Premixed amiodarone parenteral solution and method for making the same

Abstract

A premix parenteral solution for intravenous administration having amiodarone, as an active ingredient, solubilized in a solution of distilled water and about 0.4-12 mg/ml of a non-ionic surfactant to a concentration range of from 0.2 to 6 mg/ml is disclosed. The solution optionally may include an osmotic agent. No dilution of the solution is required before administering to a patient and the sterile packaged solution has an initial pH within the range of from about 2.9 to about 3.2, preferably about 3.1. Additionally, a method for producing an amiodarone solution suitable for intravenous administration is further disclosed.

We claim:  
     
         1 . A parenteral solution for intravenous administration comprising: 
 amiodarone, as an active ingredient, solubilized in a solution of distilled water and a non-ionic surfactant to a concentration range of from 0.2 to 6 mg/ml.;    optionally, an osmotic agent; and    wherein the solution requires no dilution before administering and has a pH within the range of from about 2.9 to about 3.2.    
     
     
         2 . The parenteral solution of  claim 1  wherein the osmotic agent is selected from the group consisting of dextrose, mannitol, sorbitol, glycerol, amino acids such as glycine, and salts such as sodium chloride.  
     
     
         3 . The parenteral solution of  claim 1  wherein the quantity of non-ionic surfactant is in the range of from about 0.4 to about 12 mg/ml.  
     
     
         4 . The parenteral solution of  claim 3  wherein the non-ionic surfactant is selected from the group consisting of an ethoxylated polysorbate such as polysorbate 80, an ethylene oxide/propylene oxide copolymer, a polyethoxylated castor oil, and a polyethylene glycol hydroxystearate such as SOLUTOL® HS-15.  
     
     
         5 . The parenteral solution of  claim 4  wherein the non-ionic surfactant is polysorbate 80.  
     
     
         6 . The parenteral solution of  claim 4  wherein the non-ionic surfactant is a polyethylene glycol hydroxystearate.  
     
     
         7 . The parenteral solution of  claim 1  wherein the pH of the solution is about 3.1.  
     
     
         8 . The parenteral solution of  claim 2  wherein the pH of the solution is about 3.1.  
     
     
         9 . The parenteral solution of  claim 3  wherein the pH of the solution is about 3.1.  
     
     
         10 . The parenteral solution of  claim 4  wherein the pH of the solution is about 3.1.  
     
     
         11 . A parenteral solution for intravenous administration comprising: 
 amiodarone, as an active ingredient, solubilized in a solution of distilled water and a non-ionic surfactant to a concentration range of from 0.2 to 6 mg/ml.;    optionally, an osmotic agent; and    wherein the solution is a sterilized premix.    
     
     
         12 . The parenteral solution of  claim 11  wherein the pH of the sterilized premix is in the range of from about 2.9 to about 3.2.  
     
     
         13 . The parenteral solution of  claim 12  wherein the pH of the sterilized premix is about 3.1.  
     
     
         14 . The parenteral solution of  claim 11  wherein the sterilized premix is refrigerated.  
     
     
         15 . The parenteral solution of  claim 14  wherein the sterilized premix is maintained at a temperature within the range of from 3 to about 10° C.  
     
     
         16 . A parenteral solution for intravenous administration comprising: 
 amiodarone, as an active ingredient, solubilized in a solution of distilled water and a non-ionic surfactant and wherein the solution requires no dilution before administering and has a drug degradation over time of less than 3% per year at room temperature.    
     
     
         17 . The parenteral solution of  claim 16  wherein the pH of the solution is within the range of from about 2.9 to about 3.2.  
     
     
         18 . The parenteral solution of  claim 17  wherein the pH of the solution is about 3.1.  
     
     
         19 . A parenteral solution for intravenous administration comprising: 
 amiodarone, as an active ingredient, solubilized in a solution of distilled water and a non-ionic surfactant to a concentration range of from 0.2 to 6 mg/ml.;    optionally, an osmotic agent; and    wherein the solution requires no dilution before administering and has a rate of total impurity formation of less than about 0.02% (w/v) total impurities/week at room temperature.    
     
     
         20 . The parenteral solution of  claim 19  wherein the pH of the solution is about 3.1.  
     
     
         21 . The parenteral solution of  claim 19  wherein the osmotic agent is selected from the group consisting of dextrose, mannitol, sorbitol, glycerol, amino acids such as glycine, and salts such as sodium chloride.  
     
     
         22 . The parenteral solution of  claim 19  wherein the quantity of non-ionic surfactant is in the range of from about 0.4 to about 12 mg/ml.  
     
     
         23 . The parenteral solution of  claim 22  wherein the non-ionic surfactant is selected from the group consisting of an ethoxylated polysorbate such as polysorbate 80, an ethylene oxide/propylene oxide copolymer, a polyethoxylated castor oil, and a polyethylene glycol hydroxystearate such as SOLUTOL® HS-15.  
     
     
         24 . A parenteral solution for intravenous administration comprising: 
 amiodarone, as an active ingredient, solubilized in a solution of distilled water and a non-ionic surfactant to a concentration range of from 0.2 to 6 mg/ml.;    optionally, an osmotic agent; and    wherein the solution requires no dilution before administering and has a drug adsorption of less than 3% in a plastic container which has a plastic surface area to solution volume ratio of approximately 4 cm 1 at room temperature.    
     
     
         25 . The parenteral solution of  claim 24  wherein the pH of the solution is about 3.1.  
     
     
         26 . A parenteral solution for intravenous administration consisting of: 
 amiodarone, as an active ingredient, solubilized in a solution of distilled water and about 0.4-12 mg/ml of a non-ionic surfactant to a concentration range of from 0.2 to 6 mg/ml.;    optionally, an osmotic agent; and    wherein the solution has a pH within the range of from about 2.9 to about 3.2.    
     
     
         27 . The parenteral solution of  claim 26  wherein the pH of the solution is about 3.1.  
     
     
         28 . The parenteral solution of  claim 27  wherein the osmotic agent is selected from the group consisting of dextrose, mannitol, sorbitol, glycerol, amino acids such as glycine, and salts such as sodium chloride.  
     
     
         29 . The parenteral solution of  claim 27  wherein the non-ionic surfactant is selected from the group consisting of an ethoxylated polysorbate such as polysorbate 80, an ethylene oxide/propylene oxide copolymer, a polyethoxylated castor oil, and a polyethylene glycol hydroxystearate such as SOLUTOL®HS-15.  
     
     
         30 . A parenteral solution for intravenous administration comprising: 
 amiodarone, as an active ingredient, solubilized in a solution of distilled water and a non-ionic surfactant to a concentration range of from 0.2 to 6 mg/ml.;    optionally, an osmotic agent; and    wherein the solution requires no dilution before administering and has minimal insoluble particle formation in a plastic container at room temperature.    
     
     
         31 . The parenteral solution of  claim 30  wherein the pH of the solution is about 3.1.  
     
     
         32 . A method for producing an amiodarone solution suitable for intravenous administration comprising the steps of: 
 (1) providing, as an active ingredient, an effective amount of an amiodarone solution;    (2) solubilizing the active ingredient in a water/surfactant solution to create a premix solution;    (3) diluting and cooling the premix solution;    (4) adjusting the pH of the premix solution with a suitable pH adjuster to an initial pH within the range of from about 2.9 to about 3.2;    (5) diluting the premix solution to the final active ingredient concentration; and    (6) filling suitable containers with the solution.    
     
     
         33 . The method of  claim 32  and further comprising the step of mixing into the premix solution an osmotic agent.  
     
     
         34 . The method of  claim 33  wherein the osmotic agent is selected from the group consisting of dextrose, mannitol, sorbitol, glycerol, amino acids, inorganic salts, and any combination thereof.  
     
     
         35 . The method of  claim 32  and further comprising the step of sterilizing the premix solution either before or after the filling step, by any suitable sterilization method.  
     
     
         36 . The method of  claim 32  wherein the pH of the premix solution is adjusted to about 3.1.