Method of solubilizing and encapsulating itraconazole

Abstract

Methods for preparing microspheres containing imidazole derivatives are provided. Also provided is the use of imidazole derivatives containing microspheres for treating fungal infections. Oral dosage forms for oral administration are also provided.

What is claimed is:  
     
         1 . A solution comprising: 
 (a) at least about 2.5 parts by weight, based upon 100 parts by weight of solution, of a solute having the formula                        wherein R, R 1 , and R  2  are independently hydrogen or lower alkyl;    R 3  is hydrogen, methyl or ethyl;    R 4  is hydrogen or methyl    Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;    Ar 1  is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and    n is 1 or 2; and      (b) a solubilizing effective amount of a solvent comprising at least one volatile organic acid.    
     
     
         2 . A solution as defined in  claim 1 , wherein said solute comprises itraconazole.  
     
     
         3 . A solution as defined in  claim 1 , wherein said solvent comprises an aqueous solution of said acid.  
     
     
         4 . A solution as defined in  claim 3 , wherein said solvent comprises aqueous acetic acid.  
     
     
         5 . A solution is defined as in  claim 3 , wherein said solvent comprises aqueous formic acid.  
     
     
         6 . A solution is defined in  claim 1 , wherein said solution comprises from about 3 to about 40 percent by weight of solute and from about 60 to about 97 parts by weight of solvent based upon 100 parts by weight of solution.  
     
     
         7 . A solution as defined in  claim 3 , wherein said solvent comprises from about 30 to about 80 parts by volume of acid and from about 70 to about 20 parts by volume of water, based upon 100 parts by volume of solvent.  
     
     
         8 . A solution as defined in  claim 7 , wherein said solvent comprises from about 40 to about 50 parts by volume weight of acid and from about 60 to about 50 parts by volume of water, based upon 100 parts by volume of solvent.  
     
     
         9 . A solution is defined in  claim 3 , wherein the volume:volume ratio of acid to water in said solvent is at least about 3:7.  
     
     
         10 . A microsphere comprising 
 (a) an imidazole derivative active agent having the formula                        wherein R, R 1 , and R 2  are independently hydrogen or lower alkyl;    R 3  is hydrogen, methyl or ethyl;    R 4  is hydrogen or methyl    Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;    Ar 1  is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and    n is 1 or 2; and      (b) a microsphere forming carrier selected from the group consisting of 
 (i) a proteinoid;  
 (ii) an acylated amino acid or poly amino acid or a salt thereof;  
 (iii) a sulfonated amino acid or poly amino acid or a salt thereof;  
 (iv) a protein or a salt thereof;  
 (v) an enteric coating material; or  
 (vi) any combination thereof.  
   
     
     
         11 . A microsphere as defined in  claim 10 , wherein said imidazole derivative active agent comprises itraconazole.  
     
     
         12 . A method for preparing imidazole derivative active agent containing microspheres, said method comprising 
 (A) nebulizing a solution comprising 
 (a) an imidazole active agent having the formula  
                     wherein R, R 1 , and R 2  are independently hydrogen or lower alkyl;    R 3  is hydrogen, methyl or ethyl;    R 4  is hydrogen or methyl    Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;    Ar 1  is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and    n is 1 or 2;    
 (b) a microsphere forming carrier selected from the group consisting of 
 (i) a proteinoid;  
 (ii) an acylated amino acid or poly amino acid or a salt thereof;  
 (iii) a sulfonated amino acid or poly amino acid or a salt thereof;  
 (iv) a protein or a salt thereof;  
 (v) an enteric coating material; or  
 (vi) any combination thereof; and  
 
 (c) an active agent and carrier solubilizing effective amount of a solvent comprising an aqueous solution of at least one volatile organic acid; 
 wherein the volume:volume ratio of acid to water in said solvent is at least about 3:7; and  
 
   (B) decreasing said ratio to less than about 3:7, to yield said microspheres.    
     
     
         13 . A method as defined in  claim 12 , wherein said imidazole derivative active agent comprises itraconazole.  
     
     
         14 . A method as defined in  claim 12 , wherein said aqueous solution comprises aqueous acetic acid.  
     
     
         15 . A method as defined in  claim 12 , wherein said nebulizing is performed by spray drying.  
     
     
         16 . A method wherein said ratio is decreased by volatilizing at least a portion of said acid.  
     
     
         17 . A method wherein said ratio is decreased by diluting said acid.  
     
     
         18 . A method for preparing imidazole derivative active agent containing microspheres, said method comprising 
 (A) nebulizing 
 (a) a solution comprising 
 (i) an imidazole active agent having the formula  
                     wherein R, R 1 , and R 2  are independently hydrogen or lower alkyl;    R 3  is hydrogen, methyl or ethyl;    R 4  is hydrogen or methyl    Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;    Ar 1  is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and    n is 1 or 2; and    
 (ii) an active agent solubilizing effective amount of a solvent comprising an aqueous solution of at least one volatile organic acid; 
 wherein the volume:volume ratio of acid to water in said solvent is at least about 3:7; and  
 
 
 (b) a solution of a microsphere forming carrier selected from the group consisting of 
 (i) a proteinoid;  
 (ii) an acylated amino acid or poly amino acid or a salt thereof;  
 (iii) a sulfonated amino acid or poly amino acid or a salt thereof;  
 (iv) a protein or a salt thereof;  
 (v) an enteric coating material; or  
 (vi) any combination thereof; and  
 
   (B) decreasing said ratio to less than about 3:7, to yield said microspheres.    
     
     
         19 . A method for administering itraconazole to an animal in need of such treatment, such method comprising 
 (A) preparing a composition as defined in  claim 10 , and    (B) orally administering said composition to said animal.    
     
     
         20 . A method for treating a fungal infection in an animal in need of such treatment, said method comprising administering to said animal a therapeutically effective amount of a composition as defined in  claim 10.