Process for producing a stable low concentration, injectable solution of noradrenaline

Abstract

In a first aspect, the present invention relates to a process for producing a stable, injectable solution with low content of noradrenaline, which includes dissolving noradrenaline and optionally an excipient in deoxygenated or degassed water, filtrating the resulting noradrenaline solution in a nitrogen current, distributing the solution in a nitrogen current, and sterilization, preferably hot. The invention further provides a stable, injectable solution with low content of noradrenaline, substantially free of anti-oxidizing and preservative agents, as well as uses thereof in the medical and pharmaceutical fields.

The invention claimed is: 
     
       1. A stable injectable noradrenaline solution comprising noradrenaline, a solvent, an excipient, and hydrochloric acid, wherein the amount of noradrenaline is from 0.04 to 0.2 mg/ml, the solvent is degassed or deaerated water, the excipient is NaCl, and the pH of the solution is in the range of from 3.3 to 3.6, and wherein the solution is free of preservatives and anti-oxidizing agents. 
     
     
       2. The stable injectable noradrenaline solution according to  claim 1 , obtained by a process comprising:
 a. dissolving noradrenaline and the excipient in deoxygenated or degassed water, to obtain a concentration of noradrenaline from 0.04 to 0.20 mg/ml,   b. adjusting the pH of the resulting solution by adding hydrochloric acid until a value in the range from 3.3 to 3.6 is achieved,   c. filtrating the resulting noradrenaline solution in an inert gas current,   d. distributing the noradrenaline solution in an inert gas current,   e. sterilizing the noradrenaline solution.   
     
     
       3. The stable injectable noradrenaline solution according to  claim 1 , oxygen content is equal to or lower than 100 ppb. 
     
     
       4. A container of a low concentration, preservative free, anti-oxidant-free, injectable noradrenaline bitartrate solution made by a process comprising the following steps in the substantial absence of air or oxygen:
 a) dissolving noradrenaline bitartrate in deoxygenated or degassed water to make a solution having a noradrenaline bitartrate concentration less than 1 mg/ml based on the weight of noradrenaline base;   b) adjusting the pH of the solution by adding hydrochloric acid until a value of from 3.3 to 3.6 is achieved;   c) filtrating the solution in an inert gas current;   d) distributing the solution into said one or more containers in a current of an inert gas; and   e) sterilizing the solution;   wherein said sterilizing comprises filtrating or heat sterilizing.    
     
     
       5. The container of claim 4, wherein:
 a) the solution is preservative-free, antioxidant-free, and free of complexing agents;   b) after six months storage at 25° C., the solution comprises based on the weight of the noradrenaline base:
 i) <0.2% arterenone; 
 ii) <0.5% impurities other than arterenone; and 
 iii) <10% d-noradrenaline; 
   c) the solution comprises less than 0.2 mg/ml noradrenaline bitartrate based on the weight of the weight of noradrenaline base; and   d) the deoxygenated or degassed water comprises less than 100 ppb oxygen.    
     
     
       6. The container of claim 4, wherein:
 a) after six months storage at 25° C., the solution comprises based on the weight of the noradrenaline base:
 i) <0.2% arterenone; 
 ii) <0.5% impurities other than arterenone; and 
 iii) <10% d-noradrenaline; 
   b) the solution comprises less than 0.2 mg/ml noradrenaline bitartrate based on the weight of the weight of noradrenaline base; and   c) the deoxygenated or degassed water comprises less than 100 ppb oxygen; and   d) said sterilizing comprises filtrating during step (c).