Azole pharmaceutical formulations for parenteral administration and methods for preparing and using the same as treatment of diseases sensitive to azole compounds

Abstract

A parenteral azole composition comprises a first solvent, made of benzyl alcohol and/or an acidified alcohol such as ethanol, and a lipophilic component such as PEG400, and the azole, or triazole, such as itraconazole or posaconazole dissolved in this first composite solvent vehicle that is essentially free of surfactants, particularly non-ionic surfactants, and has low levels of water, preferably less than 5% water. The composition may be further diluted with an infusion fluid, such as normal saline or 5% or 10% dextrose in water, before infusion into an immunocompromized mammal, preferably a human. The composition is useful for the treatment and suppression of infections caused by microbes such as yeast and molds that are sensitive to azoles, but it may be extended to dissolve other pharmaceutically active agents that can be used to treat other types of infectious diseases or other ailments, such as malignant and autoimmune diseases.

1 . A pharmaceutical composition suitable for parenteral administration comprising an azole pharmaceutical agent and a first solvent, said first solvent comprising a) an alcohol component selected from benzyl alcohol and/or acidified ethanol, and b) polyethylene glycol (PEG), wherein the azole agent is dissolved in said first solvent, wherein the composition is essentially free of non-ionic surfactants and comprises less than 5% water. 
     
     
         2 . The composition of  claim 1  wherein said first solvent comprises both ethanol and benzyl alcohol. 
     
     
         3 . The composition of  claim 1 , wherein the first solvent comprises acidified ethanol. 
     
     
         4 . The composition of  claim 3 , wherein the acidified ethanol is further defined as a combination of ethanol and an acid, and the first solvent has a pH of from about 1 to about 5. 
     
     
         5 . The composition of  claim 4 , wherein the first solvent has a pH of from about 3 to about 4. 
     
     
         6 . The composition of  claim 4 , wherein the acid is HCl, citric acid, acetic acid or glutamic acid. 
     
     
         7 . The composition of  claim 1 , wherein the ratio of PEG to alcohol is from 27 to 2. 
     
     
         8 . The composition of  claim 7 , wherein the ratio of PEG to alcohol is from 12 to 8. 
     
     
         9 . The composition of  claim 1 , wherein said PEG is selected from the group consisting of PEG-100, PEG-200, PEG-300, Peg-400 and PEG-800. 
     
     
         10 . The composition of  claim 9 , wherein the polyethylene glycol is PEG-400. 
     
     
         11 . The composition of  claim 1 , wherein the first solvent comprises from 10% to 90% (v/v) PEG. 
     
     
         12 . The composition of  claim 11 , wherein the first solvent comprises from 30% to 90% (v/v) PEG. 
     
     
         13 . The composition of  claim 1 , wherein the first solvent comprises from 40% to 80% (v/v) PEG. 
     
     
         14 . The composition of  claim 1 , wherein the alcohol component is from 1% to 99% of the first solvent. 
     
     
         15 . The composition of  claim 14 , wherein the alcohol component is from 5% to 60% of the first solvent. 
     
     
         16 . The composition of  claim 15 , wherein the alcohol component is from 10% to 40% of the first solvent. 
     
     
         17 . The composition of  claim 1 , wherein the azole pharmaceutical agent is an imidazole, triazole or thiazole. 
     
     
         18 . The composition of  claim 17 , wherein the azole pharmaceutical agent is miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole or abafungin. 
     
     
         19 . The composition of  claim 18 , wherein the azole agent is itraconazole. 
     
     
         20 . The composition of  claim 18 , wherein the azole agent is posconazole. 
     
     
         21 . The composition of  claim 1  wherein said composition comprises between 3 mg/ml to 25 mg/ml of the azole pharmaceutical agent. 
     
     
         22 . The composition of any one of  claims 1  through  21 , wherein the first solvent is diluted with an infusion fluid selected from the group consisting of normal saline, dextrose in water, and a lipid-based infusion emulsion fluid. 
     
     
         23 . The composition of  claim 22 , wherein said infusion fluid is dextrose in water. 
     
     
         24 . The composition of  claim 22 , wherein said composition comprises between 1 mg/ml and 5 mg/ml of the azole agent after dilution in said infusion fluid. 
     
     
         25 . The composition of  claim 22  wherein said composition is stable for at least 12 hours at room temperature. 
     
     
         26 . The composition of  claim 1 , further defined as comprising less than 3% water. 
     
     
         27 . The composition of  claim 26 , further defined as comprising less than 1% water. 
     
     
         28 . The composition of  claim 27 , further defined as essentially free of water. 
     
     
         29 . A method for preparing the composition of any one of  claims 1  through  28 , comprising admixing an a) alcohol component selected from benzyl alcohol and/or acidified ethanol, with b) polyethylene glycol (PEG), to form a first solvent and dissolving the azole agent in said first solvent. 
     
     
         30 . The method of  claim 29 , further comprising diluting the first solvent with an infusion fluid selected from the group consisting of normal saline, dextrose in water, and a lipid-based infusion emulsion fluid. 
     
     
         31 . A method for treating a patient having a disease sensitive to an azole pharmaceutical agent comprising parenterally administering a therapeutically effective amount of the composition of any one of  claims 22  through  25  to the patient. 
     
     
         32 . The method of  claim 31 , wherein the patient is a human. 
     
     
         33 . The method of  claim 31  wherein the disease is a fungal, yeast or mold disease. 
     
     
         34 . The method of  claim 33 , wherein the disease is a  Candida, Aspergillus  or  Mucorales  infection. 
     
     
         35 . The method of  claim 31  wherein the composition is administered intravascularly, intrathecally, subcutaneously, intramuscularly, or topically. 
     
     
         36 . A composition in accordance with any one of  claims 1  through  28 , or a composition prepared in accordance with any one of  claims 29 - 30 , for use in the treatment of a fungal, yeast or mold disease. 
     
     
         37 . The use of a composition in accordance with any one of  claims 1  through  28 , or a composition prepared in accordance with any one of  claims 29 - 30 , in the preparation of a medicament for the treatment of a fungal, yeast or mold disease.