Pharmaceutical composition comprising macitentan for the treatment of chronic thromboembolic pulmonary hypertension

Abstract

The present invention relates to high doses of macitentan (INN), i.e. propylsulfamic acid [5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, or of aprocitentan, for use in the treatment and/or prevention of chronic thromboembolic pulmonary hypertension (CTEPH). Moreover, the present invention relates to the use of high doses of macitentan or of aprocitentan for the manufacture of a medicament for the treatment and/or prevention of CTEPH, as well as to a method for the treatment and/or prevention of CTEPH comprising administering high doses of macitentan or of aprocitentan to a patient. Further, the present invention relates to a dosage regimen for the treatment and/or prevention of CTEPH as well as to a combination of macitentan, or of aprocitentan, with one or more phosphodiesterase type 5 (PDES) inhibitors, prostacyclin analogues, prostacyclin receptor agonists or soluble guanylate cyclase stimulators. Moreover, the present invention relates to a pharmaceutical composition for the treatment of CTEPH comprising a high dose of macitentan or of aprocitentan.

1 . A method for treating or preventing chronic thromboembolic pulmonary hypertension (CTEPH) in a human patient in need thereof, comprising administering dosage of macitentan that is from 20 mg per day to 300 mg per day to the human patient. 
     
     
         2 . The method according to  claim 1 , wherein the dosage of macitentan is from 20 mg per day to 250 mg per day. 
     
     
         3 . The method according to  claim 1 , wherein the dosage of macitentan is 25 to 50 mg per day. 
     
     
         4 . The method according to  claim 1 , wherein the dosage of macitentan is 60 to 90 mg per day. 
     
     
         5 . The method according to  claim 1 , wherein the dosage of macitentan is 100 to 200 mg per day. 
     
     
         6 . The method according to  claim 1 , wherein the dosage is administered once per day. 
     
     
         7 . The method according to  claim 1 , wherein the dosage of macitentan is 25 to 50 mg twice per day. 
     
     
         8 . The method according to  claim 1 , wherein the dosage of macitentan is 60 to 90 mg twice per day. 
     
     
         9 . The method according to  claim 1 , wherein the dosage of macitentan is escalated from 10 mg per day, followed by 25 to 50 mg per day, and optionally followed by 60 to 90 mg per day. 
     
     
         10 . The method according to  claim 1 , wherein the dosage of macitentan is escalated from 10 mg per day, followed by 25 to 50 mg per day followed by 37.5 mg twice a day. 
     
     
         11 . The method according to  claim 9 , wherein the lower dosage of macitentan is administered for 15 to 45 days in case it is followed by a higher dose. 
     
     
         12 . The method according to  claim 1 , wherein the dosage of macitentan is 25 to 50 mg per day, provided that the human patient is already treated with an endothelin receptor antagonist. 
     
     
         13 . The method according to  claim 1 , wherein the dosage of macitentan is 60 to 90 mg per day, provided that the human patient is already treated with an endothelin receptor antagonist. 
     
     
         14 . The method according to  claim 1 , wherein the dosage of macitentan is 25 to 50 mg per day; followed by 60 to 90 mg per day; provided that the human patient is already treated with an endothelin receptor antagonist. 
     
     
         15 . The method according to  claim 1 , wherein macitentan is combined with a PDES inhibitor and/or a prostacyclin analogue, and/or a prostacyclin receptor agonist and/or a soluble guanylate cyclase stimulator. 
     
     
         16 . The method according to  claim 15 , wherein the PDES inhibitor is selected from sildenafil, tadalafil, vardenafil, or udenafil; the prostacyclin analogue is selected from epoprostenol, treprostinil, iloprost, or beraprost; the prostacyclin receptor agonist is selected from selexipag or ralinepag; and the soluble guanylate cyclase stimulator is selected from riociguat, olinciguat, praliciguat or vericiguat. 
     
     
         17 . The method according to  claim 15 , wherein macitentan is combined with tadalafil and/or selexipag and/or riociguat. 
     
     
         18 . The method according to  claim 17 , wherein macitentan is combined with riociguat and riociguat has a dosage of 0.5 mg three times per day to 2.5 mg three times per day. 
     
     
         19 . The method according to  claim 1 ,wherein macitentan is administered to the human patient before pulmonary endarterectomy (PEA) surgery. 
     
     
         20 . The method according to  claim 1 , wherein the human patient is inoperable with PEA surgery. 
     
     
         21 . The method according to  claim 1 , wherein the human patient suffers from persistent or recurrent pulmonary hypertension (PH) after PEA surgery. 
     
     
         22 . The method according to  claim 1 , wherein the human patient has been treated with balloon pulmonary angioplasty (BPA) and PEA surgery prior to administering macitentan. 
     
     
         23 . The method according to  claim 1 , wherein the human patient is excluded from BPA. 
     
     
         24 . The method according to  claim 1 , wherein the human patient suffers from persistent or recurrent PH after BPA. 
     
     
         25 . The method according to  claim 1 , wherein the treating and/or preventing results in reduction of morbidity and/or mortality risk of CTEPH. 
     
     
         26 . A method for treating CTEPH in a human patient in need thereof, comprising administering a pharmaceutical composition comprising 20 mg to 300 mg of macitentan and at least a pharmaceutically acceptable excipient to the human patient. 
     
     
         27 . The method according to  claim 26 , wherein the pharmaceutical composition contains macitentan in an amount of 20 mg to 250 mg. 
     
     
         28 . The method according to  claim 26 , wherein the pharmaceutical composition comprises
 macitentan in a total amount of 10 to 50% in weight based on the total weight of the pharmaceutical composition,   a filler, consisting of lactose monohydrate with microcrystalline cellulose, in a total amount of 10 to 85% in weight based on the total weight of the pharmaceutical composition,   a disintegrant, consisting of sodium starch glycolate or a combination of sodium starch glycolate and polyvinylpyrrolidone, in a total amount of 1 to 10% in weight based on the total weight of the pharmaceutical composition,   a surfactant, consisting of a polysorbate, in a total amount of 0.1 to 1% in weight based on the total weight of the pharmaceutical composition, and   a lubricant, consisting of magnesium stearate, in a total amount of 0.05 to 5% in weight based on the total weight of the pharmaceutical composition.   
     
     
         29 . The method according to  claim 26 , wherein the pharmaceutical composition is in the form of a capsule or a tablet. 
     
     
         30 . A method for chronic thromboembolic pulmonary hypertension (CTEPH) in a human patient in need thereof, comprising administering a dosage of aprocitentan of 100 mg per day to 1500 mg per day to the human patient. 
     
     
         31 . The method according to  claim 30 , wherein the dosage of aprocitentan is from 100 mg per day to 1250 mg per day. 
     
     
         32 . The method according to  claim 30 , wherein the dosage of aprocitentan is 125 to 250 mg per day. 
     
     
         33 . The method according to  claim 30 , wherein the dosage of aprocitentan is 300 to 450 mg per day. 
     
     
         34 . The method according to  claim 30 , wherein the dosage of aprocitentan is escalated from 50 mg per day, followed by 125 to 250 mg per day, and optionally followed by 300 to 450 mg per day. 
     
     
         35 . The method according to  claim 30 , wherein the treatment and/or prevention result in the reduction of morbidity and/or mortality risk of CTEPH.