Lyophilized anti-fungal composition

Abstract

A lyophilized anti-fungal composition comprises (A) caspofungin, or a pharmaceutically acceptable salt thereof, in an effective amount; (B) one or more non-reducing sugars having a glass transition temperature T g (s) of at least about 90° C.; and (C) an acetate buffer in an amount effective to provide a pH in a range of from about 5 to about 7; wherein the weight ratio of the one or more non-reducing sugars to caspofungin is in a range of from about 1.1:1 to about 10:1; the composition has a moisture content of about 0.8 wt. % or less; and the composition has a glass transition temperature T g (c) of at least about 55° C. The lyophilized composition has good storage stability at temperatures up to and including room temperature. The composition can be reconstituted for use in preventing or treating fungal infections.

1 . A lyophilized anti-fungal composition which comprises:
 (A) caspofungin, or a pharmaceutically acceptable salt thereof, in an effective amount;   (B) one or more non-reducing sugars having a glass transition temperature T g (s) of at least about 90° C.; and   (C) an acetate buffer in an amount effective to provide a pH in a range of from about 5 to about 7;   wherein:   the weight ratio of the one or more non-reducing sugars to caspofungin is in a range of from about 1.1:1 to about 10:1;   the composition has a moisture content of about 0.8 wt. % or less; and   the composition has a glass transition temperature T g (c) of at least about 55° C.   
     
     
         2 . The lyophilized composition according to  claim 1 , wherein trehalose is the non-reducing sugar. 
     
     
         3 . The lyophilized composition according to  claim 2 , wherein the moisture content of the composition is about 0.5 wt. % or less and the glass transition temperature T g (c) of the composition is at least about 90° C. 
     
     
         4 . The lyophilized composition according to  claim 1 , which is prepared by lyophilizing an aqueous solution comprising the caspofungin or its salt, the acetate buffer, and the one or more non-reducing sugars, wherein in the solution:
 (A) the caspofungin or its salt has a concentration in a range of from about 5 mg/mL to about 200 mg/mL;   (B) the one or more non-reducing sugars has a concentration ratio on a mg/mL basis with respect to caspofungin in a range of from about 2:1 to about 10:1; and   (C) the acetate buffer has a concentration in a range of from about 12.5 mM to about 200 mM.   
     
     
         5 . The lyophilized composition according to  claim 4 , wherein trehalsoe is the non-reducing sugar, the moisture content of the lyophilized composition is about 0.5 wt. % or less, and the glass transition temperature T g (c) of the lyophilized composition is at least about 90° C. 
     
     
         6 . The lyophilized composition according to  claim 5 , wherein in the aqueous solution from which the lyophilized composition is prepared:
 (A) the concentration of caspofungin or its salt is in a range of from about 30 mg/mL to about 50 mg/mL;   (B) the concentration ratio of trehalose to caspofungin is in a range of from about 4:1 to about 8:1; and   (C) the concentration of the acetate buffer is in a range of from about 20 mM to about 60 mM.   
     
     
         7 . The lyophilized composition according to  claim 6 , wherein in the aqueous solution from which the lyophilized composition is prepared:
 (A) the concentration of caspofungin or its salt is in a range of from about 30 mg/mL to about 50 mg/mL;   (B) the concentration of trehalose is in a range of from about 180 mg/mL to about 300 mg/mL; and   (C) the acetate buffer has a concentration in a range of from about 20 mM to about 60 mM.   
     
     
         8 . A process for preparing a lyophilized anti-fungal composition with a moisture content of less than about 0.8 wt. %, which comprises
 (A) preparing an aqueous solution with a pH in a range of from about 5 to about 7 and comprising an effective amount of caspofungin or a pharmaceutically acceptable salt thereof, one or more non-reducing sugars having a glass transition temperature T g (s) of at least about 90° C., and an acetate buffer, wherein the concentration ratio, on a weight per unit volume basis, of the one or more non-reducing sugars to caspofungin is in a range of from about 1.1:1 to about 10:1; and   (B) freeze-drying the aqueous solution to provide the lyophilized anti-fungal composition.   
     
     
         9 . The process according to  claim 8 , wherein Step A further comprises:
 (a1) dissolving the one or more non-reducing sugars in water;   (a2) adding acetic acid and then adjusting the pH to be in a range of from about 4.5 to about 5.5 by addition of base;   (a3) adding caspofungin or its salt and adjusting the pH to a value in a range of from about 5 to about 7 by addition of more base; and   (a4) optionally filtering the resulting aqueous solution.   
     
     
         10 . The process according to either  claim 8  or  claim 9 , wherein trehalose is the non-reducing sugar. 
     
     
         11 . The process according to  claim 10 , wherein in the aqueous solution resulting from Step A the caspofungin or its salt has a concentration in a range of from about 5 mg/mL to about 200 mg/mL, and the concentration ratio of trehalose to caspofungin is in a range of from about 2:1 to about 10:1. 
     
     
         12 . The process according to  claim 11 , wherein in the aqueous solution resulting from Step A the concentration of caspofungin or its salt is in a range of from about 30 mg/mL to about 50 mg/mL, and the concentration ratio of trehalose to caspofungin is in a range of from about 4:1 to about 8:1. 
     
     
         13 . The process according to any one of  claims 8  to  12 , wherein the moisture content of the resulting lyophilized composition is about 0.5 wt. % or less. 
     
     
         14 . A lyophilized anti-fungal composition prepared by the process set forth in any one of  claims 8  to  13 . 
     
     
         15 . A kit comprising a first container having the lyophilized anti-fungal composition according to any one of  claims 1  to  7  and  14  and a second container having a parenterally acceptable solvent for reconstitution thereof. 
     
     
         16 . A method of preparing an anti-fungal liquid formulation for parenteral administration, which comprises reconstituting the lyophilized anti-fungal composition according to any one of  claims 1  to  7  and  14  with a parenterally acceptable solvent to form an anti-fungal solution concentrate and then mixing the concentrate with a diluent comprising water to provide the formulation. 
     
     
         17 . The method according to  claim 16 , wherein the parenterally acceptable solvent comprises water. 
     
     
         18 . The method according to  claim 17 , wherein the parenterally acceptable solvent is selected from the group consisting of 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, and Bacteriostatic Water for Injection with 0.9% benzyl alcohol. 
     
     
         19 . The method according to  claim 18 , wherein the diluent is 0.9%, 0.45% or 0.225% Sodium Chloride Injection or Lactated Ringer's Injection. 
     
     
         20 . The method according to  claim 19  wherein the concentrate contains from about 5 mg/mL to about 8 mg/mL of caspofungin, and the liquid formulation resulting from dilution of the concentrate contains from about 0.2 mg/mL to about 0.5 mg/mL of caspofungin. 
     
     
         21 . An anti-fungal liquid dosage formulation for parenteral administration prepared by the method set forth in any one of  claims 16  to  20 . 
     
     
         22 . A method for the treatment or prophylaxis of a fungal infection which comprises parenterally administering to a subject in need thereof an anti-fungal liquid dosage formulation prepared by the method set forth in any one of  claims 16  to  20 .