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Details for Patent: 8,604,164

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Details for Patent: 8,604,164

Title:High purity lipopeptides
Abstract: The invention discloses highly purified daptomycin and to pharmaceutical compositions comprising this compound. The invention discloses a method of purifying daptomycin comprising the sequential steps of anion exchange chromatography, hydrophobic interaction chromatography and anion exchange chromatography. The invention also discloses a method of purifying daptomycin by modified buffer enhanced anion exchange chromatography. The invention also discloses an improved method for producing daptomycin by fermentation of Streptomyces roseosporus. The invention also discloses high pressure liquid chromatography methods for analysis of daptomycin purity. The invention also discloses lipopeptide micelles and methods of making the micelles. The invention also discloses methods of using lipopeptide micelles for purifying lipopeptide antibiotics, such as daptomycin. The invention also discloses using lipopeptide micelles therapeutically.
Inventor(s): Kelleher; Thomas J. (Thousand Oaks, CA), Lai; Jan-Ji (Westborough, MA), DeCourcey; Joseph P. (Boston, MA), Lynch; Paul D. (Arlington, MA), Zenoni; Maurizio (Ferentino Frosinone, IT), Tagliani; Auro R. (Pavia, IT)
Assignee: Cubist Pharmaceuticals, Inc. (Lexington, MA)
Filing Date:Feb 16, 2012
Application Number:13/398,219
Claims:1. A method of manufacturing purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3, the method comprising the steps of a) forming a daptomycin aggregate, b) filtering the daptomycin aggregate under conditions in which the daptomycin aggregate is retained on the filter; c) obtaining the purified daptomycin from the daptomycin aggregate.

2. The method of claim 1, wherein the purified daptomycin is obtained from the daptomycin aggregate by a process further comprising the steps of: a) subjecting daptomycin from the daptomycin aggregate to one or more of anion exchange chromatography and hydrophobic interaction chromatography to obtain an enriched daptomycin preparation; and b) obtaining the purified daptomycin from the enriched daptomycin preparation.

3. The method of claim 1, further comprising obtaining the daptomycin aggregate from a process comprising the steps of: a) supplying a fermentation broth; b) fermenting Streptomyces roseosporus to produce daptomycin in the fermentation broth; c) clarifying the fermentation broth to obtain a clarified solution; d) subjecting the clarified solution to anion exchange chromatography to obtain a daptomycin preparation; and e) forming the daptomycin aggregate from the daptomycin preparation.

4. The method of claim 1, wherein the purified daptomycin is obtained from the daptomycin aggregate by a process further comprising the steps of: a) subjecting daptomycin from the daptomycin aggregate to hydrophobic interaction chromatography (HIC) on a HP-20ss resin to obtain an enriched daptomycin preparation; and b) obtaining the purified daptomycin from the enriched daptomycin preparation.

5. The method of claim 4, wherein the purified daptomycin is obtained by a process further comprising the steps of: a) subjecting enriched daptomycin preparation to anion exchange chromatography on a FP-DA 13 resin to obtain a second daptomycin preparation; and b) obtaining the purified daptomycin from the second daptomycin preparation.

6. The method of claim 1, wherein the purified daptomycin has greater than 98% purity measured by HPLC analysis.

7. The method of claim 1, wherein the daptomycin aggregate is formed by a process comprising one or more steps selected from the group consisting of: adjusting the pH of a daptomycin preparation to a pH of about 2.5 to 5.0, combining daptomycin with 300 to 500 mM NaCl in an aqueous solution; and providing a daptomycin preparation at a temperature of 2-15 degrees C.

8. The method of claim 1, wherein the purified daptomycin comprises daptomycin of greater than or about 93% purity relative to daptomycin impurities that arise in fermentation or purification of daptomycin, and wherein the daptomycin impurities comprise impurities 1-14 defined by peaks 1-14 shown in FIG. 12, and the purified daptomycin is obtained by a process comprising the step of forming a micelle comprising daptomycin.

9. The method of claim 8, wherein the purified daptomycin comprises daptomycin of greater than or about 93% purity relative to daptomycin impurities that arise in fermentation.

10. A method of manufacturing purified daptomycin of greater than 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3, the method comprising the steps of a) forming micelles comprising daptomycin; b) converting the micelles to a non-micellar daptomycin composition comprising daptomycin in a non-micellar state; and c) obtaining at least a portion of the purified daptomycin from the micelles, the non-micellar daptomycin composition, or a combination thereof.

11. The method of claim 10, further comprising obtaining the daptomycin micelles from a process comprising the steps of: a) supplying a fermentation broth; b) fermenting Streptomyces roseosporus to produce daptomycin in the fermentation broth; c) clarifying the fermentation broth to obtain a clarified solution; d) subjecting the clarified solution to anion exchange chromatography to obtain a daptomycin preparation; and e) forming the daptomycin micelles from the daptomycin preparation.

12. The method of claim 11, wherein micelles comprising daptomycin are converted to the non-micellar daptomycin composition by a process comprising the steps of: a) contacting the micelles comprising daptomycin with a hydrophobic interaction chromatography resin; and b) converting the micelles in contact with the hydrophobic interaction chromatography resin to a non-micellar daptomycin composition comprising daptomycin in a non-micellar state.

13. The method of claim 12, wherein the purified daptomycin is obtained from the daptomycin in the non-micellar state by a process further comprising the steps of: a) subjecting the non-micellar daptomycin to anion exchange chromatography on a FP-DA 13 resin to obtain an enriched daptomycin preparation; and b) obtaining the purified daptomycin from the enriched daptomycin preparation.

14. The method of claim 13, wherein the purified daptomycin has the purity of about 94 to 96%, less than 4% of anhydro-daptomycin and has less than 4% of the .beta.-isomer of daptomycin.

15. A method of manufacturing purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3, the method comprising the steps of a) subjecting a solution comprising daptomycin to anion exchange chromatography to obtain a first enriched daptomycin preparation; b) forming a daptomycin aggregate in the first enriched daptomycin preparation; c) filtering the daptomycin aggregate under conditions in which the filtered daptomycin aggregate is retained on the filter and separated from the first enriched daptomycin preparation; d) subjecting daptomycin from the filtered daptomycin aggregate to hydrophobic interaction chromatography (HIC) to obtain a second enriched daptomycin preparation; and e) obtaining the purified daptomycin from the second enriched daptomycin preparation.

16. The method of claim 15, wherein impurity 2 is present in the purified daptomycin in an amount no more than 0.5%.

17. The method of claim 15, wherein impurity 7 is present in the purified daptomycin in an amount no more than 1%.

18. The method of claim 15, wherein impurity 12 is present in the purified daptomycin in an amount no more than 0.5%.

19. The method of claim 15, wherein the hydrophobic interaction chromatography (HIC) is performed on a HP-20ss resin.

20. The method of claim 15, wherein the anion exchange chromatography is performed on a FP-DA 13 resin.

21. The method of claim 15, wherein the purified daptomycin is obtained from the second enriched daptomycin preparation by a process further comprising the step of subjecting daptomycin from the second enriched daptomycin preparation to a second anion exchange chromatography to obtain the purified daptomycin.

22. The method of claim 21, wherein the purified daptomycin is obtained from the second enriched daptomycin preparation by a process further comprising the step of lyophilizing a composition obtained from the second enriched daptomycin preparation.

23. A method of manufacturing purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3, the method comprising the steps of a) forming a daptomycin solution at a pH of about 2.5 to 5.0 to form daptomycin aggregates in the daptomycin solution, b) filtering the daptomycin solution under conditions in which at least a portion of the daptomycin aggregates are retained on the filter; c) obtaining the purified daptomycin from the daptomycin aggregates retained on the filter by a process comprising one or more additional steps including anion exchange chromatography and hydrophobic interaction chromatography, to obtain the purified daptomycin.

24. A method of purifying daptomycin comprising the steps of: a) subjecting a solution comprising daptomycin to anion exchange chromatography to obtain a first daptomycin preparation; b) filtering the first daptomycin preparation at a pH of about 2.5 to 5.0 to obtain a second daptomycin preparation; c) subjecting daptomycin from the second daptomycin preparation to hydrophobic interaction chromatography to obtain a third daptomycin preparation; and d) obtaining the purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3 from the third daptomycin preparation.

25. The method of claim 24, wherein impurity 2 is present in the purified daptomycin in an amount no more than 0.5%.

26. The method of claim 24, wherein impurity 7 is present in the purified daptomycin in an amount no more than 1%.

27. The method of claim 24, wherein impurity 12 is present in the purified daptomycin in an amount no more than 0.5%.

28. The method of claim 24, wherein the hydrophobic interaction chromatography (HIC) is performed on a HP-20ss resin.

29. The method of claim 24, wherein the anion exchange chromatography is performed on a FP-DA 13 resin.

30. The method of claim 24, further comprising the step of lyophilizing the daptomycin obtained from the third daptomycin preparation to obtain a lyophilized daptomycin product comprising the daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3.

31. A method of purifying daptomycin comprising the steps of: a) subjecting a solution comprising daptomycin to anion exchange chromatography to obtain a first daptomycin preparation; b) filtering the first daptomycin preparation with 300 to 500 mM NaCl in an aqueous solution to obtain a filtered daptomycin preparation; c) subjecting daptomycin from the filtered daptomycin preparation to hydrophobic interaction chromatography to obtain a second daptomycin preparation; and d) obtaining the purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3 from the second daptomycin preparation.

32. A method of purifying daptomycin comprising the steps of: a) subjecting a solution comprising daptomycin to anion exchange chromatography to obtain a first daptomycin preparation; b) filtering the first daptomycin preparation at a temperature of 2-15 degrees C. to obtain a filtered daptomycin preparation; c) subjecting daptomycin from the filtered daptomycin preparation to hydrophobic interaction chromatography to obtain a second daptomycin preparation; and d) obtaining the purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3 from the second daptomycin preparation.

33. The method of claim 32, wherein impurity 2 is present in the purified daptomycin in an amount no more than 0.5%.

34. The method of claim 32, wherein impurity 7 is present in the purified daptomycin in an amount no more than 1%.

35. The method of claim 32, wherein impurity 12 is present in the purified daptomycin in an amount no more than 0.5%.

36. The method of claim 32, wherein the hydrophobic interaction chromatography (HIC) is performed on a HP-20ss resin.

37. The method of claim 32, wherein the anion exchange chromatography is performed on a FP-DA 13 resin.

38. A method of purifying daptomycin comprising the steps of: a) subjecting a solution comprising daptomycin to anion exchange chromatography to obtain a first daptomycin preparation; b) adjusting the pH of the first daptomycin preparation to a pH of about 2.5 to 5.0, and combining the first daptomycin preparation with 300 to 500 mM NaCl in an aqueous solution at a temperature of 2-15 degrees C. to obtain a second daptomycin preparation; c) subjecting daptomycin from the second daptomycin preparation to hydrophobic interaction chromatography to obtain a third daptomycin preparation; and d) obtaining the purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3 from the third daptomycin preparation.

39. A method of manufacturing purified daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 in Table 3, the method comprising the steps of a) subjecting a solution comprising daptomycin of less than 93% purity to anion exchange chromatography to obtain a first daptomycin preparation; b) adjusting the pH of the first daptomycin preparation to a pH of about 2.5 to 5.0; c) filtering the first daptomycin preparation from step (b) under conditions in which the daptomycin from the first daptomycin preparation is retained on the filter; d) subjecting daptomycin retained on the filter from the first daptomycin preparation to hydrophobic interaction chromatography (HIC) to obtain a second daptomycin preparation; and e) obtaining the purified daptomycin having the purity of greater than or about 93% measured by HPLC from the second daptomycin preparation.

40. The method of claim 39, wherein the hydrophobic interaction chromatography (HIC) is performed on a HP-20ss resin.

41. The method of claim 39, wherein the anion exchange chromatography is performed on a FP-DA 13 resin.
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