Inhalable dry powder and aerosol formulations of jak inhibitors

Abstract

wherein R1, R2, R3, R4, R5 and R6 are as defined herein, and salts thereof that are useful as JAK kinse inhibitors are described herein. Also provided are pharmaceutical compositions that include such a JAK inhibitor and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

What is claimed is: 
     
         1 . A dry powder formulation for inhalation therapies, comprising:
 (a) a JAK1 inhibitor;   (b) a diluent selected from glucose, lactose and mannitol; and   (c) magnesium stearate   
     
     
         2 . The dry powder formulation of  claim 1 , wherein the diluent is lactose. 
     
     
         3 . The dry powder formulation of  claim 2 , wherein the JAK1 inhibitor comprises particles having a size from 1-5 microns. 
     
     
         4 . The dry powder formulation of  claim 3 , wherein the lactose comprises particles having a size from 1-5 microns. 
     
     
         5 . An aerosol-based canister formulation, comprising:
 (a) a JAK1 inhibitor;   (b) Lecithin;   (c) trichlorotrifluoromethane; and   (d) dichlorodifluoromethane.   
     
     
         6 . The aerosol-based canister formulation of  claim 5 , wherein:
 (a) the JAK1 inhibitor comprises 24 mg per canister;   (b) the lecithin comprises 1.2 mg per canister;   (c) the trichlorofluoromethane comprises 4.025 g per canister; AND   (d) the dichlorodifluoromethane comprises 12.15 g/canister.   
     
     
         7 . The dry powder formulation of  claim 1 , wherein the JAK1 inhibitor is a compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein R 2  is hydroxy-C 1-6  alkyl, or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The dry powder formulation of  claim 7 , wherein R 2  is 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-1-methyl-ethyl, or 2-hydroxy-1-methyl-propyl, or a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The dry powder formulation of  claim 8 , wherein the compound of formula (III) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A method of preventing, treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of the dry powder formulation of  claim 1 . 
     
     
         11 . The method of  claim 10 , wherein the disease or condition is cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation (e.g., transplant rejection), immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder.