Compositions containing opioid antagonists

Abstract

Compositions containing opioid antagonists, particularly alvimopan and its active metabolite, with improved solubility and bioavailability for oral or parenteral administration, injectable dosage formulations, kits, and methods of making and using same are disclosed. In preferred embodiments, invention provides injectable formulations containing opioid antagonists, particularly alvimopan and its active metabolite, having low solubility that may be readily prepared, are stable during storage, and provide maximum levels of opioid antagonists when administered parenterally, particularly via injection. The results are achieved by a combination of processing techniques and component selection.

What is claimed is: 
     
         1 . A method, comprising the steps of:
 a. providing a composition, comprising:
 (i) alvimopan 
 (ii) at least one bulking agent that crystallizes; 
 (iii) at least one weak base; and 
 (iv) water; 
 wherein said composition has an initial pH of at least about 10.5; and 
   b. adjusting the pH of said composition to a final pH in the range of about 9 to about 11;
 wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration. 
   
     
     
         2 . A method according to  claim 1 , further comprising the step of drying said composition to remove at least a portion of said water to form a partially or fully dried product. 
     
     
         3 . A method according to  claim 2 , further comprising the step of reconstituting said dried product by combining therewith a pharmaceutically acceptable solvent to form a solution of said dried product. 
     
     
         4 . A method according to  claim 1 ,
 wherein the initial pH is at least about 11.   
     
     
         5 . A method according to  claim 1 ,
 wherein the final pH is in the range of about 9.5 to about 10.5.   
     
     
         6 . A method according to  claim 1 ,
 wherein said composition is prepared by first admixing said bulking agent and a pharmaceutically-acceptable metal salt of said weak base in water and then adding said alvimopan.   
     
     
         7 . A method according to  claim 1 ,
 wherein said composition is prepared by substantially simultaneously admixing said alvimopan, said bulking agent and a pharmaceutically-acceptable metal salt of said weak base in water.   
     
     
         9 . A method according to  claim 1 ,
 wherein said weak base is bicarbonate or carbonate.   
     
     
         10 . A method according to  claim 1 ,
 wherein said weak base is carbonate.   
     
     
         11 . A method according to  claim 2 ,
 wherein said composition is annealed during said drying step.   
     
     
         12 . A method according to  claim 2 ,
 wherein said drying step comprises a process selected from the group consisting of lyophilization, spray drying, vacuum drying, and combinations thereof.   
     
     
         13 . A method according to  claim 12 ,
 wherein said process is lyophilization.   
     
     
         14 . A method according to  claim 3 ,
 wherein said solution is formed in less than about five minutes under ambient conditions.   
     
     
         15 . A method according to  claim 3 ,
 wherein said solution is formed in less than about one minute under ambient conditions.   
     
     
         16 . A method according to  claim 3 ,
 wherein said solution is formed in less than about 30 seconds under ambient conditions.   
     
     
         17 . A method according to  claim 3 ,
 wherein said pharmaceutically acceptable solvent is aqueous.   
     
     
         18 . A method according to  claim 17 ,
 wherein said pharmaceutically acceptable solvent is water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, or lactated Ringer's solution.   
     
     
         19 . A method according to  claim 3 , further comprising the step of administering said solution of said dried product to a patient. 
     
     
         20 . A method according to  claim 19 ,
 wherein said administering step occurs prior to surgery.   
     
     
         21 . A method according to  claim 19 ,
 wherein said administering step occurs during surgery.   
     
     
         22 . A method according to  claim 19 ,
 wherein said administering step is via a non-oral route.   
     
     
         23 . A method according to  claim 22 ,
 wherein said administering step is via injection.   
     
     
         24 . A method according to  claim 23 ,
 wherein said injection is subcutaneous, intramuscular, or intravenous.