Pharmaceutical formulation comprising glycine as a stabilizer

Abstract

The present invention provides pharmaceutical formulations suitable for intravenous injection comprising a lyophilized anti-ulcerative agent reconstituted in isotonic solutions suitable for intravenous administration, such as 5% dextrose or 0.9% sodium chloride. The solutions are brought to a pH of between about 9 and about 12, preferably between about pH 10 and 11, by a glycine-sodium hydroxide buffer. Such formulations are chemically and physically stable, and do not significantly change color, for at least between about 6 and about 12 hours at room temperature, and are stable to color change for from between about 24 and 48 hours if kept at 5° C.

1 . An intravenous aqueous pharmaceutical formulation comprising: 
 (a) an anti-ulcerative compound having the following formula:                          or a pharmaceutically acceptable salt thereof;    (b) glycine;    (c) sodium hydroxide; and    (c) a tonicity agent;    wherein said formulation has a concentration of glycine of between about 100 and 300 mM.    
   
   
       2 . The intravenous aqueous pharmaceutical formulation of  claim 1 , wherein said anti-ulcerative compound is present in the formulation in an amount of between about 5 and 50 mg.  
   
   
       3 . The intravenous aqueous pharmaceutical formulation of  claim 2 , wherein said anti-ulcerative compound is present in the formulation in an amount of about 10 mg.  
   
   
       4 . The intravenous aqueous pharmaceutical formulation of  claim 2 , wherein said anti-ulcerative compound in present in the formulation in an amount of about 20 mg.  
   
   
       5 . The intravenous aqueous pharmaceutical formulation of  claim 4 , wherein the glycine is has a concentration of between about 100 and 200 mM.  
   
   
       6 . The intravenous aqueous pharmaceutical formulation of  claim 5 , wherein the glycine has a concentration of about 149 mM.  
   
   
       7 . The intravenous aqueous pharmaceutical formulation of  claim 1 , wherein the tonicity agent is selected from the group consisting of sodium chloride, glycerin, mannitol, sucrose, lactose and dextrose.  
   
   
       8 . The intravenous aqueous pharmaceutical formulation of  claim 7 , wherein the tonicity agent is mannitol.  
   
   
       9 . The intravenous aqueous pharmaceutical formulation of  claim 1 , wherein the formulation has a pH of between about 9 and about 12.  
   
   
       10 . A method for stabilizing anti-ulcerative formulations suitable for intravenous injection which comprises the steps of: 
 (a) providing a compound of the formula                          or a pharmaceutically acceptable salt thereof;    (b) providing a solution suitable for intravenous injection which has a pH of between about 10 and 11 and which comprises glycine, sodium hydroxide and a tonicity agent; wherein the glycine in said solution has a concentration of between about 100 and 300 mM; and    admixing said compound and said solution until said compound is dissolved in said solution.    
   
   
       11 . The method of  claim 10 , where said tonicity agent is selected from the group consisting of sodium chloride, glycerin, mannitol, sucrose, lactose and dextrose.  
   
   
       12 . The method of  claim 11 , wherein the tonicity agent is mannitol.  
   
   
       13 . A lyophilized pharmaceutical formulation in a sealable container, wherein said formulation comprises: 
 (a) an anti-ulcerative compound having the following formula:                          or a pharmaceutically acceptable salt thereof;    (b) glycine;    (c) sodium hydroxide; and    (c) a tonicity agent;    wherein said formulation has a concentration of glycine of between about 100 and 300 mM; and    wherein said container is sealed such that exchange of air between the inside of the sealable contained and the external environment of the container is not possible.    
   
   
       14 . The lyophilized pharmaceutical formulation of  claim 13 , where said tonicity agent is selected from the group consisting of sodium chloride, glycerin, mannitol, sucrose, lactose and dextrose.  
   
   
       15 . The lyophilized pharmaceutical formulation of  claim 14 , where said tonicity agent is mannitol.