ-68006861 toward select steady-state levels, followed by a 3-day washout period, i.e., 3 full days without administration of study intervention. Following this washout period, participants were administered a single injection of a selected dose of the LAI formulation. All cohorts were followed for up to 70 days in the LAI Treatment Period with PK sample collection and for relevant safety / tolerability parameters. In Cohort 3, participants were randomized to 1 of 6 intervention arms. Six intervention arms (Arms A, B, C, D, E, and F) received a single injection (SC or IM) of a selected LAI formulation and dose. Administration of the LAI formulation was a single IM or SC injection. Subcutaneous injections occurred in the adipose tissue of the abdomen and IM injections occurred in the deltoid of the non-dominant arm. Cohort 1: Eight participants received oral JNJ-68006861100 µg BID for 2 days and only 1 dose of 100 µg oral JNJ-68006861 in the morning of Day 3 of the Oral Treatment Period. After a 3-day washout period (Day 4, 5, and 6), participant received a single JNJ- 68006861 eq.2.5 mg SC injection in the morning of Day 1 of the LAI Treatment Period. Cohort 2: Eight participants received oral ascending doses of JNJ-68006861 starting at 100 µg BID for 3 days, which were then up-titrated to 200 µg BID for 2 days and 200 µg in the morning of Day 6 of the Oral Treatment Period. After a 3-day washout period (Day 7, 8, and 9), participants received one SC injection eq.5 mg of JNJ-68006861 in the morning of Day 1 of the LAI Treatment Period. Cohort 3: Participants received multiple oral ascending doses of JNJ-68006861 starting at 100 μg BID for 3 days, which were then up-titrated by 100 μg BID every 3 days until 600 μg BID was reached on Day 16 and continued for 3 days. On Day 19, participants were up-titrated to 800 μg BID for 2 days and received only 1 dose of 800 µg in the morning of Day 21. Following up-titration with JNJ-68006861, there was a 3-day washout period (Days 22, 23, and 24). Participants were randomized to 1 of 6 intervention arms on Day 24. The participants received their randomized intervention on Day 1 of the LAI Treatment Period, consisting of 1 of up to 6 options: • SC injection eq.12.5 mg / 0.25 mL (poloxamer) Component mg / mL mg / vial Ca salt of JNJ-68006861 52.25 94.05 Poploxamer 338 7.500 13.500 Macrogol 4000 75.00 135.00 Disodium phosphate 23.38 42.08 Citric acid monohydrate 3.710 6.678 Sodium hydroxide 1.120 2.016 Water q.s ad 1 mL q.s. ad 1.8 mL q.s. = quantum satis • SC injection eq.12.5 mg / 0.25 mL (polysorbate in phosphate buffer) Component mg / mL mg / vial Ca salt of JNJ-68006861 52.25 94.05 Polysorbate 20 2.500 4.500 Macrogol 4000 75.00 135.00 Disodium phosphate 23.38 42.08 Citric acid monohydrate 3.710 6.678 Sodium hydroxide 1.120 2.016 Water q.s ad 1 mL q.s. ad 1.8 mL q.s. = quantum satis • SC injection eq.12.5 mg / 0.50 mL (polysorbate in phosphate buffer) Component mg / mL mg / vial Ca salt of JNJ-68006861 26.125 47.025 Polysorbate 20 1.250 2.250 Macrogol 4000 75.00 135.00 Disodium phosphate 23.38 42.08 Citric acid monohydrate 3.710 6.678 Sodium hydroxide 1.120 2.016 Water q.s ad 1 mL q.s. ad 1.8 mL q.s. = quantum satis • IM injection eq.5 mg / 0.20 mL (polysorbate in phosphate buffer) (see formulation above) • SC injection eq.25 mg / 0.50 mL (polysorbate in phosphate buffer) (see formulation above) • SC injection eq.25 mg / 1 mL (polysorbate in phosphate buffer) (see formulation above) Cohort 4: In the Oral Treatment Period, participants received oral ascending doses of JNJ-68006861 starting at 100 μg BID for 3 days and up-titrated every 3 days up to 800 µg BUD as described for previous cohorts. After receiving the final oral dose, participants went through a 3-day washout period, after which the participants received a single eq.25 mg dose of a selected LAI formulation of JNJ-68006861 on Day 1 of the LAI Treatment Period. Each participant received a single SC injection of the formulation listed below: • Polysorbate in tris buffer (eq.50 mg / mL) Component mg / mL mg / vial Ca salt of JNJ-68006861 52.25 94.05 Polysorbate 20 2.500 4.500 Macrogol 4000 75.00 135.00 Trometamol 3.634 6.541 Calcium Chloride Dihydrate 7.948 14.31 Hydrochloric acid, dilute 8.794 µL / mL 15.83 µL / vial Water q.s ad 1 mL q.s. ad 1.8 mL q.s. = quantum satis Cohort 5: In the Oral Treatment Period, participants received oral ascending doses of JNJ-68006861 starting at 100 μg BID for 3 days and up-titrated every 3 days up to 800 µg BUD as described for previous cohorts. After receiving the final oral dose, participants went through a 3-day washout period, after which the participants received a single eq.60 mg dose of a selected LAI formulation of JNJ-68006861 on Day 1 of the LAI Treatment Period. Each participant received a single SC injection of the same formulation used for Cohort 4. Cohort 6: In the Oral Treatment Period, participants received oral doses of JNJ- 68006861 of 100 μg BID for 2.5 days. After receiving the final oral dose (in the morning of the third day), participants went through a 3-day washout period, after which the participants received a single eq.5 mg dose of a selected LAI formulation of JNJ- 68006861 on Day 1 of the LAI Treatment Period. Each participant received a single SC injection of the same formulation used for Cohort 4. The descriptions of Cohort 1, Cohort 2, Cohort 3, Cohort 4, Cohort 5 and Cohort 6 and study interventions are provided in Table 28, Table 29, Tables 30 & 31, Table 32, Table 32a and Table 32b respectively. Table 28: Cohort 1 Study Intervention Information Group / Arm Name Treatment Period 1 Treatment Period 2 Intervention Name Oral JNJ-68006861 Subcutaneous JNJ-68006861 Type Drug Drug Dose Formulation Film-coated tablet Suspension for injection Polysorbate in phosphate buffer Unit Dose Strength(s) 100 µg eq.25 mg / mL Dosage Level(s) and 100 µg BID for 2 ½ days eq.2.5 mg Frequency Single dose (0.1 mL eq.25 mg / mL) Route of Oral Subcutaneous Administration * 100 µg BID for 21 / 2 days - 1x 100 µg in the morning and 1x100 µg in the evening. Table 29: Cohort 2 Study Intervention Information Group / Arm Name Treatment Period 1 Treatment Period 2 Intervention Name Oral JNJ-68006861 Subcutaneous JNJ-68006861 Type Drug Drug Dose Formulation Film-coated tablet Suspension for injection Polysorbate in phosphate buffer Unit Dose Strength(s) 100 μg eq.25 mg / mL Dosage Level(s) and 100 μg BID for 3 days eq.5 mg Frequency 200 μg BID for 21 / 2 days Single dose (0.2 mL eq.25 mg / mL) Route of Oral Subcutaneous Administration * 100 μg BID for 3 days - 1x 100 µg in the morning and 1x100 µg in the evening. 200 μg BID for 21 / 2 days -2x 100 µg in the morning and 2x100 µg in the evening. Table 30: Cohort 3 Study Intervention Information Group / Arm Treatment Treatment Period 2 Name Period 1 Oral LAI LAI LAI LAI Treatment Treatment Treatment Treatmen Treatment Period / Period Period t Period Period / Randomized / Randomiz / Randomi Randomize Arm D ed Arm A zed Arm d Arm C B Intervention Oral JNJ- Subcutane Subcutan Subcutaneo Intramuscular Name 68006861 ous JNJ- eous JNJ- us JNJ- JNJ-68006861 68006861 68006861 68006861 Type Drug Drug Drug Drug Drug Dose Film-coated Suspensio Suspensio Suspension Suspension for Formulation tablet n for n for for injection injection injection injection Polysorbate Polysorbate in Poloxamer Polysorbat in phosphate e in phosphate buffer phosphate buffer buffer Unit Dose 100 μg Eq.50 Eq.50 Eq.25 Eq.25 mg / mL Strength(s) mg / mL mg / mL mg / mL Dosage 100 μg BID for Eq.12.5 Eq.12.5 Eq.12.5 mg, Eq.5 mg, Level(s) and 3 days mg, single mg, single single dose single dose Frequency 200 μg BID for dose dose 3 days (0.50 mL eq. (0.20 mL eq.25 300 μg BID for (0.25 mL (0.25 mL 25 mg / mL) mg / mL) 3 days eq.50 eq.50 400 μg BID for mg / mL) mg / mL) 3 days 500 μg BID for 3 days 600 μg BID for 3 days 800 μg BID for 21 / 2 days See below* Route of Oral Subcutane Subcutan Subcutaneo Intramuscular Administrati ous eous us on *100 µg BID for 3 days - 1x 100 µg in the morning and 1x100 µg in the evening 200 µg BID for 3 days -2x 100 µg in the morning and 2x100 µg in the evening 300 µg BID for 3 days -3x 100 µg in the morning and 3x100 µg in the evening 400 µg BID for 3 days -4x 100 µg in the morning and 4x100 µg in the evening 500 µg BID for 3 days -5x 100 µg in the morning and 5x100 µg in the evening 600 µg BID for 3 days -6x 100 µg in the morning and 6x100 µg in the evening 800 µg BID for 21 / 2 days -8x 100 µg in the morning and 8x100 µg in the evening Table 31: Cohort 3 Study Intervention Information Group / Arm Treatment Treatment Period 2 Name Period 1 Oral LAI Treatment LAI Treatment Period Treatment Period / Randomized / Randomized Arm F Period Arm E Intervention Oral JNJ- Subcutaneous JNJ- Subcutaneous JNJ-68006861 Name 68006861 68006861 Type Drug Drug Drug Dose Film-coated Suspension for Suspension for injection Formulation tablet injection Polysorbate Polysorbate in phosphate in phosphate buffer buffer Unit Dose 100 μg Eq.25 mg / mL Eq.50 mg / mL Strength(s) Dosage 100 μg BID for Eq.25 mg, single Eq.25 mg, single dose Level(s) and 3 days dose Frequency 200 μg BID for (0.5 mL eq.50 mg / mL) 3 days (1 mL eq.25 mg / mL) 300 μg BID for 3 days 400 μg BID for 3 days 500 μg BID for 3 days 600 μg BID for 3 days 800 μg BID for 21 / 2 days See below* Route of Oral Subcutaneous Subcutaneous Administrati on

[0004] Table 32: Cohort 4 Study Intervention Information Group / Arm Name Treatment Period 1 Treatment Period 2 Oral Treatment Period LAI Treatment Period Intervention Name Oral JNJ-68006861 Subcutaneous JNJ- 68006861 Type Drug Drug Dose Formulation Film-coated tablet Suspension for injection Polysorbate in tris buffer Unit Dose Strength(s) 100 μg Eq.50 mg / mL Dosage Level(s) and 100 μg BID for 3 days Eq.25 mg, single dose Frequency 200 μg BID for 3 days 300 μg BID for 3 days (0.50 mL eq.50 mg / mL) 400 μg BID for 3 days 500 μg BID for 3 days 600 μg BID for 3 days 800 μg BID for 2 ½ days See below* Route of Administration Oral Subcutaneous *100 µg BID for 3 days - 1x 100 µg in the morning and 1x100 µg in the evening 200 µg BID for 3 days -2x 100 µg in the morning and 2x100 µg in the evening 300 µg BID for 3 days -3x 100 µg in the morning and 3x100 µg in the evening 400 µg BID for 3 days -4x 100 µg in the morning and 4x100 µg in the evening 500 µg BID for 3 days -5x 100 µg in the morning and 5x100 µg in the evening 600 µg BID for 3 days -6x 100 µg in the morning and 6x100 µg in the evening 800 µg for 21 / 2 days -8x 100 µg in the morning and 8x100 µg in the evening Table 32a: Cohort 5 Study Intervention Information Group / Arm Name Treatment Period 1 Treatment Period 2 Oral Treatment Period LAI Treatment Period Intervention Name Oral JNJ-68006861 Subcutaneous JNJ- 68006861 Type Drug Drug Dose Formulation Film-coated tablet Suspension for injection Polysorbate in tris buffer Unit Dose Strength(s) 100 μg Eq.50 mg / mL Dosage Level(s) and 100 μg BID for 3 days Eq.60 mg, single dose Frequency 200 μg BID for 3 days 300 μg BID for 3 days (1.20 mL eq.50 mg / mL) 400 μg BID for 3 days 500 μg BID for 3 days 600 μg BID for 3 days 800 μg BID for 2 ½ days See below* Route of Administration Oral Subcutaneous *100 µg BID for 3 days - 1x 100 µg in the morning and 1x100 µg in the evening 200 µg BID for 3 days -2x 100 µg in the morning and 2x100 µg in the evening 300 µg BID for 3 days -3x 100 µg in the morning and 3x100 µg in the evening 400 µg BID for 3 days -4x 100 µg in the morning and 4x100 µg in the evening 500 µg BID for 3 days -5x 100 µg in the morning and 5x100 µg in the evening 600 µg BID for 3 days -6x 100 µg in the morning and 6x100 µg in the evening 800 µg for 21 / 2 days -8x 100 µg in the morning and 8x100 µg in the evening Table 32b: Cohort 6 Study Intervention Information Group / Arm Name Treatment Period 1 Treatment Period 2 Oral Treatment Period LAI Treatment Period Intervention Name Oral JNJ-68006861 Subcutaneous JNJ- 68006861 Type Drug Drug Dose Formulation Film-coated tablet Suspension for injection Polysorbate in tris buffer Unit Dose Strength(s) 100 μg Eq.50 mg / mL Dosage Level(s) and 100 μg BID for 2.5 days Eq.5 mg, single dose Frequency 1x 100 µg in the morning (0.10 mL eq.50 mg / mL) and 1x 100 µg in the evening Route of Administration Oral Subcutaneous Blood, plasma and urine samples were used to evaluate the PK of JNJ-68006861 following administration of oral and LAI JNJ-68006861 formulations. The following plasma PK parameters were derived for JNJ-68006861: • AUC0-∞, AUC0-t, AUC0-28d, AUC0-14d, AUC0-24h, C14d, C28d, Cmax, tmax, t1 / 2, AUCτ,ss, AUCτ,Day 1, Cmax,ss, tmax,ss, Ctrough,ssThe mean (+ / - SD) plasma concentrations of selexipag metabolite for different formulations are shown in Table 33 and Figures 11 and 12.

[0005] Table 33: PK data Pharmacokinetics of 25 mg LAI 25 mg LAI 25 mg Ratio JNJ-68006861 Phosphate Phosphate LAI Tris / phosphate (eq.25 (eq.50 Tris formulation mg / mL) mg / mL) (eq.50 mg / mL) n 10 8 10 Cmax(ng / mL) 23.2 (6.75) 24.9 (6.37) 11.4 0.46 (3.96) tmax(h) 264 (96 - 264 (168-312) 264 311.1) (216- 648) tmax(days) 11 11 11 AUC0-24 hours(ng.h / mL) 172 (42.2) 166 (45.5) 78.3 0.47 (28.6) AUC0-14 days(ng.h / mL) 3963 (928) 4131 (1136) 2000 0.48 (731) AUC0-28 days(ng.h / mL) 6997 (1680) 7710 (1780) 4236 0.55 (1047) AUClast(ng.h / mL) 7404 (1639) 8398 (1992) 5686 0.68 (1066) t1 / 2(h) 65.6 (29.2) 84.4 (32.0) 131.5 (68.8) (mean [SD], tmax: median [range]) The LAI formulation comprising a Tris buffer showed a slow gradual onset of exposure (no initial peak within 6 hours of dosing), significantly lower Cmax, an extended release, and a ~30% lower AUClastas compared to the phosphate buffer formulation. Example 19: PK Study of Long Acting Injectable This is a prospective, multicenter, open-label, switch, multiple-dose, 3-intervention period Phase 1b study to evaluate safety, tolerability, and PK of multiple doses of a SC LAI formulation of JNJ-68006861 in participants with PAH. A schematic overview of the study design is provided in Figure 13. Up to 36 participants with PAH, currently treated with a stable oral maintenance dose of UPTRAVI (oral selexipag), also known as their iMTD (individual maximum tolerated dose), will be enrolled into 1 of 3 cohorts of up to 12 participants each based on their iMTD of UPTRAVI. • Cohort 1: Participants on a stable iMTD of 200, 400, or 600 μg UPTRAVI BID. • Cohort 2: Participants on a stable iMTD of 800, 1000, or 1200 μg UPTRAVI BID. • Cohort 3: Participants on a stable iMTD of 1400 or 1600 μg UPTRAVI BID. As the iMTD of UPTRAVI of eligible participants determines the cohorts they will be enrolled in, individual cohorts may be conducted in parallel. Not all cohorts may be initiated, and individual cohorts may also be terminated at any time if considered appropriate by the sponsor based on emerging data from the study. This study includes a Screening / Oral UPTRAVI Period, up to 3 intervention periods during which a total of up to 4 or 6 administrations of JNJ-68006861 LAI will be administered at Q2W (every 2 weeks) or Q4W (every 4 weeks) intervals, and a Follow-up Period. Participants will be evaluated for eligibility from Day -28 to Day -1, during which they will continue receiving their usual iMTD of oral UPTRAVI (ie, Screening / Oral UPTRAVI Period). Eligible participants will take the last dose of oral UPTRAVI (iMTD) in the evening of Day -1. During the 3 intervention periods, the average exposure (ie, Cavg) of JNJ- 68006861 will be progressively increased by either repeating the previous dose (to account for the predicted accumulation of JNJ-68006861 LAI) or by dose escalation. In Intervention Period 1, participants will receive an initial JNJ-68006861 LAI administration with a dose selected to achieve an average plasma concentration of JNJ- 68006861 similar to that achieved with the participant’s iMTD of UPTRAVI. To achieve an increase in JNJ-68006861 exposure (Cavg) while accounting for the predicted accumulation of the LAI, in Intervention Period 2 the same dose as given in Intervention Period 1 will be repeated for patients receiving Q4W dosing or a higher dose will be given for patients receiving Q2W dosing. In Intervention Period 3, to further increase JNJ- 68006861 exposure, the JNJ-68006861 LAI dose will be escalated for all patients. At the beginning of Intervention Periods 2 and 3, the investigator will carefully assess the cumulative safety and tolerability data prior to repeating the dose or dose escalation, respectively. If an increase in exposure is not considered in the best interest of the participant, the duration of the current intervention period may be extended (ie, additional injections at the same dose level or at a lower dose level). At each dose administration, the dose of the JNJ-68006861 LAI formulation will be administered as a single SC injection. • LAI formulation (eq.50 mg / mL) Component mg / mL mg / vial Ca salt of JNJ-68006861 52.25 94.05 Polysorbate 20 2.500 4.500 Macrogol 4000 75.00 135.00 Trometamol 3.634 6.541 Calcium Chloride Dihydrate 7.948 14.31 Hydrochloric acid, dilute 8.794 µL / mL 15.83 µL / vial Water q.s ad 1 mL q.s. ad 1.8 mL q.s. = quantum satis • LAI formulation (eq.25 mg / mL) Component mg / mL mg / vial Ca salt of JNJ-68006861 26.125 47.025 Polysorbate 20 1.250 2.25 Macrogol 4000 75.00 135.00 Trometamol 3.634 6.541 Calcium Chloride Dihydrate 7.948 14.31 Hydrochloric acid, dilute 8.794 µL / mL 15.83 µL / vial Water q.s ad 1 mL q.s. ad 1.8 mL q.s. = quantum satis Screening / Oral UPTRAVI Period (Day -28 to Day -1) Participants will continue to receive oral UPTRAVI BID (morning and evening dose, approximately 12 hours apart) at the participant’s iMTD. Intervention Period 1 (Day 1 to Day 28): Initial JNJ-68006861 LAI Dose to Match Exposure of Oral UPTRAVI iMTD On Day 1, participants will receive the first JNJ-68006861 LAI administration with an initial dose selected to achieve an average plasma concentration of JNJ-68006861 similar to that achieved with participant’s iMTD of oral UPTRAVI (see Table 34). On Day 29, the investigator should make a careful evaluation of the safety and tolerability of the initial JNJ-68006861 LAI dose received during Intervention Period 1 for each individual participant: • If the initial dose of JNJ-68006861 LAI is considered well tolerated, the participant will proceed to Intervention Period 2 to increase JNJ-68006861 exposure. • If, however, an increase in exposure is not considered in the best interest of the participant, Intervention Period 1 may be extended by 4 weeks (ie, Day 29 to 56) where the dose of JNJ-68006861 LAI will be decreased (ie, given the predicted accumulation of JNJ-68006861 LAI following Q4W administration, a decrease in dose will be needed to maintain the same exposure as that of the preceding 4 weeks) (see Table 35). On Day 57, the investigator should once again make a careful evaluation of the safety and tolerability of the initial JNJ-68006861 LAI dose for each individual participant: - If the tolerability has improved the participant may then proceed to Intervention Period 2 where the same dose as was administered on Day 1 will be administered on Day 57 and Day 85 to progressively increase JNJ-68006861 exposure. - If, however, an increase in exposure is still not considered in the best interest of the participant, Intervention Period 1 may be extended by an additional 4 weeks (ie, Day 57 to 84) where the decreased dose (same dose as was administered on Day 29; see Table 35) of JNJ-68006861 LAI will be further continued with administration on Day 57 and Day 85. If deemed appropriate by the sponsor based on emerging data, the first JNJ-68006861 LAI dose may be coadministered with oral selexipag for a limited period to ensure matching exposure to oral UPTRAVI iMTD. Intervention Period 2 (Day 29 to 56): Escalated Q2W or Repeated Q4W JNJ- 68006861 LAI Dose to Exceed Exposure of Oral UPTRAVI iMTD If the initial JNJ-68006861 LAI dose received during Intervention Period 1 is considered well tolerated in the individual participant, the participant will proceed to receive a second or third JNJ-68006861 LAI administration on Day 29. To achieve an increase in JNJ- 68006861 average exposure following Q2W administration, the second and third administrations will be of a higher dose as given on Days 1 and 15. To achieve an increase in JNJ-68006861 average exposure while accounting for the predicted accumulation of JNJ-68006861 LAI following Q4W administration, the second administration will be of the same dose as given on Day 1 (see Table 34). On Day 57, the investigator should make a careful evaluation of the safety and tolerability of the JNJ-68006861 LAI dose(s) administered in the previous period(s) for each individual participant: • If the dose of JNJ-68006861 LAI received during intervention period 2 is considered well tolerated, the participant will proceed to Intervention Period 3 for dose escalation of JNJ-68006861 LAI. • If, however, dose escalation is not considered in the best interest of the participant, Intervention Period 2 may be extended by 4 weeks (ie, Day 57 to 84) where the same dose of JNJ-68006861 LAI as received on Day 29 will be administered on Day 57 and Day 71 (for Q2W doses) or 85 (for Q4W doses). Intervention Period 3 (Day 57 to 112): Escalated Q4W JNJ-68006861 LAI Dose to Exceed Exposure in Intervention Period 2 If the JNJ-68006861 LAI dose received during Intervention Period 2 is considered well tolerated in the individual participant, the participant will proceed to receive an escalated dose of the JNJ-68006861 LAI on Day 57 and Day 85 (see Table 34) to exceed average exposure achieved during Intervention Period 2. Follow-up (Day 114 to 157 or Day 128 to 157) All participants will undergo follow-up for ongoing and newly emerging adverse events and concomitant therapies. The follow-up period will start on Day 114 or Day 128. Blood samples will be collected for measurement of plasma or blood concentrations of JNJ-68006861. The concentration of selexipag may also be measured in plasma samples if considered appropriate. The following PK parameters of JNJ-68006861 will be calculated: AUCτ, AUCτ,ss, Cmax, Cmax,ss, Cavg, Cavg,ss, tmax, tmax,ss, Ctrough, and Ctrough,ss. Other PK parameters may be estimated as appropriate for the exploration of the data. Table 34: Planned Doses of JNJ-68006861 LAI Cohort Intervention Period Intervention Period Intervention Period 1 2 3 UPTRAVI Initial Repeated Escalated iMTD JNJ-68006861 LAI JNJ-68006861 LAI JNJ-68006861 LAI (BID) Dose (eq.) Dose (eq.) Dose (eq.) Day -1 Day 1 Day 29 Day 57 and 85 1 200 µg 2.5 mg, Q2W 5 mg, Q2W 10 mg 1 400 µg 5 mg, Q2W 7.5 mg, Q2W 15 mg 1 600 µg 22.5 mg 22.5 mg 30 mg 2 800 µg 30 mg 30 mg 37.5 mg 2 1000 µg 37.5 mg 37.5 mg 45 mg 2 1200 µg 45 mg 45 mg 52.5 mg 3 1400 µg 52.5 mg 52.5 mg 60 mg 3 1600 µg 60 mg 60 mg 75 mg Table 35 Decreased Dose of JNJ-68006861 LAI When Extending Intervention Period 1 Cohort Intervention Period 1 Intervention Period 2 UPTRAVI iMTD Initial Decreased (BID) JNJ-68006861 LAI Dose (eq.) JNJ-68006861 LAI Dose (eq.) Day -1 Day 1 Day 29 1 200 µg 2.5 mg N / A 1 400 µg 5 mg 2.5 mg 1 600 µg 22.5 mg 15 mg 2 800 µg 30 mg 22.5 mg 2 1000 µg 37.5 mg 30 mg 2 1200 µg 45 mg 37.5 mg 3 1400 µg 52.5 mg 45 mg 3 1600 µg 60 mg 52.5 mg UPTRAVI All participants will be on a stable iMTD of UPTRAVI upon enrollment into the study with one of 8 approved dose levels (ie, 200, 400, 600, 800, 1000, 1200, 1400, or 1600 µg BID). Eligible participants will take the last dose of oral UPTRAVI (iMTD) in the evening of Day -1. JNJ-68006861 Selection of the initial doses of JNJ-68006861 LAI to be administered on Day 1 is based on the possible iMTD levels of oral UPTRAVI, ie, 200 to 1600 µg BID. Corresponding doses are defined as doses expected to comply with the following criteria for the exposure to JNJ-68006861: 1. A comparable Cavgfollowing the initial dose of JNJ-68006861 LAI and oral UPTRAVI administration at steady state. 2. Cmaxfollowing the initial dose of JNJ-68006861 LAI should not exceed Cmaxfollowing administration of oral UPTRAVI at steady state. 3. Ctroughfollowing the initial dose of JNJ-68006861 LAI should exceed or be comparable to Ctroughfollowing oral UPTRAVI at steady state. Corresponding oral UPTRAVI and JNJ-68006861 LAI doses together with the expected exposure to JNJ-68006861 based on simulated exposures for oral UPTRAVI and preliminary PK data for JNJ-68006861 LAI are provided in Table 36. Table 36: Corresponding Doses of Oral UPTRAVI and JNJ-68006861 LAI Including the Estimated Exposure to JNJ-68006861 Oral UPTRAVI JNJ-68006861 LAI Dose Cavg.ssCmax.ssCtrough.ssDose Dosing Cavg.initialCmax.initialCtrough.initial(μg, B (ng / mL) (ng / mL) (ng / mL) eq. Freq.dose dose dose(ng / mL) ID) (mg,) (ng / mL) (ng / mL) 200 1.85 4.07 1.43 2.5 Q2W 1.83 3.72 2.145 400 3.70 8.15 2.87 5 Q2W 3.66 7.44 4.29 600 5.55 12.20 4.30 22.5 Q4W 5.49 9.63 43.39 800 7.41 16.30 5.73 30 Q4W 7.32 12.84 5.86 1000 9.26 20.40 7.17 37.5 Q4W 9.15 16.05 7.32 1200 11.10 24.40 8.60 45 Q4W 10.98 19.26 8.78 1400 12.96 28.50 10.00 52.5 Q4W 13.59 24.81 12.14 1600 14.81 32.60 11.50 60 Q4W 15.53 28.35 13.87 75 Q4W 19.42 35.44 Q4W The doses of JNJ-68006861 LAI to be tested in Intervention Period 1 will range from eq. 2.5 mg Q2W to eq.60 mg Q4W, depending on the iMTD of oral UPTRAVI for each participant. As the proposed doses of JNJ-68006861 LAI will result in reduced peak to trough ratios and less frequent fluctuations in the plasma levels of JNJ-68006861 as that of the corresponding doses of oral UPTRAVI, this may lead to a better tolerability of JNJ- 68006861 LAI as compared with oral UPTRAVI. If the initial dose of JNJ-68006861 LAI administered in Intervention Period 1 is considered safe and well tolerated in the individual participant, a repeated dose at the same dose level for patients receiving Q4W dosing or a higher dose for patients receiving Q2W dosing, leading to an increase in JNJ- 68006861 exposure will be tested in Intervention Period 2 (see Table 34). If the repeated dose of JNJ-68006861 LAI is also considered safe and well tolerated, a dose escalation will be tested in Intervention Period 3. For participants on a JNJ-68006861 LAI dose of eq. 5 or 7.5 mg Q2W, the dose will be doubled, and the dosing frequency decreased to Q4W. For participants on a JNJ-68006861 LAI dose of eq.22.5 mg to eq.52.5 mg Q4W (inclusive), the dose is to be increased in increments of eq.7.5 mg Q4W. For participants tolerating eq.60 mg Q4W JNJ-68006861 LAI, the dose is to be increased to eq.75 mg Q4W. As a result, the highest dose of LAI, which may be tested in this study (for participants entering the study on an iMTD of oral UPTRAVI of 1600 µg BID) will be eq. 75 mg Q4W. With the LAI dose of eq.75 mg Q4W, Cavgis estimated to be higher than that obtained following oral UPTRAVI 1600 µg BID, but the estimated Cmaxwill remain comparable to that observed with oral selexipag (see Table 36). The duration of Intervention Period 1 and Intervention Period 2 are set to 4 weeks each as this is equal to one or two dosing intervals (depending on the dose level), and Intervention Period 3 is set to 8 weeks as steady state is expected with the second JNJ- 68006861 LAI administration. Upon completion of the last intervention period of the study or in case of premature discontinuation of study intervention, study participants will be switched back to their iMTD of oral UPTRAVI. Example 20: PK Study of Long Acting Injectable This study assessed the safety, tolerability, and PK of a single 5 mg, 25 mg, and 60 mg subcutaneous dose of the LAI formulation shown below. The PK data are shown in Table 37 and FIGs.14 and 15. The results show that all LAI dose levels have gradual onset and stable, extended exposure. The higher doses of 25 and 60 mg have prolonged exposure compared to the 5 mg dose. It appears that the dose is proportional to the PK data from 25 mg to 60 mg. It appears that the dose is not proportional to the PK data from 5 mg to 25 mg. • LAI formulation (eq.50 mg / mL) Component mg / mL mg / vial Ca salt of JNJ-68006861 52.25 94.05 Polysorbate 20 2.500 4.500 Macrogol 4000 75.00 135.00 Trometamol 3.634 6.541 Calcium Chloride Dihydrate 7.948 14.31 Hydrochloric acid, dilute 8.794 µL / mL 15.83 µL / vial Water q.s ad 1 mL q.s. ad 1.8 mL q.s. = quantum satis Table 37: PK data JNJ- 68006861 5 mg LAI 25 mg LAI 60 mg LAI (mean Selexipag (eq.50 (eq.50 [SD], tmax: 160 mg / mL) (eq.50 mg / mL) 0 µg BID mg / mL) median [range]) n 6 10 7* Reference Cmax(ng / mL)7.65 (2.08) 11.3 (3.95) 30.10 (11.4) 32.6AUC0-28days1794 (382) 4236 (1047) 11050 (4167) 9952 (ng.h / mL) Example 21: comparison of prostacyclin-associated Treatment-Emergent Adverse Events (TEAEs) Within the PK study summarized at Example 18, Treatment-Emergent Adverse Events (TEAEs) related to the administration of JNJ-68006861 during the study were also assessed. In this section, otherwise specified, TEAEs in the LAI Treatment Period, such as for example prostacyclin-associated TEAEs, refer to reported non-injection associated TEAEs and do not include reported injection site associated TEAEs. Prostacyclin-associated TEAEs included arthralgia, diarrhoea, dizziness, flushing, headache, musculoskeletal pain, myalgia, nausea, pain in extremity, pain in jaw, temporomandibular joint syndrome, and vomiting. Said prostacyclin-associated TEAEs occured at systemic level following both the multiple oral dose administration of JNJ-68006861 and the single-dose subcutaneous administration of a LAI formulation of JNJ-68006861. Most frequently reported prostacyclin-associated TEAEs during the Oral Treatment Period and / or the LAI Treatment Period are headache, nausea, myalgia, pain in jaw and constipation. For patients assigned to Cohort 3, Randomized Arms E and F, and to Cohort 4, observed headache, nausea, myalgia, pain in jaw and constipation TEAEs are summarized in Table 38 below. Table 38: Most frequently reported prostacyclin-associated TEAEs Treatment Cohort 3, Arm E Cohort 3, Arm F Cohort 4 TEAE Period (n=10) (n=9) (n=10) Oral 8 (80.0%) 8 (88.9%) 5 (50.0%) Headache LAI 6 (60.0%) 6 (66.7%) 1 (10.0%) Oral 7 (70.0%) 6 (66.7%) 4 (40.0%) Nausea LAI 2 (20.0%) 2 (22.2%) 3 (30.0%) Oral 6 (60.0%) 3 (33.3%) 3 (30.0%) Myalgia LAI 5 (50.0%) 5 (55.6%) 2 (20.0%) Oral 5 (50.0%) 4 (44.4%) 2 (20.0%) Pain in jaw LAI 0 1 (11.1%) 0 Oral 4 (40.0%) 2 (22.2%) 1 (10.0%) Constipation LAI 2 (20.0%) 0 0 As can be understood from the above, the number of prostacyclin-associated TEAEs was lower after single-dose subcutaneous administration of a LAI formulation of JNJ-68006861 (follow-up for up to 90 days) compared to multiple oral doses of JNJ-68006861 (adverse events collected for up to 24 days from the initial administration of oral JNJ-68006861, including 3-day washout period following the last oral administration).

Claims

Claims 1. A pharmaceutical composition for use as a long acting injectable in the treatment of and / or prevention of pulmonary hypertension, wherein the pharmaceutical composition is administered at a time interval of one week to eight weeks, wherein the pharmaceutical composition is in the form of an aqueous suspension comprising: (a) about eq.1 mg to about eq.160 mg of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:Formula (I) having a Dv50 particle size of 1 to 50 µm; (b) a surfactant and / or wetting agent; (c) a buffer and / or pH adjusting agent; and (d) a pharmaceutically acceptable aqueous carrier; wherein the pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C; wherein the concentration of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate is from eq.25 mg / mL to eq.100 mg / mL.

2. The pharmaceutical composition for use according to claim 1, wherein the composition further comprises a flocculating agent.

3. The pharmaceutical composition for use according to claims 2, wherein the flocculating agent comprises calcium chloride, calcium chloride dihydrate, calcium acetate, calcium saccharate, calcium hydroxide, calcium citrate, calcium disodium edetate, calcium saccharin, calcium lactate, or mixtures thereof.

4. The pharmaceutical composition for use according to claim 3, wherein the flocculating agent comprises calcium chloride or calcium chloride dihydrate.

5. The pharmaceutical composition for use according to claim 4, wherein the buffering and / or pH adjusting agent comprises histidine, tris(hydroxymethyl)aminomethane, HCl, NaOH, or mixtures thereof.

6. The pharmaceutical composition for use according to claim 5, wherein the buffering and / or pH adjusting agent comprises tris(hydroxymethyl)aminomethane.

7. The pharmaceutical composition for use according to claim 6, wherein the flocculating agent comprises calcium chloride or calcium chloride dihydrate.

8. The pharmaceutical composition for use according to any one of claims 4 to 9, wherein the buffering agent(s) is a buffer of a buffer strength of 5 to 100 millimolar (mM).

9. The pharmaceutical composition for use according to claim 7, wherein the pharmaceutically composition comprises 1 to 8 mg / mL of calcium chloride or calcium chloride dihydrate.

10. The pharmaceutical composition for use according to claim 7, wherein the pharmaceutical composition is administered at a time interval of one week to four weeks.

11. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the pharmaceutical composition is administered at a time interval of four weeks.

12. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein the pharmaceutical composition comprises eq.2.5 mg to about eq.100 mg of the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof.

13. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the pharmaceutical composition is administered at a time interval of two weeks.

14. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein the pharmaceutical composition comprises eq.2.5 mg to about eq.50 mg of the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof.

15. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the pharmaceutical composition is administered at a time interval of three weeks.

16. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein the pharmaceutical composition comprises eq.5 mg to about eq.80 mg of the calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate, or a pharmaceutically acceptable hydrate or solvate thereof.

17. The pharmaceutical composition for use according to any one of claims 1 to 16, wherein 6 hours after administration of the pharmaceutical composition to a subject in need thereof, the Cmaxis less than 10 ng / mL.

18. The pharmaceutical composition for use according to any one of claims 1 to 17, wherein four weeks after administration, the blood plasma concentration is greater than 40% of the Cmax.

19. The pharmaceutical composition for use according to claim 1, wherein the ratio of the Cmax to Ctrough ranges from 4:1 to 1.5:1 when administered once every 4 weeks.

20. The pharmaceutical composition for use according to any one of claims 1 to 19, wherein the pharmaceutical composition is in the form of an intramuscular or subcutaneous injectable.

21. The pharmaceutical composition for use according to any one of claim 1 to 20, wherein the pharmaceutical composition has a volume of 0.1 to 2 mL.

22. The pharmaceutical composition for use according to any one of claims 1 to 21, wherein the Dv50 particle size is from 2 to 30 µm.

23. The pharmaceutical composition for use according to any one of claims 1 to 22, wherein the surfactant and / or wetting agent comprises a polysorbate, a poloxamer, an α-tocopheryl polyethylene glycol succinate (TPGS), a salt of a negatively charged phospholipid, lecithin, polyvinylpyrrolidone (PVP), docusate sodium, sodium deoxycholate, sodium dodecyl sulphate (SDS), polyoxyethylene castor oil derivatives, macrogol 15 hydroxystearate, or mixtures thereof.

24. The pharmaceutical composition for use according to any one of claims 1 to 23, wherein the surfactant and / or wetting agent comprises poloxamer 338, polysorbate 20, TPGS, or mixtures thereof.

25. The pharmaceutical composition for use according to any one of claims 1 to 24, further comprising a resuspending agent.

26. The pharmaceutical composition for use according to claim 25, wherein the resuspending agent comprises polyethylene glycol (PEG), carmellose sodium, poloxamer, or mixtures thereof.

27. The pharmaceutical composition for use according to claim 26, wherein the resuspending agent comprises PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, carmellose sodium, or mixtures thereof; in particular PEG 4000.

28. The pharmaceutical composition for use according to any one of claims 1 to 27, wherein the pulmonary hypertension comprises pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis.

29. The pharmaceutical composition for use according to claim 28, for use in the treatment and / or prevention of pulmonary arterial hypertension (PAH).

30. The pharmaceutical composition for use according to claim 28, for use in the treatment and / or prevention of chronic thromboembolic pulmonary hypertension (CTEPH).

31. A method of transitioning a patient being treated with an oral dosage form of selexipag to a long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof for treating and / or prevention of pulmonary hypertension, wherein the long acting injectable is a pharmaceutical composition in the form of an aqueous suspension comprising: (a) about eq.1 mg to about eq.160 mg of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:Formula (I) having a Dv50 particle size of 1 to 50 µm; (b) a surfactant and / or wetting agent; (c) a buffer and / or pH adjusting agent; and (d) a pharmaceutically acceptable aqueous carrier; wherein the pharmaceutical composition has a pH in the range of 6 to 8.5 at 20-25°C; wherein the concentration of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate is from eq.25 mg / mL to eq.100 mg / mL; wherein the oral dosage form of selexipag is administered at an individual maximum tolerated dose (iMTD), where administration of said iMTD of selexipag provides to the patient an individual average plasma concentration CiMTDavgof 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861), the oral dosage form is discontinued, andthe pharmaceutical composition is administered at a time interval of one week to eight weeks at a dosage of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof selected to provide to the patient an average plasma concentration of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is about equal to or higher than CiMTDavg.

32. The method of claim 31, wherein the iMTD of the oral form of selexipag is 200 µg, 400 µg, 600 µg, 800 µg, 100 µg, 1200 µg, 1400 µg, or 1600 µg twice daily, and the corresponding dose of the long acting injectable form of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof is eq.1-5 mg Q2W, eq.2.5-10 mg Q2W, eq.10- 30 mg Q4W, eq.22.5-37.5 mg Q4W, eq.30-45 mg Q4W, eq.37.5-52.5 mg Q4W, eq. 45-60 mg Q4W, or eq.52.5-75 mg Q4W, respectively, of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate.

33. The method of claim 32, wherein the corresponding dose of the long acting injectable form of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof is eq.2.5 mg Q2W, eq.5 mg Q2W, eq.22.5 mg Q4W, eq.30 mg Q4W, eq.37.5 mg Q4W, eq.45 mg Q4W, eq.52.5 mg Q4W, or eq.60 mg Q4W, respectively, of calcium;{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}acetate.

34. The method of any one of claims 31- 33, wherein the dose of calcium;{4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetate is selected to provide to the patient an average plasma concentration of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) that is higher than CiMTDavg.

35. The method of any one of claims 31-34, wherein after an initial administration of the long acting injectable, the dose of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof administered to the patient is increased so the average plasma concentration of 2-(4- ((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) is at least 20% greater than the CiMTDave.

36. The method of any of claims 31-34, wherein after an initial administration of the long acting injectable, the dose of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof administered to the patient is increased so the average plasma concentration of 2-(4- ((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) is at least 30% greater than the CiMTDave.

37. The method of any one of claims 31-34, wherein after an initial administration of the long acting injectable, the dose of calcium;{4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy}acetate or a pharmaceutically acceptable hydrate or solvate thereof administered to the patient is increased so the average plasma concentration of 2-(4- ((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (JNJ-68006861) is at least 50% greater than the Ctroughof the CiMTDave.

38. The method of any one of claims 31-37, wherein the pulmonary hypertension is pulmonary arterial hypertension (PAH).

39. The method of any one of claims 31-37, wherein the pulmonary hypertension is chronic thromboembolic pulmonary hypertension (CTEPH).

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