WO2023214059A1

WO2023214059A1 - Diphenylpyrazine compounds as prodrugs

Info

Publication number: WO2023214059A1
Application number: PCT/EP2023/062025
Authority: WO
Inventors: Tianbao Lu; Tobias SCHIPS; Katie AMSSOMS; Wilhelmina BODE
Original assignee: Actelion Pharmaceuticals Ltd
Priority date: 2022-05-06
Filing date: 2023-05-05
Publication date: 2023-11-09

Abstract

The present invention relates to a pharmaceutical composition comprising a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof; in particular to long-acting injectables comprising the same, the use of the pharmaceutical composition for the treatment or prevention of specific diseases, and a process to produce it.

Description

DIPHENYLPYRAZINE COMPOUNDS TECHNICAL FIELD [01] The disclosure is directed to prodrugs of selexipag metabolite, pharmaceutical compositions comprising those prodrugs, and uses of those prodrugs in treating disease. BACKGROUND [02] 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, 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)). [03] 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 WO2021/033702, WO2022/162158 and WO2022/162163. US20190022004 describes liposome compositions comprising weak acid drugs and uses thereof. EP3718537 describes stealth liposomes having a prostaglandin I2 receptor agonist encapsulated therein. [04] 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. [05] 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 hydroxypropylcellulose, hydroxypropylcellulose, 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. [06] 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 min. The dose was individualized for each patient to correspond to his/her current oral dose of selexipag. [07] Selexipag is thought to function as a prodrug (while retaining some agonistic activity on the 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). [08] 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. [09] Moreover, in general, it is desirable to reduce the drug burden, particularly for treatment regimens that may last several months or more. [010] 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. [011] 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), i.e. three months. [012] 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 and safety. 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. SUMMARY [013] In some aspects, the disclosure is directed to prodrugs of selexipag metabolite having the formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein R is

[014] In some aspects, the disclosure is directed to prodrugs of selexipag metabolite having the formula (IA): [015] In other aspects, the disclosure is directed to prodrugs of selexipag metabolite having the formula (IB):

[016] In other aspects, the disclosure is directed to pharmaceutical compositions in the form of an aqueous suspension comprising (a) a compound of formula (I), formula (IA), or formula (IB), having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer); (b) a surfactant and/or wetting agent; and (c) a pharmaceutically acceptable aqueous carrier at a pH in the range of 5 to 8. [017] In other aspects, the disclosure is directed to pharmaceutical compositions 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 a compound of formula (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein R is [018] In other aspects, the disclosure is directed to microparticles of a compound of formula (IA):

or a pharmaceutically acceptable salt or solvate thereof, wherein said microparticles have a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm, or 2 to 20 µm, or 2 to 10 µm, or 2 to 5 µm. [019] In other aspects, the disclosure is directed to microparticles of a compound of formula (IB):

or a pharmaceutically acceptable salt or solvate thereof, wherein said microparticles have a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 0.5 to 30 µm, or 0.5 to 20 µm, or 0.5 to 10 µm, or 0.5 to 5 µm, or 0.5 to 2 µm. [020] The pharmaceutical compositions of the disclosure are in the form of an aqueous suspension suitable for intramuscular or subcutaneous injection. They may also by filled as a solid product into vials 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. BRIEF DESCRIPTION OF THE DRAWINGS [021] Fig.1 shows the particle size distribution of the formulation used in Example 5 on the day of dosing. [022] Fig.2 shows the particle size distribution of the formulation used in Example 5 at 14 days post dosing. [023] Fig.3 shows the plasma Formula IB concentration as a function of time as observed in Example 5. [024] Fig.4 shows the plasma 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid concentration as a function of time as observed in Example 5. [025] Fig.5 shows the particle size distribution of the formulation used in Example 6 on the day of dosing. [026] Fig.6 shows the particle size distribution of the formulation used in Example 6 at 14 days post dosing. [027] Fig.7 shows the plasma 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid concentration as a function of time as observed in Example 6 after subcutaneous administration of Formula IA. [028] Fig.8 shows the plasma 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid concentration as a function of time as observed in Example 6 after intramuscular administration of Formula IA. [029] Fig.9 compares the mean plasma 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid concentration as a function of time as observed in Example 6 - intramuscular administration of Formula IA vs. subcutaneous administration of Formula IA. [030] Fig.10 shows the individual and mean plasma concentrations of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid as a function of time resulting from IV administration of Formula IB. See Example 7. [031] Fig.11 shows the individual and mean plasma concentrations of 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid as a function of time resulting from IV administration of Formula IA. See Example 8. [032] Fig.12 shows an XRPD for PSD-QC-Formula IA_125MGML-0-0(A14375- 038)1T; (Type: Coupled TwoTheta/Theta; start: 3.000^o, End: 40.006^o; step: 0.020 ^o; step time: 19.20 s; WL1: 1.54060 Å; W)(top) and an XRPD for Solid-PSD-QC-Formula IA; (Type: Coupled TwoTheta/Theta; start: 3.000 ^o, End: 40.006 ^o; step: 0.020 ^o; step time: 19.20 s; WL 1: 1.54060 Å; WL2: 1.54439 Å.) (bottom). [033] Fig.13 shows an XRPD for PSD-QC-Formula IB_125WGML-0-0(A14375- 040)1T; (Type: Coupled TwoTheta/Theta; start: 3.000 ^o, End: 40.006 ^o; step: 0.020 ^o; step time: 19.20 s; WL1: 1.54060 Å; W)(top) and an XRPD for Soid-PSD-QC-Formula IB; (Type: Coupled TwoTheta/Theta; Start: 3.000 ^o, End: 40.006 ^o; Step: 0.020 ^o; step time: 19.20 s; WL1: 1.54060 Å; WL2: 1.54439 Å.)(bottom). DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS [034] In some aspects, the disclosure is directed to compounds of formula (I):

or a pharmaceutically acceptable salts or solvates thereof, wherein

[035] In some embodiments, the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt or solvate thereof. [036] In other embodiments, the compound of formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt or solvate thereof. [037] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of formula (I). [038] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of formula (IA). [039] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of formula (IB). [040] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic, may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [041] In other embodiments, the compound is a pharmaceutically acceptable solvate of a compound of formula (I). [042] In some embodiments, the compound is a pharmaceutically acceptable solvate of a compound of formula (IA). [043] In some embodiments, the compound is a pharmaceutically acceptable solvate of a compound of formula (IB). [044] As used herein, the term "pharmaceutically acceptable solvate" refers to a solvate of the compound, or of a pharmaceutically acceptable salt of the compound, that retains the desired biological activity of the compound and exhibits minimal undesired toxicological effects. [045] In some embodiments in which the compound of the disclosure is a solvate, the solvate may comprise about 0.1 to about 1 solvent molecule per compound of formula (I). In some embodiments, the molar ratio of solvent to compound of formula (I) 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 solvent in the solvate form may change based on storage conditions of the compound, the method of formation of the compound, and the crystal structure of the compound. [046] In some embodiments, the solvate is a hydrate, i.e., a solvate in which the solvent is water. [047] In some aspects, the disclosure is directed to pharmaceutical compositions in the form of an aqueous suspension comprising: (d) a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer); (e) a surfactant and/or wetting agent; and (f) a pharmaceutically acceptable aqueous carrier at a pH in the range of 5 to 8. [048] In some embodiments, the pharmaceutical compositions of the disclosure are aqueous suspensions, meaning that the active ingredient is present as a solid phase that is suspended in an aqueous liquid phase, i.e., the pharmaceutically acceptable aqueous carrier. [049] 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. [050] In some embodiments, the pharmaceutical compositions of the disclosure comprise a compound of Formula (I). [051] In other embodiments, the pharmaceutical compositions of the disclosure comprise a pharmaceutically acceptable salt of a compound of Formula (I). [052] In other embodiments, the pharmaceutical compositions of the disclosure comprise a pharmaceutically acceptable solvate of a compound of Formula (I). [053] In some embodiments, the pharmaceutical compositions of the disclosure comprise a compound of Formula (IA). [054] In other embodiments, the pharmaceutical compositions of the disclosure comprise a pharmaceutically acceptable salt of a compound of Formula (IA). [055] In other embodiments, the pharmaceutical compositions of the disclosure comprise a pharmaceutically acceptable solvate of a compound of Formula (IA). [056] In some embodiments, the pharmaceutical compositions of the disclosure comprise a compound of Formula (IB). [057] In other embodiments, the pharmaceutical compositions of the disclosure comprise a pharmaceutically acceptable salt of a compound of Formula (IB). [058] In other embodiments, the pharmaceutical compositions of the disclosure comprise a pharmaceutically acceptable solvate of a compound of Formula (IB). [059] In some embodiments of the pharmaceutical compositions of the disclosure, the compound of formula (I) (or formula (IA) or formula (IB)) or pharmaceutically acceptable salt or solvate thereof, is provided in a micronized form, i.e. in particles having a particle size distribution (PSD) Dv50 of 0.5 to 50 µm (micrometer), or 0.5 to 40 µm (micrometer), or 0.5 to 30 µm (micrometer), or 0.5 to 20 µm (micrometer), or 0.5 to 18 µm (micrometer), or 0.5 to 15 µm (micrometer), 0.5 to 10 µm (micrometer), or 0.5 to 5 µm (micrometer), 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), 1 to 10 µm (micrometer), or 1 to 5 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 2 to 10 µm (micrometer), or 2 to 5 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 3 to 10 µm (micrometer), or 3 to 5 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 4 to 10 µm (micrometer), or 4 to 5 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), or 5 to 10 µm (micrometer). [060] In some embodiments of the pharmaceutical compositions of the disclosure, the compound of formula (I) (or formula (IA) or formula (IB)) or pharmaceutically acceptable salt or solvate thereof, is provided in a micronized form, i.e. in particles having a particle size distribution (PSD) Dv50 of 0.5 to 50 µm (micrometer). [061] In some embodiments of the pharmaceutical compositions of the disclosure, the compound of formula (I) (or formula (IA) or formula (IB)) or pharmaceutically acceptable salt or solvate thereof, is provided in a micronized form, i.e. in particles having a particle size distribution (PSD) Dv50 of 0.5 to 10 µm (micrometer). [062] In some embodiments of the pharmaceutical compositions of the disclosure, the compound of formula (I) (or formula (IA) or formula (IB)) or pharmaceutically acceptable salt or solvate thereof, is provided in a micronized form, i.e. in particles having a particle size distribution (PSD) Dv50 of 0.5 to 5 µm (micrometer). [063] In some embodiments, the particle size distribution (PSD) Dv50 is 0.5 µm (micrometer) ±10%, or 0.5 µm (micrometer) ±5%; or 1 µm (micrometer) ±10%, or 1 µm (micrometer) ±5%; or 1.5 µm (micrometer) ±10%, or 1.5 µm (micrometer) ±5%; or 2 µm (micrometer) ±10%, or 2 µm (micrometer) ±5%; or 2.5 µm (micrometer) ±10%, or 2.5 µm (micrometer) ±5%; or 3 µm (micrometer) ±10%, or 3 µm (micrometer) ±5%, or 3.5 µm (micrometer) ±10%; or 3.5 µm (micrometer) ±5%; or 4 µm (micrometer) ±10%, or 4 µm (micrometer) ±5%; or 4.5 µm (micrometer) ±10%, or 4.5 µm (micrometer) ±5%; or 5 µm (micrometer) ±10%, or 5 µm (micrometer) ±5%. [064] In other embodiments, the particle size distribution (PSD) Dv50 is 6 µm (micrometer) ±10%, or 6 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 7 µm (micrometer) ±10%, or 7 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 8 µm (micrometer) ±10%, or 8 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 9 µm (micrometer) ±10%, or 9 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 10 µm (micrometer) ±10%, or 10 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 11 µm (micrometer) ±10%, or 11 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 12 µm (micrometer) ±10%, or 12 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 13 µm (micrometer) ±10%, or 13 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 14 µm (micrometer) ±10%, or 14 µm (micrometer) ±5%; in some embodiments, the particle size distribution (PSD) Dv50 is 15 µm (micrometer) ±10%, or 15 µm (micrometer) ±5%. [065] The particles used herein are micro-particles, and the aqueous suspension is termed a micro-suspension, i.e. an aqueous micro-suspension. [066] Particle size distributions are 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 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. [067] Particle size distributions (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. [068] Thereby, laser diffraction measures particle size distribution by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. [069] 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. [070] 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 analysis are reported based on the particle size volume distribution as the cumulative undersize values Dv50. The measurement method is disclosed in the experimental part. [071] In some embodiments of the pharmaceutical compositions of the disclosure, the compound of formula (I) (or formula (IA) or formula (IB)) or pharmaceutically acceptable salt or solvate thereof, is used in crystalline form. [072] In some embodiments, the crystalline form of the compound of formula IA has an XRPD as shown in Fig.12. In other embodiments, the crystalline form of the compound of formula IB has an XRPD as shown in Fig.13. [073] In some aspects, the pharmaceutical compositions of the disclosure comprise a surfactant and/or wetting agent. [074] A “surfactant and/or wetting agent” (surfactant/wetting agent) as used herein is pharmaceutically acceptable and able to stabilise the aqueous suspension in order to avoid particle size growth during shelf-life. The surfactant and/or wetting agent may be non- ionic or ionic. Surfactants and/or wetting agents are well known in the art. [075] 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 (CremophorTM EL) or polyoxyl 40 hydrogenated castor oil (CremophorTM RH40); polyoxyethylene stearates, colloidal silicon dioxide, sodium dodecylsulfate, carboxymethylcellulose sodium, bile salts such as sodium taurocholate, sodium desoxytaurocholate, sodium desoxycholate; methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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; Vitamin E-TGPS (α tocopheryl polyethylene glycol succinate, 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 sulfate (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 Tweens™ 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; hexyldecyl trimethyl ammonium chloride (CTAC); polyvinylpyrrolidone (PVP), sodium dodecyl sulphate (SDS), docusate sodium, sodium deoxycholate, macrogol 15 hydroxystearate (SolutolTM HS 15), octoxynol (octoxynol-9, octoxynol-10), or simethicone. [076] If desired, two or more surfactants and or wetting agents can be used in combination. Thus, in some embodiments, the surfactant and/or wetting agent is a mixture of surfactants and/or wetting agents. [077] 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. [078] In other embodiments, the surfactants/wetting agents are polysorbates, poloxamers and α-tocopheryl polyethylene glycol succinates, for example polysorbate 20, polysorbate 80, poloxamer 188, poloxamer 338, poloxamer 407, vitamin E TPGS, egg phosphatidylglycerol (Egg PG), and mixtures thereof. [079] In other embodiments, the surfactants/wetting agents are polysorbate 20, poloxamer 338, and vitamin E TPGS, for instance polysorbate 20 and/or poloxamer 338. [080] In some embodiments, the surfactant/wetting agent is poloxamer 338. [081] 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 TweenTM 20. [082] Poloxamers are nonionic 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. [083] α-Tocopheryl polyethylene glycol succinate as used herein refers to vitamin E TPGS, i.e. d- α -tocopheryl polyethylene glycol 1000 succinate, also referred to as tocophersolan (INCI), CAS No.9002-96-4. [084] 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. [085] 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). [086] 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 PVPK17. [087] The optimal relative amount of the compound of formula (I) (or formula (IA) or formula (IB)) or pharmaceutically acceptable salt or solvate thereof, 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, such as, for example, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1. [088] In some aspects, the pharmaceutical compositions of the disclosure 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 needly clogging, or to facilitate resuspending the formulation after storage. [089] The resuspending agent is polyethylene glycol (PEG) of various polymerization grades, carmellose sodium, poloxamers, α-Tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, polysorbates, or a mixture thereof; preferably polyethylene glycol (PEG) of various polymerization grades, and carmellose sodium, or a mixture thereof. [090] 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. [091] In some embodiments, the surfactant/wetting agent can also act as a resuspending agent. [092] It may be noted that poloxamers can function as surfactants/wetting agents, but also as resuspending agents, because they contribute 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. [093] 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. [094] A preferred carmellose sodium (carboxymethylcellulose sodium) has a viscosity of 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. [095] The relative amount (w/w) of the drug, i.e. the compound of formula (I) (or formula (IA) or formula (IB)) or pharmaceutically acceptable salt or solvate thereof, in relation to the resuspending agent depends on the resuspending agent selected, and is generally in the range of 2:1 to 1:3, in particular 2:1 to 1:1. [096] 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, vitamin E TPGS with PEG 4000, poloxamer 338 and carmellose sodium, polysorbate 80 and carmellose sodium, and poloxamer 338 and vitamin E TPGS. [097] In some aspects, the pharmaceutical compositions of the disclosure comprise a pharmaceutically acceptable aqueous carrier. In some embodiments, the aqueous carrier comprises water. In some embodiments, the water is sterile water, i.e. water suitable for injection, optionally in admixture with other pharmaceutically acceptable ingredients. These ingredients may be one or more of a buffering agent, a pH adjusting agent, a preservative, or an isotonizing agent. [098] In some embodiments, the aqueous carrier has a pH in the range of 5 to 8, such as, for example, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8. [099] In other embodiments, the aqueous carrier has a pH in the range of from 5 to 6, or from 6 to 7, or from 6 to 8, or from 7 to 8. [0100] In other embodiments, the aqueous carrier has a pH 5 ±0.5, or pH 5.5 ±0.5, or pH 6 ±0.5, or pH 6.5 ±0.5, or 7 ±0.5, or pH 7.5 ±1/2, pH 8 ±0.5. [0101] In some embodiments, the buffering and/or pH adjusting agent(s) is/are disodium hydrogen phosphate, citric acid, tris(hydroxymethyl)aminomethane (TRIS), histidine, HCl or NaOH, or a mixture thereof. Thereby, the buffering agents are disodium hydrogen phosphate, citric acid, tris(hydroxymethyl)aminomethane (TRIS) or histidine; and the pH- adjusting agents are HCl or NaOH, preferably in aqueous solution. [0102] In some embodiments, the buffering and/or pH adjusting agent(s) is/are disodium hydrogen phosphate, citric acid, tris(hydroxymethyl)aminomethane (TRIS), HCl or NaOH, or a mixture thereof. Thereby, the buffering agents are disodium hydrogen phosphate, citric acid, or tris(hydroxymethyl)aminomethane (TRIS); and the pH-adjusting agents are HCl or NaOH, preferably in aqueous solution. [0103] In some embodiments, the pharmaceutically acceptable aqueous carrier comprises citric acid. Citric acid thereby serves as buffering agent, but also as chelating agent and antioxidant. [0104] In some embodiments, the pH of the aqueous suspension is pH 8 ±0.5. Micro- suspensions may be formulated with TRIS buffer, however, McIlvaine buffer (citric acid and disodium hydrogen phosphate) may also be used. McIlvaine buffer at pH 8±0.5 consists of disodium hydrogen phosphate anhydrous and citric acid, the buffer strength ranging from 5 to 100 mM. In some embodiments, the buffer strength ranges from 10 to 50 mM. However, it is also possible to add more citric acid and adjust the pH with NaOH to pH 8±0.5. [0105] In some embodiments, the buffer strength ranges from 5 to 100 millimolar (mM), or from 10 to 50 mM. [0106] Suitable optional preservatives for the pharmaceutical compositions of the disclosure comprise antimicrobials and anti-oxidants which can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-y-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. [0107] An isotonizing agent or isotonifier may be present in the disclosed pharmaceutical compositions 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 sulfate, 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 isotonizing agent. Of interest are nonionic isotonifiers, e.g. glucose, as electrolytes may affect colloidal stability. In one embodiment, the composition contains an isotonizing agent or isotonifier, which, in a further embodiment is a nonionic isotonifier, such as a suitable sugar such as mannitol. [0108] A desirable feature for a pharmaceutical composition of the disclosure 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 1 mPa · s to 75 mPa · s at 200 s-1, or from 5 mPa · s to 40 mPa · s at 200 s-1. [0109] In some embodiments, the aqueous suspension will comprise as much of the compound of formula (I) (or formula (IA) or formula (IB)), or pharmaceutically acceptable salt or solvate thereof, as can be tolerated so as to keep the injection volume to a minimum, in particular 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), in particular from 2.5% to 10% (w/v). [0110] In some embodiments, 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. [0111] In some embodiments, 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. [0112] In some embodiments, 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. [0113] In one embodiment, the pharmaceutical composition comprises by weight based on the total volume of composition: (a) 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 the compound of formula (I) (or formula (IA) or formula (IB)), or pharmaceutically acceptable salt or solvate thereof; (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; (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) water for injection q.s. ad 100%. [0114] In another 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 the compound of formula (I) (or formula (IA) or formula (IB)), or pharmaceutically acceptable salt or solvate thereof; (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; (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) water for injection q.s. ad 100%. [0115] Thereby, the surfactant/wetting agent, the optional resuspending agent, and buffering agents, as well as mixtures thereof, are as described above. [0116] The compounds of formula (IA) or formula (IB) can be prepared as described in the example part. [0117] The pharmaceutical compositions as described herein may be in a container, notably in a vial or in a syringe; especially in a syringe. [0118] In some embodiments, a pharmaceutical composition as described herein can be prepared by a process comprising the steps of: (a) adding a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, to a liquid medium comprising a surfactant and/or wetting agent at a pH in the range of 5 to 8, optionally a resuspending 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. [0119] In other embodiments, a pharmaceutical composition as described herein can be prepared by a process comprising the steps of: (a) subjecting a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, to mechanical means in the presence of a grinding medium to reduce the average effective particle size; (b) adding a liquid medium comprising a surfactant and/or wetting agent at a pH in the range of 5 to 8, optionally a resuspending agent; and a pharmaceutically acceptable aqueous carrier. [0120] The particle size of the micro-particles can be prepared by mechanical means known in the art. [0121] In one embodiment a method is used comprising the steps of dispersing a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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 particle size distribution Dv50 as indicated above. [0122] In another embodiment a method is used comprising the steps of applying to a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, 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 particle size distribution Dv50 as indicated herein. [0123] 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 ZrO₂ such as 95% ZrO₂ stabilized 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/cm3 and include 95% ZrO₂ stabilized with magnesia and polymeric beads. [0124] 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. [0125] 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 5 to 8, 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. [0126] The final formulation is separated from the grinding media by adequate separation methods known in the field. [0127] The compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, 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. [0128] 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. [0129] Suitable conditions for gamma irradiation are achieved by exposure to ionizing radiation in the form of gamma radiation from a suitable radioisotopic source such as 60Co (cobalt 60) or of electrons energized by a suitable electron accelerator. Suitable conditions are radiation levels of 5 to 40 kGy, for instance 5 kGy, 25 kGy or 40 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. [0130] 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 a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, is sterilised with gamma-irradiation and which is then used for preparing the pharmaceutical composition. [0131] A sterile pharmaceutical composition is obtainable by said process. [0132] 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. [0133] 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. [0134] The pharmaceutical compositions as described herein can further be lyophilized, i.e. freeze-dried, and a lyophilized injectable composition will be obtained. [0135] The pharmaceutical composition will, prior to freeze drying, preferably be filled into containers (unit dose or multi-dose containers such as vials) 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, an ampoule, a syringe, a coupled chamber device, a pen device, or an autoinjector device, especially a vial, filled with a pharmaceutical composition as described above. [0136] 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. [0137] 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. [0138] 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. [0139] 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. [0140] 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. [0141] 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. [0142] Moreover, the container can be stoppered after the freeze-drying procedure. Stoppering the container may further include a step of capping the container. [0143] 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. [0144] 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. [0145] The term “cake” refers to a dry solid material that results when a liquid formulation has been lyophilized or freeze dried. [0146] 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. [0147] 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. [0148] 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. [0149] 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. [0150] As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder. [0151] 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. [0152] 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). [0153] The pharmaceutical compositions described herein, in particular for the treatment of the above-indicated diseases and/or disorders, is preferably in the form of an intramuscular or subcutaneous injectable. Thereby, the injectable is a long-acting injectable (LAI). The term "long acting injectable" is used herein for an administration interval (i.e., the time between administrations) 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. [0154] 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. Without intending to be bound by theory, after administration, the composition stays in the body and steadily releases the compound of formula (I), which is converted to the selexipag active metabolite, i.e., 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid, keeping such levels of the active metabolite 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. [0155] 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. [0156] The pharmaceutical compositions of the disclosure include a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, in a therapeutically effective amount. [0157] The term "therapeutically effective amount" refers to amounts, or concentrations, of the composition (or amounts/ concentrations of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, 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 1 to 200 mg, for example 2 to 150 mg or 5 to 100 mg, and notably 25 mg to 100 mg of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, per month. The term "efficacious plasma levels" means 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. [0158] The dose (or amount) of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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. [0159] The term "subject" in particular relates to a human being. [0160] 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 intramuscular or subcutaneous injection. [0161] 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. [0162] The present invention also concerns the use of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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 a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, in the form of an aqueous suspension. [0163] The present invention also concerns a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of the above-indicated diseases and/or disorders, in particular PAH and CTEPH, wherein said a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, is within an aqueous suspension. [0164] The present invention also concerns the use of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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 a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, in the form of a lyophilized cake. [0165] The present invention also concerns a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of the above-indicated diseases and/or disorders, in particular PAH and CTEPH, wherein said a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, is in the form of a lyophilized cake. [0166] The present invention also concerns the use of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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 a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 µm; a surfactant and/or wetting agent; and a pharmaceutically acceptable aqueous carrier at a pH in the range of 5 to 8, in the form of an aqueous suspension. [0167] The present invention also concerns a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of the above-indicated diseases and/or disorders, in particular PAH and CTEPH, wherein said a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 µm; a surfactant and/or wetting agent; and a pharmaceutically acceptable aqueous carrier at a pH in the range of 5 to 8, is within an aqueous suspension. [0168] The present invention also concerns the use of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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 a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, in the form of an intramuscular or subcutaneous injectable. [0169] The present invention also concerns a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of the above-indicated diseases and/or disorders, in particular PAH and CTEPH, wherein said a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, is in the form of an intramuscular or subcutaneous injectable. [0170] The present invention also concerns the use of a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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 a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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. [0171] The present invention also concerns a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of the above-indicated diseases and/or disorders, in particular PAH and CTEPH, wherein said a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt 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. [0172] 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 a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof. [0173] 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 an intramuscular or subcutaneous injectable. In particular, said intramuscular or subcutaneous 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 intramuscular or subcutaneous injectable may have a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 µm. [0174] The present invention further relates to a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 µm. [0175] The present invention further relates to a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 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 5 to 8, and in particular in the range of 5 to 7. [0176] Moreover, the present invention relates to a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 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. 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 5 to 8, and in particular in the range of 5 to 7. [0177] In particular, the present invention relates to a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 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 intramuscular or subcutaneous 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 5 to 8, and in particular in the range of 5 to 7. In particular, said intramuscular or subcutaneous 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. [0178] Finally, the invention also relates to an investigational drug (‘ID’) in the form of an aqueous suspension comprising a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof. By “Investigational New Drug” or “investigational drug” 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. [0179] 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 an intramuscular or subcutaneous injectable. In particular, said intramuscular or subcutaneous 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 intramuscular or subcutaneous injectable may have a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 µm. [0180] The present invention further relates to an ID in the form of an aqueous suspension comprising a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 µm. [0181] The present invention further relates to an ID in the form of an aqueous suspension comprising a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 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 5 to 8, and in particular in the range of 5 to 7. [0182] In particular, the present invention relates to an ID in the form of an aqueous suspension comprising a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt or solvate thereof having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm or 2 to 20 µm or 5 to 15 µm or 0.5 to 10 µm or 0.5 to 5 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 intramuscular or subcutaneous 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 5 to 8, and in particular in the range of 5 to 7. In particular, said intramuscular or subcutaneous 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. [0183] All documents cited herein are incorporated by reference in their entirety. [0184] 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 hexyldecyl trimethyl ammonium chloride EDTA ethylenediaminetetraacetic acid HPLC high performace liquid chromatography IM intramuscular 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 NMP N-methylpyrrolidone PEG polyethylene glycol PSD particle size distribution PAH Pulmonary Arterial Hypertension CTEPH chronic thromboembolic pulmonary hypertension PBS Phosphate Buffered Saline pK pharmacokinetic PVP polyvinylpyrrolidone q.s. quantum satis (as much as is sufficient) q.s. ad quantum satis (as much as is sufficient) to make RT room temperature SC subcutaneous SDS sodium dodecyl sulphate 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 XRPD X-ray powder diffraction PSD Measurements [0185] PSD was measured with a Malvern Mastersizer 2000 apparatus from Malvern Instruments. Example 1: Synthesis of the compound of formula (IA)

[0186] To a 250 ml stand-up flask equipped with a stirring bar was added 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (5.7 g, 13.66 mmol), 4- (hydroxymethyl)-5-methyl-1,3-dioxol-2-one (1.6 g, 12.30 mmol), EDCI (3.5 g, 20.43 mmol), DMAP (167 mg, 1.37 mmol) and 60 mL DCM under N₂. The mixture was stirred at room temperature overnight to yield a yellow homogeneous mixture. Monitored the reaction progress by LCMS which showed the reaction was completed. The solvent was removed under vacuum and the residue was purified by silica gel column with EA/PE (0%-50%) to afford the crude product which was further recrystallized by EA/n-heptane (1/20) to afford the (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetate (formula (IA)) as an off-white solid (5285.0 mg, 72.9% yield), mp 106~107 °C. MS (ESI) calcd. for C₃₀H₃₃N₃O₆: 531.24 m/z, found 532.25 [M+H]+. ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.16 – 7.42 (m, 10H), 5.02 (s, 2H), 4.70 – 4.85 (m, 1H), 4.16 (s, 2H), 3.50 – 3.61 (m, 2H), 3.36 – 3.49 (m, 2H), 2.14 (s, 3H), 1.57 – 1.74 (m, 4H), 1.23 (d, J = 6.7 Hz, 6H). Example 2: Synthesis of the compound of formula (IB)

[0187] 2-(4-((5,6-Diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (1.5 g, 3.58 mmol), a stir bar and 20 mL DCM were added to a 100 mL flask and stirred at r.t until homogeneous, and then treated with 3-hydroxyisobenzofuran-1(3H)-one (540 mg, 3.60 mmol), EDCI (1030 mg, 5.37 mmol) and DMAP (44 mg, 0.36 mmol). The color of the colorless solution turned to yellow. The mixture was stirred at r.t for 1.5 hours and monitored by TLC which showed the S.M. consumed. Following this, the mixture was concentrated. The residue obtained was purified by silica gel chromatography (0-30% EA/PE) and the solvent was removed under vacuum to afford 3-oxo-1,3- dihydroisobenzofuran-1-yl 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetate (formula (IB)) as a white solid (977.2 mg, 48.6% yield). MS (ESI) calcd. for C₃₃H₃₃N₃O₅: 551.24 m/z, found 552.25 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.76 - 7.82 (m, 1H), 7.64 - 7.75 (m, 2H), 7.55 - 7.63 (m, 1H), 7.42 (s, 1H), 7.21 - 7.28 (m, 2H), 7.05 - 7.20 (m, 8H), 4.52 - 4.76 (m, 1H), 4.16 (d, J = 2.0 Hz, 2H), 3.41 - 3.54 (m, 2H), 3.25 - 3.36 (m, 2H), 1.41 - 1.64 (m, 4H), 1.09 (dd, J = 6.7, 2.2 Hz, 6H). Example 3: Preparation of a pharmaceutical composition comprising the compound of formula (IA) [0188] Weighed 409.10 mg of the compound of formula (IA) and transferred aseptically into a sterilized agate mortar. [0189] Crushed the neat powder gently with a sterilized pestle to obtain a fine powder. [0190] Added 1.000 ml of “3% Poloxamer 338” to the agate mortar. [0191] Stirred with the pestle until a homogeneous fluid paste is obtained. [0192] Transferred the content into a 4 ml pre sterilized glass injection vial containing a magnetic stirring bar. [0193] Added the 1.966 ml of “3% Poloxamer 338” to the mortar and stir briefly with the pestle and washed the mortar. Transferred the wash into the same glass injection vial as previous step and mixed. [0194] Stirred overnight, speed at 800 RPM, at room temperature. [0195] The resulting pharmaceutical composition has a pH=6.50. Example 4: Preparation of a pharmaceutical composition comprising the compound of formula (IB) [0196] Weighed 399.00 mg of compound of formula (IB) and transfered aseptically into a sterilized agate mortar. [0197] Crushed the neat powder gently with a sterilized pestle to obtain a fine powder. [0198] Added 0.500 ml of 3% Poloxamer 338 to the agate mortar. [0199] Stirred with the pestle until a homogeneous fluid past is obtained. [0200] Transfered the content into a 4 ml pre sterilized glass injection vial containing a magnetic stirring bar. [0201] Added the 2.393 ml of 3% Poloxamer 338 to the mortar and stir briefly with the pestle and washed the mortar. Transferred the wash into the same glass injection vial as previous step and mixed. [0202] Stirred overnight, speed at 800 RPM, at room temperature. [0203] The resulting pharmaceutical composition has a pH=5.16. Example 5: Pharmacokinetic Study of a Composition of the Compound of Formula (IB), administered intramuscularly [0204] A pharmacokinetic study was conducted to demonstrate the long-acting injectable potential of an aqueous micro-suspension of the compound of formula (IB). [0205] Fed male Sprague-Dawley rats were administered by intramuscular injection 50 mg/kg of the suspension formulation (125 mg/mL) of Example 4. The suspension had the following particle size distribution:

[0206] See Figs.1 and 2. [0207] The range of rat body weight:260~273 g; the individual body weight of these 3 rats: Rat #1(IM_R1):273 g; Rat #2(IM_R2):267 g; Rat #3(IM_R3):260 g. No abnormal clinical symptoms were observed during the entire experiment. [0208] Blood samples were taken from the jugular vein at 1, 2, 4, 7, 24, 48, 72, 144, 168, 240, 336, 504, 672, 840, and 1008 hr. EDTA-K2 was used as anticoagulant. [0209] Plasma derived from individual blood samples was analyzed for the compound of Formula IB and for the active selexipag active metabolite, i.e., 2-(4-((5,6-diphenylpyrazin- 2-yl)(isopropyl)amino)butoxy)acetic acid. [0210] Plasma samples were analyzed by HPLC-MS:

[0211] For the compound of formula (IB): [0212] For all plasma samples: 5 µL of blank solution + 50 µL of plasma sample + 200 µL of acetonitrile for protein precipitation. The glucuronidation was not detected in all samples. [0213] For 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid: [0214] For all plasma samples: 5 µL of blank solution + 50 µL of plasma sample + 200 µL of acetonitrile for protein precipitation. The glucuronidation was detected in IV 2~240 h samples. [0215] The plasma concentrations of the compound of formula (IB) are given below:

[0216] The plasma 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid concentrations are given below:

[0217] The observed AUC and release rate for the compound of formula (IB) are shown below:

[0218] The observed AUC and release rate for 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid are shown below:

[0219] The pharmacokinetic parameters for the compound of formula (IB) are:

Last time point for AUC_last: 4 or 7 h AUC/D was calculated based on AUClast. NA: Not available F was caculated based on AUClast . t1/2 was reported as NA since calculated with the last 2 time points. 135022. Mean Plasma concentration vs time profile after IM in SD rat [0220] The pharmacokinetic parameters for 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid are shown below:

Last time point for AUC_last: 672 or 840 h AUC/D was calculated based on AUClast. NA: Not available 3 male rats were in IM group. Example 6: Pharmacokinetic Study of a Composition of the Compound of Formula (IA), administered intramuscularly and subcutaneously [0221] A pharmacokinetic study was conducted to demonstrate the long-acting injectable potential of an aqueous micro-suspension of the compound of formula (IA). [0222] Fed male Sprague-Dawley rats were administered by intramuscular injection of 50 mg/kg of the suspension formulation (125 mg/mL) of Example 3, or subcutaneous injection of 50 mg/kg of the suspension formulation (125 mg/mL) of Example 3. [0223] The suspension formulation had the following particle size distribution:

[0224] The range of rat body weight:254~269 g; the individual body weight of these 6 rats: Rat #1(SC_R1):267 g; Rat #2(SC_R2):269 g; Rat #3(SC_R3):254 g; Rat #4(IM_R4):265 g; Rat #5(IM_R5):257 g; Rat #6(IM_R6):254 g. No abnormal clinical symptoms were observed during the entire experiment. [0225] Blood samples were taken from the jugular vein at 1, 2, 4, 7, 24, 48, 72, 144, 168, 240, 336, 504, 672, 840, 1008 hr. EDTA-K2 was used as anticoagulant. [0226] Plasma derived from individual blood samples was analyzed for the compound of Formula IA and for the active selexipag active metabolite, i.e., 2-(4-((5,6-diphenylpyrazin- 2-yl)(isopropyl)amino)butoxy)acetic acid. [0227] Plasma samples were analyzed by HPLC-MS:

[0228] For the compound of formula (IA): For all plasma samples: 5 µL of blank solution + 50 µL of plasma sample + 200 µL of acetonitrile for PPE (protein precipitation extraction). The glucuronidation was not detected in samples. [0229] For 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid: For all plasma samples: 5 µL of blank solution + 50 µL of plasma sample + 200 µL of acetonitrile for PPE (protein precipitation extraction). The glucuronidation was detected at IM_2H~168H,SC_4H~240H samples. [0230] For the subcutaneously administered formula (IA) compound composition, the plasma concentrations of the compound of formula (IA) are given below:

[0231] For the subcutaneously administered formula (IA) compound composition, the plasma 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid concentrations are given below:

[0232] For the subcutaneously administered formula (IA) compound composition, the observed AUC and release rate for the compound of formula (IA) are shown below:

R-square was poor (< 0.85), values were excluded from the mean AUCextrap > 20 %, values were excluded from the mean [0233] For the subcutaneously administered formula (IA) compound composition, the observed AUC and release rate for 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid are shown below:

[0234] For the intramuscularly administered formula (IA) compound composition, the plasma concentrations of the compound of formula (IA) are given below:

[0235] For the intramuscularly administered formula (IA) compound composition, the plasma 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid concentrations are given below:

[0236] For the intramuscularly administered formula (IA) compound composition, the observed AUC and release rate for the compound of formula (IA) are shown below:

R-square was poor (< 0.85), values were excluded from the mean AUCextrap > 20 %, values were excluded from the mean [0237] For the intramuscularly administered formula (IA) compound composition, the observed AUC and release rate for 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid are shown below:

[0238] The pharmacokinetic parameters for the compound of formula (IA) are:

AUC/D was calculated based on AUClast. NA: Not available 6 male rats were randomly divided into two groups, with 3 rats in each group. 022. Mean Plasma concentration vs time profile after IM in SD rat [0239] The pharmacokinetic parameters for 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid are shown below:

Last time point for AUC_last: 336, 504, 672 h AUC/D was calculated based on AUClast. NA: Not available 6 male rats were randomly divided into two groups, with 3 rats in each group. t1/2 was reported as NA since Rsq < 0.85. Example 7: Pharmacokinetic study of intravenously administered Compound of Formula (IB) [0240] For comparison purposes, a pharmacokinetic study was conducted to demonstrate the pharmacokinetics of intravenously injected compound of formula (IB). [0241] Fed male Sprague-Dawley rats were administered by intravenous injection in the tail vein 1 mg/kg of a solution formulation (0.5 mg/mL) of the Compound of Formula IB in 90% PEG400/10% Ethanol (v/v). [0242] The range of rat body weight:273~274 g; the individual body weight of these 3 rats: Rat #1(IV_R1):274 g; Rat #2(IV_R2):273 g; Rat #3(IV_R3):273 g. No abnormal clinical symptoms were observed during the entire experiment. [0243] Blood samples were taken from the jugular vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 7, 24 hr. EDTA-K2 was used as anticoagulant. [0244] Plasma derived from individual blood samples was analyzed for the compound of Formula IB and for the active selexipag active metabolite, i.e., 2-(4-((5,6-diphenylpyrazin- 2-yl)(isopropyl)amino)butoxy)acetic acid. [0245] Plasma samples were analyzed by HPLC-MS:

[0246] For the compound of formula (IB): [0247] IV all samples: 50 µL of plasma sample + four volume of acetonitrile (200 µL) for PPE (protein precipitation extraction) + 5 µL of blank solution. The glucuronidation was not detected in all samples. [0248] For 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid: [0249] IV 0.033~1 h plasma samples: step1: 5 µL of blank solution + 50 µL of plasma sample+ four volume of acetonitrile (200 µL) for PPE (protein precipitation extraction), step2: 5 µL of supernatant solution +95 µL CB. Therefore, the final compound concentration in plasma (ng/ml) was corrected by multiplying 20. IV other samples: 5 µL of blank solution + 50 µL of plasma sample + four volume of acetonitrile (200 µL) for PPE (protein precipitation extraction). The glucuronidation was not detected in all samples. [0250] For the compound of formula (IB), the plasma concentration was below the lower limit of quantitation in all samples. [0251] For 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid, the plasma concentartions were:

BQL: Below lower limit of quantitation (LLOQ for STD samples: 0.5 ng/mL ) NA: Not available The concentration value reported as 0.00 when concentrations were BQL If less than 50% of the concentrations have numerical values above the LLOQ, the mean should be reported as BQL. [0252] The pharmacokinetic parameters for 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid wereas follows:

Last time point for AUC_last: 24 h. AUC/D was calculated based on AUClast. NA: Not available 3 male rats were in IV group. Example 8: Pharmacokinetic study of intravenously administered Compound of Formula (IA) [0253] For comparison purposes, a pharmacokinetic study was conducted to demonstrate the pharmacokinetics of intravenously injected compound of formula (IA). [0254] Fed male Sprague-Dawley rats were administered by intravenous injection in the tail vein 1 mg/kg of a solution formulation (0.5 mg/mL) of the compound of formula (IA) in 90% PEG400/10% Ethanol (v/v). [0255] The range of rat body weight:268~279 g; the individual body weight of these 3 rats: Rat #1(IV_R1):276 g; Rat #2(IV_R2):279 g; Rat #3(IV_R3):268 g. No abnormal clinical symptoms were observed during the entire experiment. [0256] Blood samples were taken from the jugular vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 7, 24 hr. EDTA-K2 was used as anticoagulant. [0257] Plasma derived from individual blood samples was analyzed for the compound of formula (IA) and for the active selexipag active metabolite, i.e., 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid. [0258] Plasma samples were analyzed by HPLC-MS:

[0259] For the compound of formula (IA): [0260] IV all samples: 50 µL of plasma sample + four volume of acetonitrile (200 µL) for PPE (protein precipitation extraction) + 5 µL of blank solution. The glucuronidation was not detected in all samples. [0261] For 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid: [0262] IV 0.033~1 h plasma samples: step1: 5 µL of blank solution + 50 µL of plasma sample+ four volume of acetonitrile (200 µL) for PPE (protein precipitation extraction), step2: 5 µL of supernatant solution +95 µL CB. Therefore, the final compound concentration in plasma (ng/ml) was corrected by multiplying 20. IV other samples: 5 µL of blank solution + 50 µL of plasma sample + four volume of acetonitrile (200 µL) for PPE (protein precipitation extraction). The glucuronidation was not detected in all samples. [0263] For the compound of formula (IA), the plasma concentration was below the lower limit of quantitation in all samples. [0264] For 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid, the plasma concentrations were:

BQL: Below lower limit of quantitation (LLOQ for STD samples: 0.5 ng/mL ) NA: Not available The concentration value reported as 0.00 when concentrations were BQL If less than 50% of the concentrations have numerical values above the LLOQ, the mean should be reported as BQL. [0265] The pharmacokinetic parameters for 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid wereas follows:

Last time point for AUC_last: 24 h. t1/2 was reported as NA since Rsq<0.85. AUC/D was calculated based on AUClast. NA: Not available 3 male rats were in IV group. Example 9 – Solubility of Compound of Formula (IA) and Compound of Formula (IB) in various media [0266] Solubility test results in aqueous buffers:

“*”: The LOQ of Formula IB and Formula IA are 0.1 μg/mL. [0267] Solubility test of compounds of formula (IB) and formula (IA) in different vehicles:

“*” means the pH was adjusted as the pH shift >0.1. “/” means not performed. [0268] Solubility check for the compound of formula (IA):

[0269] Solubility test of new scaled-up batch of the compound formula (IA):

“*”: The LOQ of Formula IA is 0.05 μg/mL. [0270] Formulation confirmation of new scaled-up batch of the compound of formula (IA):

[0271] Solubility results for the compound of formula (IA) in various vehicles:

“*” means the pH was adjusted as the pH shift >0.1. “/” means not performed. [0272] Solubility results for the compound of formula (IB) in various vehicles:

“*” means the pH was adjusted as the pH shift >0.1. “/” means not performed. “&” the LOQ of the compound of formula (IB) was 0.1 µg/mL. [0273] In some embodiments, the disclosure is directed to the following aspects: Aspect 1: A pharmaceutical compositions in the form of an aqueous suspension comprising (a) a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

; having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer); (b) at least one of 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 (CremophorTM EL) or polyoxyl 40 hydrogenated castor oil (CremophorTM RH40); polyoxyethylene stearates, colloidal silicon dioxide, sodium dodecylsulfate, carboxymethylcellulose sodium, bile salts such as sodium taurocholate, sodium desoxytaurocholate, sodium desoxycholate; methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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; Vitamin E-TGPS (α tocopheryl polyethylene glycol succinate, 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 sulfate (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 Tweens™ 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; hexyldecyl trimethyl ammonium chloride (CTAC); polyvinylpyrrolidone (PVP), sodium dodecyl sulphate (SDS), docusate sodium, sodium deoxycholate, macrogol 15 hydroxystearate (SolutolTM HS 15), octoxynol (octoxynol-9, octoxynol-10), simethicone, a polyethylene glycol (PEG), carmellose sodium; and (c) a pharmaceutically acceptable aqueous carrier at a pH in the range of 5 to 8. Aspect 2: A pharmaceutical compositions in the form of an aqueous suspension comprising (a) a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

; having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer); (b) poloxamer 338; and (c) a pharmaceutically acceptable aqueous carrier at a pH in the range of 5 to 8.

Claims

What is claimed: 1. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof,

2. The compound of claim 1, wherein the compound has formula (IA):

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, wherein the compound has formula (IB):

or a pharmaceutically acceptable salt or solvate thereof.

4. A pharmaceutical composition in the form of an aqueous suspension comprising (d) a compound of any one of claims 1-3 having a particle size distribution Dv50 of 0.5 to 50 µm (micrometer); (e) a surfactant and/or wetting agent; and (f) a pharmaceutically acceptable aqueous carrier at a pH in the range of 5 to 8.

5. The pharmaceutical composition according to claim 4, further comprising a resuspending agent.

6. The pharmaceutical composition according to claim 4 or 5, wherein the particle size distribution Dv50 is from 0.5 to 10 µm (micrometer).

7. The pharmaceutical composition according to any one of claims 4 -6, wherein the particle size distribution Dv50 is from 0.5 to 5 µm (micrometer).

8. The pharmaceutical composition according to any one of claims 4 to 7, wherein the surfactant and/or wetting agent is a polysorbate, a poloxamer, an α-tocopheryl polyethylene glycol succinate, 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.

9. The pharmaceutical composition according to any one of claims 4 to 8, wherein the surfactant and/or wetting agent is poloxamer 338, polysorbate 20, Vitamin E TPGS, or a mixture thereof.

10. The pharmaceutical composition according to any one of claims 5 to 9, wherein the resuspending agent is polyethylene glycol (PEG), carmellose sodium, α-Tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, poloxamer, or a mixture thereof.

11. The pharmaceutical composition according to any one of claims 5 to 10, wherein the resuspending agent is PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, carmellose sodium, or a mixture thereof; in particular polyethylene glycol 4000.

12. The pharmaceutical composition according to any one of claims 4 to 11, wherein the aqueous carrier comprises one or more buffering and/or pH adjusting agent(s), rendering the pH in the range of 5 to 8.

13. The pharmaceutical composition according to claim 12, wherein the buffering and/or pH adjusting agent(s) is/are disodium hydrogen phosphate, citric acid, tris(hydroxymethyl)aminomethane, HCl, or NaOH, or a mixture thereof.

14. The pharmaceutical composition according to any one of claim 12 or 13, wherein the buffering agent(s) is a buffer of a buffer strength of 5 to 100 millimolar (mM).

15. The pharmaceutical composition according to any one of claims 4 to 14, comprising by weight based on the total volume of composition: (a) 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 the compound of formula (IA) or the compound of formula (IB) (or a pharmaceutically acceptable salt or solvate thereof); (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 and/or wetting agent, or a mixture of surfactants and/or 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) water for injection q.s. ad 100%.

16. A container containing the pharmaceutical composition according to any one of claims 4 to 15, wherein the container is a syringe or a vial.

17. A process for preparing a pharmaceutical composition according to any one of claims 4 to 15, said process comprising the steps of: (a) subjecting the compound of formula (IA) or the compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof, to a grinding medium to reduce the average effective particle size; and (b) adding to the product of step (a) a liquid medium comprising a surfactant and/or wetting agent, optionally a resuspending agent; and a pharmaceutically acceptable aqueous carrier.

18..A process for preparing a lyophilized pharmaceutical composition, said process comprising the steps of freezing the pharmaceutical composition according to any one of claims 4 to 15, followed by a drying step comprising applying a vacuum.

19. A lyophilized pharmaceutical composition obtainable by the process according to claim 18.

20. A reconstituted pharmaceutical composition prepared from the lyophilized pharmaceutical composition according to claim 19, by adding at least one diluent.

21. A process for preparing a sterile pharmaceutical composition according to any one of claims 4 to 15, wherein the pharmaceutical composition is sterilized with autoclavation (steam sterilisation), or with gamma-irradiation; or wherein the compound of formula (IA) or the compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof, is sterilised with gamma-irradiation and is used for preparing the pharmaceutical composition.

22. A sterile pharmaceutical composition obtainable by the process of claim 21.

23. The compound according to any one of claim 1-3, or the pharmaceutical composition according to any one of claims 4-15, or 18-20, 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, pulmonary hypertension, Fontan disease, 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.

24. The compound or pharmaceutical composition for the use according to claim 23, wherein the disease or condition is pulmonary hypertension, and the pulmonary hypertension comprises pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis.

25. The compound or pharmaceutical composition according to claim 24, for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH).

26. The compound or pharmaceutical composition according to claim 24, for use in the treatment and/or prevention of chronic thromboembolic pulmonary hypertension (CTEPH).

27. The compound or pharmaceutical composition for the use according to any one of claims 23 to 26, wherein the pharmaceutical composition is in the form of an intramuscular or subcutaneous injectable.

28. The pharmaceutical composition for the use according to claim 27, wherein pharmaceutical composition is administered at a time interval of one week to three months.

29. 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 a compound of formula (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein R is

30. The pharmaceutical composition of claim 29, wherein the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt or solvate thereof.

31. The pharmaceutical composition of claim 29, wherein the compound of formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt or solvate thereof.

32. The pharmaceutical composition for the use according to any one of claims 29-31, wherein the pulmonary hypertension comprises pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis.

33. The pharmaceutical composition according to claim 32, for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH).

34. The pharmaceutical composition according to claim 32, for use in the treatment and/or prevention of chronic thromboembolic pulmonary hypertension (CTEPH).

35. The pharmaceutical composition for the use according to any one of claims 29 to 34, wherein the pharmaceutical composition is in the form of an intramuscular or subcutaneous injectable.

36. The pharmaceutical composition for the use according to claim 35, wherein pharmaceutical composition is administered at a time interval of one week to three months.

37. Microparticles of a compound of formula (IA):

or a pharmaceutically acceptable salt or solvate thereof, wherein said microparticles have a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 2 to 30 µm, or 2 to 20 µm, or 2 to 10 µm, or 2 to 5 µm.

38. Microparticles of a compound of formula (IB):

or a pharmaceutically acceptable salt or solvate thereof, wherein said microparticles have a particle size distribution Dv50 of 0.5 to 50 µm (micrometer), preferably 0.5 to 30 µm, or 0.5 to 20 µm, or 0.5 to 10 µm, or 0.5 to 5 µm, or 0.5 to 2 µm.

39. The microparticles according to claim 37 or claim 38, wherein the microparticles are suspended in an aqueous medium, which aqueous medium, in addition to water, may comprise (i) a surfactant and/or wetting agent; and optionally (ii) a resuspending agent; and optionally a buffering agent.

40. The microparticles according to any one of claims 37-39, for use in the treatment of pulmonary hypertension.

41. The microparticles according to any one of claims 37-40, which are for administration by intramuscular or subcutaneous injection.

42. The microparticles according to claim 41, wherein said intramuscular or subcutaneous 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.