Pharmaceutical Composition Comprising Mineralocorticoid Receptor Antagonist and Use Thereof

Abstract

Provided are a pharmaceutical composition comprising a mineralocorticoid receptor antagonist and use thereof. When the pharmaceutical composition is orally administered to a patient having chronic kidney disease in need thereof, the effective and safe AUC ranges from 188 ng*h/mL to 3173 ng*h/mL, with bioavailability of 50% or more in mammals. When the pharmaceutical composition is orally administered at a daily dose of 0.1 to 1.0 mg to treat chronic kidney disease, the AUC is controlled at a safe and effective level.

1 - 20 . (canceled) 
     
     
         21 . A method of treating chronic kidney disease in a human patient, comprising administering to the patient a pharmaceutical composition comprising 2-chloro-4-[(3S,3aR)-3-cyclopentyl-7-(4-hydroxylpiperidine-1-carbonyl)-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinolin-2-yl]benzonitrile: 
       
         
           
           
               
               
           
         
         and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is administered as an oral dosage form at a daily dose of 0.1 to 1.0 mg. 
       
     
     
         22 . The method of  claim 21 , wherein the daily dose is from 0.1 to 0.5 mg. 
     
     
         23 . The method of  claim 21 , wherein the daily dose is from 0.2 to 0.5 mg. 
     
     
         24 . The method of  claim 21 , wherein administration of the composition to the human results in a bioavailability of Compound I of 50% or more. 
     
     
         25 . The method of  claim 24 , wherein the D 90  of Compound I is 25 μm or less. 
     
     
         26 . The method of  claim 24 , wherein the D 90  of Compound I is 10 μm or less. 
     
     
         27 . The method of  claim 24 , wherein the pharmaceutical composition comprises one or more surfactants selected from the group consisting of benzalkonium chloride, sodium lauryl sulfonate, sodium dodecyl sulfate, glycerol, cholic acid, poloxamer, polyvinyl alcohol, Polysorbate 80, PVP K 30  and polyethylene glycol. 
     
     
         28 . The method of  claim 24 , wherein the pharmaceutical composition comprises one or more surfactants selected from the group consisting of benzalkonium chloride, sodium lauryl sulfonate, and sodium dodecyl sulfate. 
     
     
         29 . The method of  claim 24 , wherein the pharmaceutical composition comprises one surfactant selected from the group consisting of benzalkonium chloride, sodium lauryl sulfonate, and sodium dodecyl sulfate. 
     
     
         30 . The method of  claim 27 , wherein the weight ratio of Compound I to the surfactant is between 1:0.1 to 1:20. 
     
     
         31 . The method of  claim 30 , wherein the weight ratio is between 1:1 to 1:20. 
     
     
         32 . The method of  claim 31 , wherein the pharmaceutical composition is a tablet, a sustained release tablet, a capsule, a granule, a soft capsule, a dripping pill, a micro-capsule, a micro-sphere, a liposome, a self-emulsifying drug delivery system, a solid dispersion, a micelle, an oral melt tablet, a solution, a suspension, or an emulsion. 
     
     
         33 . The method of  claim 31 , wherein administration to the patient results in a safe and effective area under plasma concentration-time curve (AUC) of from 188 ng*h/mL to 3173 ng*h/mL. 
     
     
         34 . The method of  claim 33 , wherein the AUC ranges from 188 ng*h/mL to 2893 ng*h/mL. 
     
     
         35 . The method of  claim 33 , wherein-the AUC ranges from 188 ng*h/mL to 2613 ng*h/mL. 
     
     
         36 . The method of  claim 33 , wherein the AUC ranges from 188 ng*h/mL to 1117 ng*h/mL. 
     
     
         37 . The method of  claim 33 , wherein the AUC ranges from 188 ng*h/mL to 885 ng*h/mL. 
     
     
         38 . The method of  claim 21 , wherein the pharmaceutical composition is administered in the form of a single dose of 0.1 to 1.0 mg. 
     
     
         39 . The method of  claim 21 , wherein the pharmaceutical composition is administered in the form of a single dose of 0.1 to 0.5 mg. 
     
     
         40 . The method of  claim 21 , wherein the pharmaceutical composition is administered in the form of a single dose of 0.2 to 0.5 mg. 
     
     
         41 . A solid pharmaceutical composition, comprising Compound I: 
       
         
           
           
               
               
           
         
         in the amount of 0.1 to 2.5 mg, and one or more pharmaceutically acceptable carriers.