Pharmaceutical composition comprising selexipag

Abstract

To provide pharmaceutical compositions comprising 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (selexipag), which are suitable for oral administration (p.o.).SOLUTION: There is provided a coated tablet-form pharmaceutical composition, comprising a predetermined amount of selexipag, and further comprising predetermined amounts of D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and magnesium stearate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (selexipag, NS-304, ACT-293987, hereinafter the compound), which is suitable for oral administration (po).

[0002] [ka] [Background technology]

[0003] The preparation and pharmaceutical use of selexipag and its active metabolite 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (MRE-269, ACT-333679) are disclosed in WO 2002 / 088084, WO 2009 / 157396, WO 2009 / 107736, WO 2009 / 154246, WO 2009 / 157397, WO 2009 / 157398, WO 2010 / 150865, WO 2011 / 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. Certain formulations are disclosed in WO 2013 / 024051, WO 2014 / 069401, and WO 2018 / 162527.

[0004] Selexipag has been shown to be beneficial in the treatment of pulmonary arterial hypertension in adults. In a Phase III clinical trial, among patients with pulmonary arterial hypertension, the risk of the primary composite endpoint of death or complications related to pulmonary arterial hypertension was significantly lower among patients receiving selexipag than among patients receiving placebo. Selexipag, for example, has received marketing approval in the United States and is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO group I) to slow disease progression and reduce the risk of hospitalization for PAH.

[0005] Selexipag is believed to function as a prodrug (while retaining some agonist activity at IP receptors itself) that can exert sustained selective IP receptor agonist activity of the active metabolite 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid in mammals, particularly humans. The in vivo metabolism of selexipag may potentially effectively act as a "slow release mechanism" that prolongs activity and reduces typical adverse reactions associated with high concentrations of PGI2 agonists (Kuwano et al., J Pharmacol Exp Ther (2007), 322(3), 1181-1188).

[0006] Adverse reactions associated with PGI2 agonists are also addressed by a specific up-titration schedule. The recommended starting dose of oral selexipag for adults is 200 micrograms, given twice daily. The dose is then increased in increments of 200 micrograms twice daily, usually at one-week intervals, up to a maximum tolerated dose of 1600 micrograms twice daily. If a dose that the patient cannot tolerate is reached, the dosage should be reduced to the previous tolerated dose.

[0007] Selexipag is a selective IP receptor agonist for oral use with proven efficacy and safety in adults with PAH. To date, selexipag is the only IP receptor agonist approved worldwide for long-term treatment across WHO FC II-III, primarily in combination with current frontline oral PAH-specific medications, in adult patients who require additional treatment for inadequate disease control. Selexipag represents an important additional treatment option for these patients.

[0008] The availability of selexipag, a highly selective IP receptor agonist for oral use that demonstrates benefit on PAH disease outcomes in add-on therapy, provides an important rationale for initiating prostacyclin pathway therapy at a medically appropriate stage of PAH disease without significant impact on patient lifestyle.

[0009] Pediatric PAH is a rare progressive disease associated with significant morbidity and mortality. Current recommended treatments in the pediatric population include PDE-5 inhibitors, ERAs, and inhaled, subcutaneous and intravenous (iv) prostacyclin pathway agonists. However, in the absence of randomized controlled clinical trials conducted to demonstrate the efficacy of these treatments in pediatric patients, treatment algorithms are based on evidence from adult studies. A biocomparison study between adult and pediatric active ingredient strengths of selexipag was conducted (M.Boehler et al,Eur J Drug Metab Pharmacokinet.201 Feb;43(1):115-120.doi:10.1007 / s13318-017-0424-z).

[0010] Patients with hepatic impairment or who experience drug interactions with CYP 2C8 inhibitors may also benefit from dose adaptation to their condition. Preferably, these patients are adults.

[0011] Additionally, patients who do not tolerate the 200 mcg starting dose may benefit from the new dosage.

[0012] Therefore, there is a need to develop a treatment that may be disease-modifying in all patients with PAH and other diseases, including pediatric patients or patients with hepatic impairment, or patients who experience drug interactions with CYP 2C8 inhibitors. Furthermore, weight-based dosing should be possible. Furthermore, the treatment should be in a child-friendly form, such as a mini-tablet. Summary of the Invention

[0013] The present invention provides, for example, a means for treating pediatric patients with PAH, which is effective and safe for children having different age groups, such as 2 to <6 years, 6 to <12 years, and 12 to <18 years.

[0014] Additionally, the present invention provides a means for treating patients with, for example, PAH, who suffer from liver impairment or experience drug interactions with CYP 2C8 inhibitors.

[0015] 1) The first embodiment comprises a dose of 80 to 170 mcg of formula (I)

[0016] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, or morphological form thereof.

[0017] In that regard, the abbreviation "mcg" stands for microgram, i.e. 1 × 10 -6 represents grams.

[0018] In a preferred embodiment, the pharmaceutical composition comprises a compound of formula (I) in an amount of 80-160mcg, more preferably in an amount of 90-110mcg and 140-160mcg, most preferably in an amount of 93-107mcg and 143-157mcg, for example 100mcg with a tolerance of ±7% and 150mcg with a tolerance of ±7%, whereby the tolerances apply to groups of 20 tablets.

[0019] Preferably, the compound of formula (I), i.e. 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, is used for the preparation of the composition in crystalline form, in particular in essentially pure crystalline form (preferably essentially pure crystalline form I or essentially pure crystalline form II as disclosed in WO 2010 / 150865 / EP 2 447 254).

[0020] 2) A further embodiment relates to the composition according to embodiment 1), which comprises a) a filler, b) a disintegrant; c) a binder, and d) lubricants.

[0021] Fillers, also called bulking agents or diluents, have several functions, such as diluting the active ingredient within a pharmaceutical composition, they may ensure long-term stabilization, or they may provide therapeutic enhancements, such as facilitating drug absorption or increasing solubility. Fillers may also be useful in the manufacturing process to aid in handling the active substance.

[0022] Disintegrants swell when wet, eg, causing the tablet to break apart during a specific segment of the digestive process, releasing the active ingredient for absorption.

[0023] Binders hold the ingredients in a tablet together. Binders ensure that tablets and granulations can be formed with the necessary mechanical strength.

[0024] Lubricants prevent ingredients from clumping together and sticking to the tablet punch or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solids and the die walls.

[0025] 3) A further embodiment relates to a pharmaceutical composition according to embodiment 2), the filler, if present, is one or more selected from the group consisting of D-mannitol, corn starch, lactose, pregelatinized starch, calcium hydrogen phosphate dihydrate (CaHPO4·2H2O), microcrystalline cellulose and maltodextrin, preferred fillers being D-mannitol and corn starch; the disintegrant, if present, is one or more selected from the group consisting of low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium starch glycolate, and cross-linked polyvinylpyrrolidone, the preferred disintegrant being low-substituted hydroxypropylcellulose; the binder, if present, is one or more selected from the group consisting of hydroxypropylcellulose, sucrose, gelatin, starch, pregelatinized starch, alginic acid, sodium alginate, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidinone, calcium carboxymethylcellulose, sodium carboxymethylcellulose, guar gum, clays, ion exchange resins, and calcium silicate, the preferred binder being hydroxypropylcellulose; the lubricant, if present, is one or more selected from the group consisting of magnesium stearate, aluminum stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl monoacrylates, polyethylene glycol, hydrogenated cottonseed oil, castor seed oil, sucrose esters, calcium silicate, and silicon dioxide, the preferred lubricant being magnesium stearate.

[0026] All of the excipients listed are commercially available and well known to those skilled in the art.

[0027] A preferred disintegrant is low substituted hydroxypropyl cellulose (L-HPC), IUPAC name: Cellulose, 2-hydroxypropyl ether (low substitution). Particularly preferred is L-HPC having a hydroxypropoxyl content of 7-13%, especially about 10-13% (according to the USP / NF method).

[0028] A preferred binder is hydroxypropyl cellulose (HPC), which is soluble in water due to its large amount of hydroxypropoxyl groups in the cellulose backbone. IUPAC name: Cellulose, 2-hydroxypropyl ether. In a 2% aqueous solution, it has a viscosity (mPa) of 2.0 to 6.0, preferably 2.0 to 5.9, particularly preferably 2.0 to 2.9 at 20°C. * The molecular weight (by GPC method) is preferably 34,000 to 110,000, more preferably 40,000 to 100,000, and most preferably 40,000 (±15%, preferably ±10%).

[0029] For these and other pharma- ceutically acceptable excipients and procedures mentioned herein, reference is made to the extensive literature on the subject. For example, see RC Rowe, PJ Eskey, SCOwen, Handbook of Pharmaceutical Excipients, 5th edition (and 6th edition) Pharmaceutical Press 2006; Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" (published by Lippincot Williams & Wilkins). Also, see the pamphlet of Shin-Etsu Chemical Co., Ltd, Cellulose & Pharmaceutical Excipative Department, 05.8 / 1000.

[0030] 4) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 3), the pharmaceutical composition comprising: D-mannitol and corn starch, low-substituted hydroxypropyl cellulose; hydroxypropyl cellulose, - magnesium stearate.

[0031] 5) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 2) to 4), (i) the filler is included in an amount of 11.5 to 145.0 mg, preferably 12.0 to 45.0 mg, for example, 12.0 to 35.0 mg; (ii) the disintegrant is included in an amount of 0.6 to 8.5 mg, preferably 0.6 to 2.5 mg, for example, 0.7 to 2.0 mg; (iii) the binder is present in an amount of 0.5 to 6.5 mg, preferably 0.5 to 2.0 mg, for example, 0.5 to 1.5 mg; (iv) The lubricant is included in an amount of 0.2 to 2.5 mg, preferably 0.2 to 0.7 mg, for example, 0.2 to 0.5 mg.

[0032] 6) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 5), the pharmaceutical composition comprising: D-mannitol in an amount of 7.0 to 90.0 mg, preferably 7.0 to 25.0 mg, for example 7.0 to 20 mg; corn starch in an amount of 4.5 to 60.0 mg, preferably 4.5 to 20.0 mg, for example 4.5 to 15.0 mg; low-substituted hydroxypropylcellulose in an amount of 0.6 to 9.0 mg, preferably 0.6 to 3.0 mg, for example 0.7 to 1.8 mg; hydroxypropylcellulose in an amount of 0.5 to 6.5 mg, preferably 0.5 to 2.0 mg, for example 0.5 to 1.5 mg, - magnesium stearate in an amount of 0.2 to 2.5 mg, preferably 0.2 to 0.7 mg, for example 0.2 to 0.5 mg.

[0033] 7) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 6), wherein the pharmaceutical composition is in the form of a tablet or a capsule. Preferably, the pharmaceutical composition is in the form of a tablet.

[0034] The tablets may vary in shape, for example round, oval, elliptical, cylindrical, cloverleaf, or any other suitable shape. Preferably, the tablets are round.

[0035] The procedures that may be used may be conventional or known in the art or may be based on such procedures, e.g., as described in L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd Ed., 1986; H. Sucker et al., Pharmazeutische Technologie, Thieme, 1991; Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or subsequent editions.

[0036] 8) A further embodiment relates to the pharmaceutical composition according to embodiment 7), wherein the tablet is coated, and the coating material comprises one or more selected from the group consisting of plasticizers, film-forming agents, and pigments.

[0037] Preferably, the tablets are film coated.

[0038] Examples of film-forming agents are hypromellose, cellulose acetate phthalate (CAP), acrylate polymers, hydroxypropyl methyl cellulose phthalate (HPMCP), or polyvinyl acetate phthalate (PVAP). Note that this list is not limiting. A preferred film-forming agent is hypromellose (INN), also known as hydroxypropyl methyl cellulose (HPMC).

[0039] Plasticizers are added to polymers used as film-forming agents to make them pliable and flexible, and to increase the flexibility and plasticity of the coating. Plasticizers play an important role in formulations such as gastroretentive coatings, ophthalmic coatings, transdermal coatings, buccal coatings, and orodisintegrative coatings, and are added to these products to lower the glass transition temperature, aiding in the thermal stability of drugs and other ingredients.

[0040] Preferably, the plasticizer is a hydrophilic plasticizer. Examples of hydrophilic plasticizers are glycerin, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol sorbitan solution, and triethyl citrate. Propylene glycol is preferred.

[0041] Glidants are substances added to improve powder flow and reduce interparticle friction or cohesion. Common examples are magnesium stearate, Aerosil (colloidal silicon dioxide), starch, and talc. The preferred concentration of glidants is 5-10%.

[0042] See Aulton's Pharmaceutics (The Design and Manufacture of Medicines), 5th edition (editors: Kevin Taylor Michael Aulton), Elsevier.

[0043] The preferred coating method used herein is water-based coating.

[0044] The preferred pigments are titanium dioxide or iron dioxide of any color.

[0045] Additionally, polishes such as carnauba wax, beeswax or paraffin may be applied, with carnauba wax being preferred.

[0046] For the avoidance of doubt, it is to be well understood that the pharmaceutical compositions defined in embodiments 1) to 9) may additionally comprise further conventional ingredients and / or additives, which may be used alone or in combination.

[0047] Preferred excipients are specified in the table below, all of which are compendial.

[0048] [Table 1]

[0049] A more preferred excipient is talc, which acts as a glidant.

[0050] All excipients comply with the European Pharmacopoeia, the United States Pharmacopoeia, and the Japanese Pharmacopoeia.

[0051] 9) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 7) to 9), wherein the tablets are mini-tablets having a diameter of 1.5 to 4 mm, preferably 2.5 to 4 mm, more preferably 2.7 to 3.5 mm, most preferably 3 mm ± 0.3 mm.

[0052] The pharmaceutical compositions according to embodiments 1) to 8), which are preferably mini-tablets, have a weight of 12 to less than 50 mg, preferably 12 to 47 mg.

[0053] The pharmaceutical compositions according to embodiments 1) to 8) are considered "stable" if, during a certain period of time, 70%, preferably 80%, more preferably 90%, and most preferably 95% of the initial content of the compound of formula I, or a pharma- ceutically acceptable salt, solvate, hydrate, or morphological form thereof, is maintained over said period of time.

[0054] The stability of the pharmaceutical compositions can be tested in conventional manner, e.g. by measurement of the compound of formula I and its decomposition products, dissolution, friability, disintegration time, appearance and / or microscopic examination, e.g. after storage at 25° C. and 60% relative humidity, 30° C. and 75% relative humidity, and / or 40° C. and 75% relative humidity for defined periods of time.

[0055] Preferably, the solid composition of the present invention is stable for at least 6 months or 12 months when maintained at a temperature of 5 to 50° C. More preferably, the solid composition of the present invention is stable for at least 6 months or 12 months when maintained at a temperature of 15 to 45° C. Most preferably, the solid composition of the present invention is stable for at least 12 months or 36 months when maintained at a temperature of 25 to 40° C.

[0056] In a more preferred embodiment, the pharmaceutical composition is stable for a certain period of time, such as 1 year, preferably 2 years, and more preferably, the pharmaceutical composition is stable for 3 to 5 years.

[0057] In a preferred embodiment, the mini-tablets according to the invention exhibit a particular stability.

[0058] The term "pharmaceutical composition" is interchangeable with the terms "formulation" or "composition."

[0059] Whenever the words "between" or "to" are used to describe a numerical range, the endpoints of the stated range are to be understood as expressly disclosed and included within that range. For example, when a temperature range is stated as being between 40° C. and 80° C. (or 40° C. to 80° C.), this means that the endpoints 40° C. and 80° C. are included in the range; or, when a variable is defined as an integer between 1 and 4 (or 1 and 4), this means that the variable is the integer 1, 2, 3, or 4.

[0060] 10) The pharmaceutical compositions according to embodiments 1) to 9) can be preferably used as pharmaceuticals for oral administration.

[0061] 11) The pharmaceutical compositions according to embodiments 1) to 10) can be used as pediatric medicines. Preferably, pediatric patients are aged 2 to 18 years.

[0062] 12) The pharmaceutical compositions according to embodiments 1) to 11) may further be used in patients with liver impairment or who experience drug interactions with CYP 2C8 inhibitors such as clopidogrel.

[0063] The pharmaceutical composition may also be used for patients who do not tolerate a starting dose of 200 mcg.

[0064] 13) The pharmaceutical composition according to any one of embodiments 1) to 12) is useful for treating ulcers, digital ulcers, diabetic gangrene, diabetic foot ulcers, bedsores, hypertension, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disorders (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease), connective tissue diseases (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitis syndrome), reocclusion / restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute cerebral thrombosis, pulmonary embolism), transient ischemic attack (TIA), and / or other vascular diseases.diabetic neuropathy, ischemic disorders (e.g. cerebral infarction, myocardial infarction), angina (e.g. stable angina, unstable angina), chronic kidney disease including any stage of glomerulonephritis and diabetic nephropathy, allergies, bronchial asthma, restenosis after coronary interventions such as atherectomy and stent implantation, dialysis-induced thrombocytopenia, diseases involving organ or tissue fibrosis [e.g. kidney diseases such as tubulointerstitial nephritis], respiratory diseases (e.g. interstitial pneumonia / (idiopathic) pulmonary fibrosis, chronic obstructive pulmonary disease), digestive diseases (e.g. liver cirrhosis, viral hepatitis, chronic pancreatitis, and scirrhous gastric cancer), cardiovascular diseases (e.g. myocardial fibrosis), bone and joint diseases (e.g. myelofibrosis and rheumatoid arthritis), skin diseases (e.g. postoperative scars, burn scars, keloids, and hypertrophic scars), obstetric diseases (e.g. uterine fibroids), urological diseases (e.g., prostatic hyperplasia), other diseases (e.g., Alzheimer's disease, sclerosing peritonitis, type I diabetes, and postoperative organ adhesions)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychopathic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after pelvic surgery to remove the prostate, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., intestinal ulcers associated with ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, and Behcet's disease), gastritis, gastric ulcers, ischemic ophthalmological disorders (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular bone necrosis, intestinal damage caused by administration of nonsteroidal anti-inflammatory drugs, and lumbar spinal canal stenosis.

[0065] Preferably, the pharmaceutical composition according to any one of embodiments 1) to 12) may be used for the prevention or treatment of ulcers, digital ulcers, diabetic gangrene, diabetic foot ulcers, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disorders, connective tissue diseases, chronic kidney diseases including any stage of glomerulonephritis and diabetic nephropathy, diseases involving organ or tissue fibrosis, or respiratory diseases.

[0066] Preferably, the pharmaceutical composition according to any one of embodiments 1) to 12) can be used for the prevention or treatment of pulmonary arterial hypertension (PAH).

[0067] It should be understood that the pharmaceutical composition according to any one of embodiments 1) to 12) may be used for the manufacture of a medicament, in particular a medicament for the prevention and / or treatment of the above-mentioned indications.

[0068] It should further be understood that the present invention also relates to a method for preventing and / or treating a disease according to embodiment 13).

[0069] 14) A further embodiment of the present invention relates to a process for producing a pharmaceutical composition according to any one of embodiments 1) to 9), the process comprising: (a) mixing a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, hydrate, or morphological form thereof, with a bulking agent; (b) adding a filler and a disintegrant to the blend of step (a) and mixing it; (c) wet granulating the blend received from step (b) with a solution comprising a binder; (d) drying and grinding the granules of step (c); (e) lubricating the granulation with a lubricant in a suitable blender; (f) compressing the granulation into core tablets.

[0070] Further, the tablet cores are film coated, dried and polished. Preferably, the tablets are film coated.

[0071] The invention is illustrated by the following non-limiting examples. EXAMPLES

[0072] [Table 2]

[0073] 1. Preparation of compounds: The preparation of selexipag (compound: 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide) is described in WO 2002 / 088084. The preparation of polymorphic forms, i.e., crystalline forms I, II, and III of the free base, is disclosed in WO 2010 / 150865. Polymorphic forms of pharma- ceutically acceptable salts are disclosed in WO 2011 / 024874. In the following examples and assays, the compound was used in the form of the free base, in particular the crystalline form of polymorphic form I.

[0074] 2. Quantitative composition of selexipag film-coated tablets

[0075] [Table 3]

[0076] [Table 4]

[0077] The film-coated tablets shown in Tables 2 and 3 are mini-tablets with a diameter of approximately 3 mm, which makes the mini-tablets easier for children to swallow.

[0078] 4. Manufacturing Process i) Mixture Selexipag and D-mannitol are blended in a suitable blender.

[0079] ii) Mixing The corn starch and low substituted hydroxypropyl cellulose are then added to the blender. The mixture is blended.

[0080] iii) Wet granulation The blend is transferred to a fluid bed granulator / dryer and sprayed with a solution of hydroxypropyl cellulose in water, maintaining the product at a temperature of approximately 30-35°C.

[0081] iv) Drying and grinding The wet granulation is dried in a fluid bed dryer and milled.

[0082] v) Lubrication The granulation is lubricated with magnesium stearate in a suitable blender.

[0083] vi) Compression The final blend is compressed into core tablets.

[0084] vii) Coating The tablet cores are loaded into a pan and sprayed with the coating suspension until the tablet match weight is reached. The tablets are cooled until completely dry.

[0085] viii) Polishing The film-coated tablets are polished using carnauba wax.

[0086] ix) Packaging The film-coated tablets are packaged in high-density polyethylene bottles with child-resistant polypropylene caps and contain one desiccant.

Claims

1. Formula (I) in an amount of 80 to 170 mcg 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, or crystalline form thereof, D-mannitol in an amount of 7.0 to 90.0 mg, corn starch in an amount of 4.5 to 60.0 mg; low-substituted hydroxypropylcellulose in an amount of 0.6 to 9.0 mg; Hydroxypropylcellulose in an amount of 0.5 to 6.5 mg, and Magnesium stearate in an amount of 0.2 to 2.5 mg A pharmaceutical composition in the form of a tablet comprising: The tablet is coated, and the coating material comprises one or more selected from the group consisting of plasticizers, film-forming agents, and pigments. Pharmaceutical compositions.

2. 10. The pharmaceutical composition of claim 1 for use as a pediatric drug.

3. 10. The pharmaceutical composition of claim 1 for use as a medicament for oral administration.

4. 10. The pharmaceutical composition of claim 1 for use in patients with hepatic impairment or experiencing drug interactions with CYP 2C8 inhibitors.

5. The pharmaceutical composition according to any one of claims 1 to 4 for use in the prevention or treatment of ulcers, digital ulcers, diabetic gangrene, diabetic foot ulcers, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disorders, connective tissue diseases, chronic kidney diseases including any stage of glomerulonephritis and diabetic nephropathy, diseases involving organ or tissue fibrosis, or respiratory diseases.

6. A pharmaceutical composition according to any one of claims 1 to 4 for use in the prevention or treatment of pulmonary arterial hypertension (PAH).

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