Method of treatment and compositions comprising a dual p13k delta-gamma kinase inhibitor and a corticosteroid

Abstract

This present disclosure relates to a method of treating autoimmune, respiratory and/or inflammatory diseases or conditions, e.g., asthma, COPD, rheumatoid arthritis and idiopathic pulmonary fibrosis (IPF). The method comprises administering a dual PI3K delta and gamma inhibitor and a corticosteroid. The present invention also relates to pharmaceutical compositions containing a dual PI3K delta and gamma inhibitor and a corticosteroid.

1 . A method of treating an autoimmune, respiratory and/or inflammatory disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of (i) a dual PI3K delta and gamma inhibitor, and (ii) a corticosteroid. 
     
     
         2 . The method according to  claim 1 , wherein the dual PI3K delta and gamma inhibitor is a compound of formula A: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method according to  claim 1 , wherein the corticosteroid is selected from the group consisting of dexamethasone, betamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, fluticasone, triamcinolone, budesonide or cortisone prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, deprodone propionate, fluticasone propionate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate, hydrocortisone probutate, and pharmaceutically acceptable salts thereof. 
     
     
         4 . The method according to  claim 1 , wherein the corticosteroid is selected from the group consisting of dexamethasone, betamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, fluticasone, triamcinolone, budesonide, cortisone, and pharmaceutically acceptable salts thereof. 
     
     
         5 . The method according to  claim 1 , wherein the corticosteroid is selected from dexamethasone, fluticasone, and pharmaceutically acceptable salts thereof. 
     
     
         6 . The method according to  claim 1 , wherein the therapeutically effective amount of (i) the dual PI3K delta and gamma inhibitor, and the therapeutically effective amount of (ii) a corticosteroid are administered simultaneously as a combined formulation. 
     
     
         7 . The method according to  claim 1 , wherein the therapeutically effective amount of (i) the dual PI3K delta and gamma inhibitor, and the therapeutically effective amount of (ii) a corticosteroid are administered sequentially. 
     
     
         8 . The method according to  claim 7 , wherein the therapeutically effective amount of the corticosteroid is administered before the therapeutically effective amount of the dual PI3K delta and gamma inhibitor. 
     
     
         9 . The method according to  claim 1 , wherein the therapeutically effective amount of the dual PI3K delta and gamma inhibitor is administered twice daily to once every three weeks, and the therapeutically effective amount of the corticosteroid is administered twice daily to once every three weeks. 
     
     
         10 . The method according to  claim 1 , wherein the autoimmune, respiratory and/or inflammatory disease or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuro inflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, atopic dermatitis, and combinations thereof. 
     
     
         11 . The method according to  claim 1 , wherein the autoimmune, respiratory and/or inflammatory disease or condition is selected from the group consisting of asthma, allergic rhinitis, non-allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis (IPF) and atopic dermatitis. 
     
     
         12 . The method according to  claim 1 , wherein the dual PI3K delta and gamma inhibitor and the corticosteroid are each administered in an amount ranging from about 0.01 mg to about 1000 mg. 
     
     
         13 . The method of  claim 1 , wherein the dual PI3K delta and gamma inhibitor and the corticosteroid are administered at a ratio of about 1:100 to about 100:1 by weight. 
     
     
         14 . A pharmaceutical composition comprising (i) a dual PI3K delta and gamma inhibitor, (ii) a corticosteroid, and (iii) optionally, a pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein the dual PI3K delta and gamma inhibitor is a compound of formula A: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The pharmaceutical composition according to  claim 14 , wherein the corticosteroid is selected from the group consisting of dexamethasone, betamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, fluticasone, triamcinolone, budesonide or cortisone prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, deprodone propionate, fluticasone propionate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate, hydrocortisone probutate, and pharmaceutically acceptable salts thereof. 
     
     
         17 . The method according to  claim 14 , wherein the corticosteroid is selected from the group consisting of dexamethasone, betamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, fluticasone, triamcinolone, budesonide, cortisone, and pharmaceutically acceptable salts thereof. 
     
     
         18 . The method according to  claim 14 , wherein the corticosteroid is selected from dexamethasone, fluticasone, and pharmaceutically acceptable salts thereof. 
     
     
         19 . The pharmaceutical composition of  claim 14 , wherein the composition comprises about 0.01 mg to about 1000 mg of the dual PI3K delta and gamma inhibitor and about 0.01 mg to about 1000 mg of the corticosteroid. 
     
     
         20 . The pharmaceutical composition according to  claim 14 , for use in a method of treating an autoimmune, respiratory and/or inflammatory disease or condition selected from the group consisting of asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, Idiopathic pulmonary fibrosis (IPF), chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis, and combinations thereof. 
     
     
         21 . The use of a pharmaceutical composition according to  claim 14  in the manufacture of a medicament for the treatment of autoimmune, respiratory and inflammatory diseases and conditions are selected from asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, Idiopathic pulmonary fibrosis (IPF), chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis, and combinations thereof. 
     
     
         22 . A kit for treating an autoimmune, respiratory or inflammatory disease or condition, the kit comprising:
 (i) a dual PI3K delta and gamma inhibitor, and (ii) a corticosteroid, or a pharmaceutically acceptable salt thereof, either in a single pharmaceutical composition or in separate pharmaceutical compositions,   (ii) optionally, instructions for treating the autoimmune, respiratory or inflammatory disease or condition with the dual PI3K delta and gamma inhibitor and corticosteroid and   (iii) optionally, a container for placing the pharmaceutical composition or pharmaceutical compositions.   
     
     
         23 . The kit of  claim 22 , wherein the dual PI3K Delta and Gamma inhibitor and Corticosteroid are for in the treatment of an autoimmune, respiratory or inflammatory disease or condition selected from asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, Idiopathic pulmonary fibrosis (IPF), chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis. 
     
     
         24 . The kit of  claim 22 , wherein the dual PI3K delta and gamma inhibitor is a compound of formula A: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.