Controlled release oral pharmaceutical dosage forms comprising mgbg

Abstract

Disclosed herein are controlled-release oral pharmaceutical dosage forms comprising MGBG, and their application for the improved treatment of diseases with reduced side effects and/or longer time at maximum concentration.

1 . A controlled-release oral pharmaceutical dosage form comprising MGBG. 
     
     
         2 . The oral pharmaceutical dosage form as recited in  claim 1 , wherein the dosage form is chosen from extended-release, sustained-release, delayed-release, and pulsed-release. 
     
     
         3 . The oral pharmaceutical dosage form as recited in  claim 2 , wherein the dosage form is a delayed-release tablet or a delayed-release capsule. 
     
     
         4 . The oral pharmaceutical dosage form as recited in  claim 3 , wherein the dosage form is a delayed-release capsule comprising an enteric coating. 
     
     
         5 . The oral pharmaceutical dosage form as recited in  claim 4 , comprising about 25 to about 350 mg MGBG. 
     
     
         6 . The oral pharmaceutical dosage form as recited in  claim 4 , wherein the enteric coating begins to substantially dissolve, and drug release commences, in the duodenum. 
     
     
         7 . The oral pharmaceutical dosage form as recited in  claim 4 , wherein the enteric coating begins to substantially dissolve and drug release commences at about or more hours after ingestion. 
     
     
         8 . The oral pharmaceutical dosage form as recited in  claim 4 , wherein the enteric coating begins to substantially dissolve and drug release commences at about 1 or more hours after ingestion. 
     
     
         9 . The oral pharmaceutical composition as recited in  claim 4 , which has reduced side effects in patients compared to a non-enterically-coated capsule. 
     
     
         10 . The oral pharmaceutical composition as recited in  claim 4 , which has reduced dose-limiting side effects as compared to a non-enterically-coated capsule. 
     
     
         11 . The oral pharmaceutical dosage form as recited in  claim 9 , wherein said side effects are gastrointestinal. 
     
     
         12 . The oral pharmaceutical composition as recited in  claim 11 , which is orally bioavailable. 
     
     
         13 . The oral pharmaceutical dosage form as recited in  claim 11 , wherein said gastrointestinal side effects are chosen from nausea, emesis, diarrhea, abdominal pain, oral mucositis, oral ulceration, pharyngitis, stomatitis, irritation of the gastric mucosa, and gastrointestinal ulceration. 
     
     
         14 . The oral pharmaceutical composition as recited in  claim 4 , wherein emesis is reduced by at least 50% compared to a reference standard that is not enterically coated. 
     
     
         15 . The oral pharmaceutical composition as recited in  claim 4 , wherein emesis is reduced by at least 70% compared to a reference standard that is not enterically coated. 
     
     
         16 . The oral pharmaceutical composition as recited in  claim 4 , wherein emesis is reduced by at least 80% compared to a reference standard that is not enterically coated. 
     
     
         17 . The oral pharmaceutical dosage form as recited in  claim 11 , 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. 
     
     
         18 . The oral pharmaceutical dosage form as recited in  claim 4 , which exhibits dose-proportional increases in C max  and AUC. 
     
     
         19 . The oral pharmaceutical dosage form as recited in  claim 4 , which exhibits a half life comparable to a reference standard that is not enterically coated. 
     
     
         20 . A delayed-release oral pharmaceutical dosage form comprising MGBG dihydrochloride hydrate in capsule enterically-coated for duodenal release. 
     
     
         21 . The delayed-release oral pharmaceutical dosage form as recited in  claim 20 , wherein the enteric coating comprises a methacrylic acid/ethyl acrylate copolymer. 
     
     
         22 . The delayed-release oral pharmaceutical dosage form as recited in  claim 21 , wherein the methacrylic acid/ethyl acrylate copolymer is Eudragit® L100-55. 
     
     
         23 . The delayed-release oral pharmaceutical dosage form as recited in  claim 21 , wherein the capsule comprises 25-350 mg MGBG. 
     
     
         24 . The delayed-release oral pharmaceutical dosage form as recited in  claim 23 , reduced gastrointestinal side effects in patients compared to a non-enterically-coated capsule. 
     
     
         25 . A method of treating pain comprising the administration, to a patient in need thereof, a delayed-release oral pharmaceutical dosage form comprising MGBG. 
     
     
         26 . The method as recited in  claim 25 , wherein said delayed-release oral pharmaceutical dosage form is an enterically-coated capsule comprising MGBG. 
     
     
         27 . The method as recited in  claim 26 , wherein the administration of the enterically-coated capsule comprising MGBG results in a reduction of gastrointestinal side effects when compared to a reference standard that is not enterically coated. 
     
     
         28 . The method as recited in  claim 27 , wherein said gastrointestinal side effects are chosen from nausea, emesis, diarrhea, abdominal pain, oral mucositis, oral ulceration, pharyngitis, stomatitis, irritation of the gastric mucosa, and gastrointestinal ulceration. 
     
     
         29 . The method as recited in  claim 28 , wherein said gastrointestinal side effect is emesis. 
     
     
         30 . The method as recited in  claim 27 , wherein MGBG is administered at a dosage level which would result in dose-limiting side effects if administered as a non-enteric coated dosage form.