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.

What is claimed is:  
     
         1 . A method for preventing or treating a peptic ulcer in a person requiring the same comprising intravenously administering to the person an effective amount of a pharmaceutical formulation having a pH between about 10 and about 11; 
 wherein the pharmaceutical formulation comprises glycine at a concentration between about 1 mM and about 300 mM; sodium hydroxide; a tonicity agent selected from the group consisting of dextrose and sodium chloride; and a compound of formula (C) or a pharmaceutically acceptable salt thereof;    wherein the compound of formula (C) is:                          or a stereoisomer thereof.    
     
     
         2 . A method for preventing or treating a disorder associated with the secretion of gastric acid in a person requiring the same comprising administering to the person an aqueous pharmaceutical formulation suitable for intravenous injection comprising glycine and a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier; 
 wherein the compound of formula (I) is:                          or a stereoisomer thereof;    wherein R 1  and R 2  are each independently a hydrogen atom, a halogen atom, a lower alkyl, lower alkoxy, a halogenated lower alkyl, a lower alkoxycarbonyl or carboxyl group;    X is —O—, —S— or ═N—R 3 , wherein R 3  is a hydrogen atom, a lower alkyl, phenyl, benzyl or lower alkoxycarbonyl group; and    Z is: 
 1. —O(CH 2 ) p —O—R 4  
 wherein p is an integer of 1 to 3 and R 4  is hydrogen atom or a lower alkyl, aryl or aralkyl group,  
 
 2. —O—(CH 2 ) q —R 5  
 wherein q is an integer of 1 to 3 and R is a halogen atom or an alkoxycarbonyl, aryl or heteroaryl group,  
 
 3. —O—(CH 2 ) r —O—(CH 2 ) s —O—R 6  
 wherein r and s are each independently an integer of 1 to 5 and R 6  is a hydrogen atom or a lower alkyl group,  
                     
 
 7. —S(O) t —A 
 wherein t is an integer of 0 to 2, and A is a lower alkyl, alkoxycarbonylmethyl, pyridyl, furyl,  
                     
 wherein P is —NH—, —O— or —S—; R 7  is hydrogen or lower alkyl; and w is an integer of 0or 3;  
 
 8. —N(R 8 )—CH 2 —C 6 H 5  
 wherein R 8  is an acetoxy or lower alkyl group;  
 
 9. —OR 9  
 wherein R 9  is a hydrogen atom, a lower alkyl or aryl group; n is an integer of 0 to 2; m is an integer of 2 to 10, and J and K are each independently a hydrogen atom or a lower alkyl group; with the proviso that when Z is a group falling under the above category (9), then R 9  is a lower alkyl group and m is an integer of 3 to 10.  
 
   
     
     
         3 . The method of  claim 2 , wherein the disorder associated with the secretion of gastric acid is a peptic ulcer.  
     
     
         4 . The method of  claim 2 , wherein the disorder associated with the secretion of gastric acid is heartburn.  
     
     
         5 . The method of  claim 2 , wherein the disorder associated with the secretion of gastric acid is gastroesophageal reflux.  
     
     
         6 . The method of  claim 2 , wherein the aqueous pharmaceutical formulation further comprises a tonicity agent.  
     
     
         7 . The method of  claim 6 , wherein the tonicity agent is sodium chloride, glycerin, mannitol, sucrose, lactose, or dextrose.  
     
     
         8 . The method of  claim 2 , wherein the aqueous pharmaceutical formulation has a pH between about 9 and about 12, and wherein the glycine in the aqueous pharmaceutical formulation is present at a concentration of between about 1 mM and about 300 mM.  
     
     
         9 . The method of  claim 2 , wherein the aqueous pharmaceutical formulation further comprises sodium hydroxide.  
     
     
         10 . The method of  claim 2 , comprising administering the aqueous pharmaceutical formulation to the person intravenously.  
     
     
         11 . The method of  claim 2 , wherein the pharmaceutical formulation has an alkaline pH, and wherein the glycine in the formulation is present at a concentration between about 1 mM and about 300 mM.  
     
     
         12 . The method of  claim 11 , wherein the alkaline pH is between about 9 and about 12.  
     
     
         13 . The method of  claim 2 , wherein the aqueous pharmaceutical formulation further comprises sodium hydroxide and a tonicity agent; and wherein the compound of formula (I) is a compound of formula (A) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof; 
 wherein R 1  and R 2  each independently a hydrogen, a lower alkyl, a lower alkoxy, a halogenated lower alkyl, a lower alkoxycarbonyl, a carboxyl or a halogen;  
 R 9  is hydrogen, lower alkyl or aryl;  
 J is hydrogen or lower alkyl;  
 m is an integer from 2 to 10.  
 
     
     
         14 . The method of  claim 13 , wherein the tonicity agent is sodium chloride or dextrose.  
     
     
         15 . The method of  claim 2 , wherein the aqueous pharmaceutical formulation further comprises sodium hydroxide and a tonicity agent; and wherein the compound of formula (I) is a compound of formula (B) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof; 
 wherein R 1  and R 2  are each independently a hydrogen, a lower alkyl, a lower alkoxy, a halogenated lower alkyl, a lower alkoxycarbonyl, a carboxy, or a halogen;  
 R 9  is a hydrogen, a lower alkyl, or an aryl;  
 J is a hydrogen or a lower alkyl; and  
 m is an integer from 2 to 10.  
 
     
     
         16 . The method of  claim 15 , wherein the tonicity agent is sodium chloride or dextrose.  
     
     
         17 . The method of  claim 2 , wherein the compound of formula (I) is a compound of formula (C) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof.  
     
     
         18 . The method of  claim 17 , wherein the aqueous pharmaceutical formulation further comprises sodium chloride or dextrose.  
     
     
         19 . The method of  claim 17 , wherein the aqueous pharmaceutical formulation further comprises dextrose in a concentration of about 5% by weight.  
     
     
         20 . The method of  claim 17 , wherein the aqueous pharmaceutical formulation further comprises sodium chloride in a concentration of about 0.9% by weight.  
     
     
         21 . The method of  claim 18 , wherein the aqueous pharmaceutical formulation has a pH between about 9 and about 12, and wherein the glycine in the aqueous pharmaceutical formulation is present at a concentration between about 1 mM and about 300 mM.  
     
     
         22 . The method of  claim 2 , wherein the concentration of the compound of formula (I) is between about 1 mg/ml and 50 mg/ml.