Acetylcysteine Composition and Uses Thereof

Abstract

This invention relates to novel acetylcysteine compositions in solution, comprising acetylcysteine and which are substantially free of metal chelating agents, such as EDTA. Further, this invention relates to methods of making and using the acetylcysteine compositions. The present compositions and methods are designed to improve patient tolerance and compliance, while at the same time maintaining the stability of the pharmaceutical formulation. The compositions and methods of this invention are useful in the treatment of acetaminophen overdose, acute liver failure, various cancers, methacrylonitrile poisoning, reperfusion injury during cardio bypass surgery, and radiocontrast-induced nephropathy, and can also be used as a mucolytic agent.

1 . An aqueous pharmaceutical composition comprising acetylcysteine, wherein the composition is substantially free of EDTA or pharmaceutically acceptable salts thereof. 
     
     
         2 . An aqueous pharmaceutical composition comprising acetylcysteine, wherein the composition contains less than 0.05% w/v EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         3 . The aqueous pharmaceutical composition of  claim 2 , wherein the composition contains less than 0.02% w/v EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         4 . The aqueous pharmaceutical composition of  claim 3 , wherein the composition contains no EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         5 . The aqueous pharmaceutical composition of claim or  2 , wherein the pH of the composition is from 6 to 8. 
     
     
         6 . The aqueous pharmaceutical composition of  claim 5 , wherein the pH of the composition is from 6.5 to 7.0. 
     
     
         7 . The aqueous pharmaceutical composition of  claim 6 , wherein the pH of the composition is 6.8. 
     
     
         8 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition is stable for at least 12 months at 25° C. 
     
     
         9 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition is stable for at least 6 months at 40° C. 
     
     
         10 . An aqueous pharmaceutical composition consisting of from 10 to 400 mg/mL acetylcysteine, dissolved in deaerated water, and wherein the pH of the composition is adjusted with a pH-adjusting agent to a pH of from 6 to 8. 
     
     
         11 . A method of treating acetaminophen overdose, comprising administering to a patient in need thereof an effective amount of an aqueous composition of acetylcysteine, wherein said composition is substantially free of EDTA or pharmaceutically acceptable salts thereof. 
     
     
         12 . A method of treating acetaminophen overdose, comprising administering to a patient in need thereof an effective amount of an aqueous composition of acetylcysteine, wherein said composition contains less than 0.05% w/v EDTA or pharmaceutically acceptable salts thereof. 
     
     
         13 . The method of  claim 12 , wherein the composition contains less than 0.02% w/v EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         14 . The method of  claim 13 , wherein the composition contains no EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         15 . The method of  claim 11 , wherein the pH of the composition is from 6 to 8. 
     
     
         16 . The method of  claim 15 , wherein the pH of the composition is from 6.5 to 7.0. 
     
     
         17 . The method of  claim 16 , wherein the pH of the composition is 6.8. 
     
     
         18 . The method of  claim 11 , wherein the administration occurs via intravenous injection, orally, or by inhalation. 
     
     
         19 . The method of  claim 18  wherein the method of administration occurs via intravenous injection. 
     
     
         20 . The method of  claim 11 , wherein the composition is mixed in an aqueous solution of at least one of dextrose and sodium chloride prior to administration. 
     
     
         21 . The method of  claim 20 , wherein the composition is mixed in an aqueous solution of 5% w/v dextrose prior to administration. 
     
     
         22 . The method of  claim 20 , wherein the composition is mixed in an aqueous solution of 0.45% or 0.90% w/v sodium chloride prior to administration. 
     
     
         23 . A method of making an aqueous acetylcysteine pharmaceutical composition, comprising dissolving acetylcysteine in deaerated water and adding a basic agent to achieve a pH of 6 to 8, wherein the composition is substantially tree of EDTA or pharmaceutically acceptable salts thereof. 
     
     
         24 . A method of making an aqueous acetylcysteine pharmaceutical composition, comprising dissolving acetylcysteine in deaerated water and adding a basic agent to achieve a pH of 6 to 8, wherein the composition contains less than 0.05% w/v EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         25 . The method of  claim 23 , wherein the method further comprises passing the solution through a sterilizing filter and filling under an inert atmosphere. 
     
     
         26 . The method of  claim 24 , wherein the composition contains less than 0.02% w/v EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         27 . The method of  claim 26 , wherein the composition contains no EDTA, or pharmaceutically acceptable salts thereof. 
     
     
         28 . The method of  claim 23 , wherein the pH of the composition is from 6.5 to 7.0. 
     
     
         29 . The method of  claim 28 , wherein the pH of the composition is 6.8. 
     
     
         30 . The method of  claim 23 , wherein the composition is stable for at least 6 months at 25° C. 
     
     
         31 . The method of  claim 23 , wherein the composition is stable for at least 6 months at 40° C. 
     
     
         32 . The method of  claim 23 , wherein the basic agent is sodium hydroxide. 
     
     
         33 . A method of treating liver failure, comprising:
 using a stable aqueous pharmaceutical composition comprising from 10 to 250 mg/mL acetylcysteine or pharmaceutically acceptable salts thereof, wherein the composition contains less than 0.05% w/v chelating agents, wherein said composition is in a suitable form for intravenous administration;   diluting the composition in an aqueous solution; and   administering the diluted composition to a patient in need thereof.   
     
     
         34 . The method of  claim 33 , wherein the pH of the composition in an undiluted state is from 5 to 9. 
     
     
         35 . The method of  claim 33 , wherein the pH of the composition in an undiluted state is from 6.0 to 7.5. 
     
     
         36 . The method of  claim 33 , wherein the composition in an undiluted state comprises from 100 to 250 mg/mL acetylcysteine or pharmaceutically acceptable salts thereof. 
     
     
         37 . The method of  claim 33 , wherein the composition in an undiluted state comprises about 200 mg/mL acetylcysteine or pharmaceutically acceptable salts thereof. 
     
     
         38 . The method of  claim 33 , wherein the diluted composition is administered as a loading dose of about 150 mg/kg, followed by a second dose of about 50 mg/kg. 
     
     
         39 . The method of  claim 33 , wherein the diluted composition is administered as a loading dose over a period of 15 minutes to 2 hours, followed by a second dose over about 4 hours. 
     
     
         40 . The method of  claim 33 , wherein the aqueous solution comprises at least one of 5% dextrose, 0.45% sodium chloride, and water for injection. 
     
     
         41 . The method of  claim 33 , wherein the composition contains less than 0.02% chelating agents. 
     
     
         42 . The method of  claim 33 , wherein the liver failure is acute liver failure. 
     
     
         43 . The method of  claim 33 , wherein said composition is sealed in an airtight container comprising a fill volume of said composition and a headspace volume occupied by a pharmaceutically inert gas. 
     
     
         44 . The method of  claim 33 , wherein chelating agents are not added to the composition but may be present as an impurity or undesired contaminant. 
     
     
         45 . The method of  claim 33 , wherein the composition is free of chelating agents.