Lyophilized anti-fungal compositions

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;

trehalose is the non-reducing sugar;

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 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.

3. 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.

4. The lyophilized composition according to claim 3 , wherein trehalose 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.

5. The lyophilized composition according to claim 4 , 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.

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 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.

7. A process for preparing a lyophilized anti-fungal composition with a moisture content of less than about 0.8 wt. %, which process 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 wherein trehalose is the non-reducing sugar; and

(B) freeze-drying the aqueous solution to provide the lyophilized anti-fungal composition;

wherein the lyophilized anti-fungal composition with a moisture content of less than about 0.8 wt. % 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; and

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; and

the composition has a glass transition temperature T g (c) of at least about 55° C.

8. The process according to claim 7 , 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.

9. The process according to claim 8 , 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.

10. The process according to claim 9 , 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.

11. The process according to claim 7 , wherein the moisture content of the resulting lyophilized composition is about 0.5 wt. % or less.

12. A lyophilized anti-fungal composition prepared by the process set forth in claim 7 .

13. A kit comprising a first container having the lyophilized anti-fungal composition according to claim 1 and a second container having a parenterally acceptable solvent for reconstitution thereof.

14. A method of preparing an anti-fungal liquid formulation for parenteral administration, which comprises reconstituting the lyophilized anti-fungal composition according to claim 1 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.

15. The method according to claim 14 , wherein the parenterally acceptable solvent comprises water.

16. The method according to claim 15 , 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.

17. The method according to claim 16 , wherein the diluent is 0.9%, 0.45% or 0.225% Sodium Chloride Injection or Lactated Ringer's Injection.

18. The method according to claim 17 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.

19. An anti-fungal liquid dosage formulation for parenteral administration prepared by the method set forth in claim 14 .

20. 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 claim 14 .

21. A kit comprising a first container having the lyophilized anti-fungal composition according to claim 12 and a second container having a parenterally acceptable solvent for reconstitution thereof.

22. A method of preparing an anti-fungal liquid formulation for parenteral administration, which comprises reconstituting the lyophilized anti-fungal composition according to claim 12 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.

23. The method according to claim 22 , wherein the parenterally acceptable solvent comprises water.

24. The method according to claim 23 , 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.

25. The method according to claim 24 , wherein the diluent is 0.9%, 0.45% or 0.225% Sodium Chloride Injection or Lactated Ringer's Injection.

26. The method according to claim 25 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.

27. An anti-fungal liquid dosage formulation for parenteral administration prepared by the method set forth in claim 22 .