Pharmaceutical for oral delivery comprising mgbg and methods of treating disease

Abstract

Disclosed herein are new oral pharmaceutical compositions of MGBG and related polyamine analogs, polyamine biosynthesis inhibitors, polyamine inhibitors of AMD-I and regulators of osteopontin, and their application for the treatment of disease.

What is claimed is: 
     
         1 . An oral pharmaceutical composition, comprising MGBG together with at least one oral pharmaceutically acceptable excipient, which yields a therapeutically effective systemic plasma MGBG level when orally administered to a subject. 
     
     
         2 . (canceled) 
     
     
         3 . The oral pharmaceutical composition as recited in  claim 1 , which yields a therapeutically effective systemic plasma MGBG level for at least a 12-hour period when orally administered to a subject. 
     
     
         4 . The oral pharmaceutical composition as recited in  claim 1 , which yields a therapeutically effective systemic plasma MGBG level for at least a 24-hour period when orally administered to a subject. 
     
     
         5 . The oral pharmaceutical composition as recited in  claim 1 , wherein the plasma level of MGBG is at least 75% of the peak plasma concentration for 4 or more hours. 
     
     
         6 . The oral pharmaceutical composition as recited in  claim 1 , having an oral bioavailability of at least 20%. 
     
     
         7 . The oral pharmaceutical composition as recited in  claim 1 , having an oral bioavailability of at least 20%. 
     
     
         8 . The oral pharmaceutical composition as recited in  claim 6 , having an oral bioavailability of at least 30%. 
     
     
         9 . The oral pharmaceutical composition as recited in  claim 8 , which yields a therapeutically effective plasma level of MGBG for at least a 24 hour period in the subject with once-daily dosing. 
     
     
         10 . The oral pharmaceutical composition as recited in  claim 1 , having a half life of at least 12 hours. 
     
     
         11 . The oral pharmaceutical composition as recited in  claim 10 , having a half life of at least 18 hours. 
     
     
         12 . The oral pharmaceutical composition as recited in  claim 11 , which yields a plasma level of MGBG of at least 75% of the peak plasma concentration for 4 or more hours. 
     
     
         13 . The oral pharmaceutical composition as recited in  claim 1 , which does not have substantially dose-limiting side effects. 
     
     
         14 . The oral pharmaceutical composition as recited in  claim 1 , wherein said side effects are gastrointestinal. 
     
     
         15 . The oral pharmaceutical composition as recited in  claim 14 , wherein said gastrointestinal side effects are chosen from nausea, vomiting, diarrhea, abdominal pain, oral mucositis, oral ulceration, pharyngitis, stomatitis, and gastrointestinal ulceration. 
     
     
         16 . The oral pharmaceutical composition as recited in  claim 14 , wherein said gastrointestinal side effects are chosen from inhibition of gastrointestinal mucosal proliferation, inhibition of migration of developing epithelial lumen cells, and inhibition of differentiation of stem or progenitor cells into epithelial lumen cells. 
     
     
         17 . (canceled) 
     
     
         18 . A low-dose oral pharmaceutical composition for chronic delivery, comprising a therapeutically effective amount of MGBG and at least one pharmaceutically acceptable excipient, which does not have substantial gastrointestinal side effects. 
     
     
         19 . (canceled) 
     
     
         20 . The oral pharmaceutical composition as recited in  claim 1 , comprising about 25 mg to about 350 mg of MGBG. 
     
     
         21 . The oral pharmaceutical composition as recited in  claim 1 , comprising about 250 mg to about 350 mg of MGBG. 
     
     
         22 . The oral pharmaceutical composition as recited in  claim 21 , which yields a therapeutically effective plasma level of MGBG for at least a 24 hour period in the subject with once-daily dosing. 
     
     
         23 . The oral pharmaceutical composition as recited in  claim 22  which does not have substantially dose-limiting side effects. 
     
     
         24 . The oral pharmaceutical composition as recited in  claim 1 , formulated as a tablet or capsule. 
     
     
         25 - 30 . (canceled) 
     
     
         31 . A method of treating or delaying the onset or development of a condition chosen from a proliferative disorder, an inflammatory disease, and an autoimmune disease, and neuropathy, comprising administering to a subject in need thereof a therapeutically effective amount of an oral pharmaceutical composition comprising MGBG and at least one pharmaceutically acceptable excipient. 
     
     
         32 . The method as recited in  claim 31 , wherein said oral pharmaceutical composition has an oral bioavailability of at least 30%. 
     
     
         33 . The method as recited in  claim 32 , wherein said oral pharmaceutical composition does not have substantially dose-limiting side effects. 
     
     
         34 - 39 . (canceled) 
     
     
         40 . The method as recited in  claim 31 , wherein the plasma level of MGBG is at least 75% of the peak plasma concentration for 4 or more hours. 
     
     
         41 . The method as recited in  claim 31 , wherein said oral pharmaceutical composition yields a therapeutically effective systemic plasma MGBG level for at least a 12-hour period when orally administered to a subject. 
     
     
         42 - 52 . (canceled)