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Claims for Patent: 6,960,564

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Claims for Patent: 6,960,564

Title: Echinocandin pharmaceutical formulations containing micelle-forming surfactants
Abstract:Pharmaceutical formulations are described comprising an echinocandin compound or echinocandin/carbohydrate complex and a pharmaceutically acceptable micelle-forming surfactant in a non-toxic aqueous solvent such that the solubilization of the echinocandin compound is optimized and the ability to freeze-dry the solution is maintained. Both the solution and freeze-dried formulations have increased stability. A bulking agent, tonicity agent buffer and/or a stabilizing agent may optionally be added to the formulations to further enhance the stability of the formulation.
Inventor(s): Milton; Nathaniel (Indianapolis, IN), Moder; Kenneth Philip (West Lafayette, IN), Sabatowski; James Lawrence (Holland, MI), Sweetana; Stephanie Ann (Bloomington, IN)
Assignee: Eli Lilly and Company (Indianapolis, IN)
Application Number:09/942,431
Patent Claims: 1. A freeze-dried formulation comprising (i) an echinocandin compound, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable micelle-forming surfactant; (iii) a bulking agent; and (iv) a stabilizing agent, wherein said micelle-forming surfactant is present in said freeze-dried formulation in an amount greater than 5% by weight and wherein said micelle-forming surfactant is a polysorbate, a polyoxyethylene castor oil derivative, a polyoxyethylene stearate or combinations thereof; wherein said echinocandin compound is represented by the following structure: ##STR10## or a pharmaceutically acceptable salt thereof; wherein said bulking agent is mannitol, sucrose, trehalose, lactose, or mixtures thereof; and wherein said stabilizing agent is sucrose, fructose, trehalose or mixtures thereof.

2. The formulation of claim 1 wherein said surfactant is represented by the following formula: ##STR11## wherein x+y+z+w is equal to an integer between 5 and 20.

3. The formulation of claim 1 wherein said surfactant is present in said formulation at a weight ratio of echinocandin to surfactant from 1:1.75 to 1:25.

4. The formulation of claim 3 wherein said weight ratio of echinocandin to surfactant is from 1:2 to 1:3.

5. A parenteral formulation comprising the freeze-dried formulation of claim 1 and an aqueous solvent.

6. The formulation of claim 5 wherein said stabilizing agent is fructose, trehalose, or mixtures thereof.

7. The formulation of claim 5 wherein said surfactant is present in said formulation at a weight ratio of echinocandin to surfactant from 1:1.75 to 1:25.

8. The formulation of claim 5 further comprising a buffer.

9. The formulation of claim 8 wherein said buffer is selected from the group consisting of acetates, tartrates, citrates, phosphates and amino acids.

10. A process for making a freeze-dried formulation comprising in the following order the steps of: (i) dissolving into an aqueous solvent an echinocandin compound or echinocandin/carbohydrate complex containing said echinocandin compound in the presence of a pharmaceutically acceptable micelle-forming surfactant to form a solution, wherein said surfactant is present in an amount greater than 1% weight per volume of solution; (ii) sterile filtering said solution; and (iii) freeze-drying said solution; wherein said micelle-forming surfactant is present in said freeze-dried formulation in an amount greater than 5% by weight and wherein said micelle-forming surfactant is a polysorbate, a polyoxyethylene castor oil derivative, a polyoxyethylene stearate or combinations thereof; wherein said echinocandin compound is represented by the following structure: ##STR12## or a pharmaceutically acceptable salt thereof; further comprising the step of adding one or more bulking agents and one or more stabilizing agents before step (ii); wherein said bulking agent is mannitol, sucrose, trehalose, lactose, or mixtures thereof; and wherein said stabilizing agent is sucrose, fructose, trehalose or mixtures thereof.

11. The process of claim 10 further comprising the step of adding one or more, buffers, tonicity agents, or combinations thereof before step (ii).

12. The process of claim 10 wherein said micelle-forming surfactant is a polysorbate.

13. A process for preparing a freeze-dried formulation comprising the steps of (i) buffering a non-toxic aqueous solvent to a pH between 4.0 and 5.5 to form a buffered solution; (ii) adding to said buffered solution a pharmaceutically acceptable, micelle-forming surfactant; (iii) cooling the solution from step (ii) to a temperature between 5.degree. and 15.degree. C. to form a cooled solution; (iv) adding a slurry comprising an echinocandin compound or echinocandin/carbohydrate complex containing said echinocandin compound and a second non-toxic aqueous solvent to said cooled solution; (v) sterile filtering said solution from step (iv); and (vi) freeze-drying said solution from step (v); wherein said micelle-forming surfactant is present in said freeze-dried formulation in an amount greater than 5% by weight and wherein said micelle-forming surfactant is a polysorbate, a polyoxyethylene castor oil derivative; a polyoxyethylene stearate or combinations thereof; wherein said echinocandin compound is represented by the following structure: ##STR13## or a pharmaceutically acceptable salt thereof; further comprising the step of adding one or more bulking agents and one or more stabilizing agents before step (v); wherein said bulking agent is mannitol, sucrose, trehalose, lactose, or mixtures thereof; and wherein said stabilizing agent is sucrose, fructose, trehalose or mixtures thereof.

14. The process of claim 13 wherein said temperature in step (iii) is from 7.degree. C. to 10.degree. C.

15. The process of claim 13 further comprising the step of adding one or more tonicity agents before step (v).

16. A parenteral formulation comprising an aqueous solvent and a freeze-dried formulation prepared by the process of claim 13.

17. A method of treating a fungal infection in a mammal in need thereof comprising the step of administering to said mammal a parenteral formulation of claim 5.

18. A method of treating a fungal infection in a mammal in need thereof comprising the step of administering to said mammal a parenteral formulation of claim 16.

19. The formulation of claim 1 wherein said stabilizing agent is present in an amount from 0.5% to 10% by weight per volume.

20. The formulation of claim 1 wherein said stabilizing agent is present in an amount from 1% to 6% by weight per volume.

21. The formulation of claim 1 further comprising a buffer.

22. The formulation of claim 21 wherein said buffer is selected from the group consisting of acetates, citrates, tartrates, lactates, succinates and phosphates and amino acids.

23. The formulation of claim 1, wherein said bulking agent is mannitol.

24. The formulation of claim 1, further comprising a buffer and, wherein said stabilizing agent is fructose, said bulking agent is mannitol, and said micelle forming surfactant is a polysorbate.

25. The formulation of claim 24 where said buffer is a citrate, acetate or tartrate.

26. The formulation of claim 2 wherein said micelle-forming surfactant is polysorbate 80, polysorbate 20 or polysorbate 40.

27. The formulation of claim 1 wherein said stabilizing agent is fructose.

28. The formulation of claim 23 wherein said stabilizing agent is fructose.

29. The formulation of claim 26 wherein said stabilizing agent is fructose.

30. The formulation of claim 1 wherein said bulking agent is mannitol, and said micelle-forming surfactant is a polysorbate.

31. The formulation of claim 1 wherein said stabilizing agent is fructose, said bulking agent is mannitol, and said micelle forming surfactant is a polysorbate.

32. The formulation of claim 1 wherein said echinocandin compound is present prior to freeze drying at a concentration from 1 mg/ml to 30 mg/ml.

33. The formulation of claim 1 wherein said echinocandin compound is present prior to freeze drying at a concentration from 8 mg/ml to 12 mg/ml.

34. The formulation of claim 31 wherein said echinocandin compound is present prior to freeze drying at a concentration from 1 mg/ml to 30 mg/ml.

35. The formulation of claim 31 wherein said echinocandin compound is present prior to freeze drying at a concentration from 8 mg/ml to 12 mg/ml.
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