Daptomycin formulations and uses thereof

Abstract

Lyophilized daptomycin formulations having improved reconstitution times are provided. The lyophilized daptomycin formulations include an additive, which can be a pharmaceutically acceptable antioxidant, a pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable glucose derivative or a pharmaceutically acceptable salt thereof, or a combination thereof. Also provided are methods of methods of preparing the lyophilized daptomycin formulations, and methods of treating bacterial infections and treating or preventing biofilms by using the lyophilized daptomycin formulations.

What is claimed is: 
     
         1 . A lyophilized daptomycin formulation comprising daptomycin and an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof. 
     
     
         2 . The lyophilized daptomycin formulation of  claim 1 , wherein the formulation comprises from about 200 mg to about 600 mg of daptomycin. 
     
     
         3 . The lyophilized daptomycin formulation of  claim 1 , wherein the formulation comprises from about 0.01 mM to about 500 mM of the additive. 
     
     
         4 . The lyophilized daptomycin formulation of  claim 1 , wherein the pharmaceutically acceptable antioxidant is ascorbic acid. 
     
     
         5 . The lyophilized daptomycin formulation of  claim 1 , wherein the pharmaceutically acceptable organic acid is selected from the group consisting of monocarboxylic organic acids, dicarboxylic organic acids, hydroxyl substituted dicarboxylic organic acids, tricarboxylic organic acids, hydroxyl substituted tricarboxylic organic acids, tetracarboxylic organic acids, and combinations thereof. 
     
     
         6 . The lyophilized daptomycin formulation of  claim 5 , wherein the pharmaceutically acceptable organic acid is a hydroxyl substituted tricarboxylic organic acid. 
     
     
         7 . The lyophilized daptomycin formulation of  claim 6 , wherein the hydroxyl substituted tricarboxylic organic acid is citric acid. 
     
     
         8 . The lyophilized daptomycin formulation of  claim 1 , wherein the pharmaceutically acceptable glucose derivative is acetyl glucosamine. 
     
     
         9 . The lyophilized daptomycin formulation of  claim 1 , wherein when the formulation is reconstituted in a pharmaceutically acceptable diluent to obtain a reconstituted lyophilized daptomycin formulation. 
     
     
         10 . The lyophilized daptomycin formulation of  claim 9 , wherein the formulation is reconstituted in the pharmaceutically acceptable diluent in less than about 5 minutes. 
     
     
         11 . The lyophilized daptomycin formulation of  claim 9 , wherein the concentration of daptomycin in the reconstituted lyophilized daptomycin formulation is from about 20 mg/mL to about 100 mg/mL. 
     
     
         12 . The lyophilized daptomycin formulation of  claim 9 , wherein the concentration of the additive in the reconstituted lyophilized daptomycin formulation is from about 1 mM to about 500 mM. 
     
     
         13 . The lyophilized daptomycin formulation of  claim 12 , wherein the concentration of the additive in the reconstituted lyophilized daptomycin formulation is about 237.5 mM. 
     
     
         14 . The lyophilized daptomycin formulation of  claim 12 , wherein the concentration of the additive in the reconstituted lyophilized daptomycin formulation is about 300 mM. 
     
     
         15 . The lyophilized daptomycin formulation of  claim 9 , wherein the concentration of the additive in the reconstituted lyophilized daptomycin formulation is from about 1 mg/mL to about 500 mg/mL. 
     
     
         16 . The lyophilized daptomycin formulation of  claim 9 , wherein the pH of the reconstituted lyophilized daptomycin formulation is from about 4.0 to about 5.0. 
     
     
         17 . The lyophilized daptomycin formulation of  claim 16 , wherein the pH of the reconstituted lyophilized daptomycin formulation is about 4.7. 
     
     
         18 . The lyophilized daptomycin formulation of  claim 9 , wherein the diluent is selected from the group consisting of sterile water for injection, bacteriostatic water for injection, 0.45% sodium chloride solution for injection, 0.9% sodium chloride solution for injection, Ringer's solution, lactated Ringer's solution, and combinations thereof. 
     
     
         19 . The lyophilized daptomycin formulation of  claim 18 , wherein the diluent is 0.9% sterile sodium chloride solution for injection. 
     
     
         20 . The lyophilized daptomycin formulation of  claim 18 , wherein the diluent is sterile water for injection. 
     
     
         21 . A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof, an effective amount of a lyophilized daptomycin formulation comprising daptomycin and an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof. 
     
     
         22 . A method of treating or preventing a biofilm, the method comprising exposing a surface of a device to a solution comprising an effective amount of a lyophilized daptomycin formulation comprising daptomycin and an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof. 
     
     
         23 . A method for preparing a lyophilized daptomycin formulation, wherein the method comprises:
 (a) forming an aqueous solution of daptomycin and an additive, which is selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof;   (b) adjusting the pH to from about 4.0 to about 5.0; and   (c) lyophilising the solution to obtain a lyophilisate.   
     
     
         24 . A method for preparing a lyophilized daptomycin formulation, wherein the method comprises:
 (a) forming an aqueous solution of daptomycin at a pH of from about 4.0 to 5.0;   (b) dissolving an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof in the aqueous solution of the daptomycin;   (c) adjusting the pH to from about 4.0 to about 5.0; and   (d) lyophilising the solution to obtain a powder.