Formulations of daptomycin
Long term storage stable daptomycin-containing compositions are disclosed. The compositions include daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL, a buffer having an acidic functional group and have a pH of from about 6.0 to about 7. The formulations are surprisingly free of degradation products such as the hydrolysis product of daptomycin and the β-isomer of daptomycin after storage periods of at least about 18 months.
1. A long term storage stable daptomycin-containing composition, comprising:
daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL;
b) buffer having an acidic functional group,
c) calcium hydroxide,
said composition having a pH of from about 6.0 to about 7.0;
said daptomycin-containing composition having less than about 10% total impurities, area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 18 months of storage at a temperature of from about 5° C. to about 25° C.
2. The long term storage stable daptomycin-containing composition of claim 1 , wherein the less than about 10% total impurities include less than about 5% of the hydrolysis product of daptomycin and less than about 5% of the β-isomer of daptomycin, based on the amount daptomycin included in said composition.
3. The long term storage stable daptomycin-containing composition of claim 1 , wherein the buffer concentration is from about 0.02M to about 0.075M.
4. The long term storage stable daptomycin-containing composition of claim 3 , wherein the buffer concentration is about 0.05M.
5. The long term storage stable daptomycin-containing composition of claim 1 , wherein the buffer is selected from the group consisting of ADA (N-(2-acetamido)-2-iminodi acetic acid), ACES (N-(carbamoylmethyl)-2-amino-ethanesulfonaic acid), PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid)) and MOPSO (3-(N-morpholino)-2-hydroxpropanesulfonic acid).
6. The long term storage stable daptomycin-containing composition of claim 1 , further comprising a tonicifying agent.
7. The long term storage stable daptomycin-containing composition of claim 6 , wherein the tonicifying agent is selected from the group consisting of NaCl, MgCl 2 and CaCl 2 .
8. The long term storage stable daptomycin-containing composition of claim 6 , wherein the amount of tonicifying agent content in the composition is from about 1.5% (v/v) to about 5.0% (v/v).
9. The long term storage stable daptomycin-containing composition of claim 8 , wherein the amount of tonicifying agent in the composition is about 1.8% (v/v).
10. The long term storage stable daptomycin-containing composition of claim 1 , wherein the composition is maintained at a temperature of from about 5° C. to about 15° C. during storage.
11. The long term storage stable daptomycin-containing composition of claim 10 , wherein the composition is maintained at a temperature of from about 5° C. to about 10° C. during storage.
12. The long term storage stable daptomycin-containing composition of claim 11 , wherein the composition is maintained at a temperature of about 5° C. during storage.
13. The long term storage stable daptomycin-containing composition of claim 1 , wherein the pH is from about 6.25 to about 6.75.
14. The long term storage stable daptomycin-containing composition of claim 13 , wherein the pH is about 6.5.
15. The long term storage stable daptomycin-containing composition of claim 1 , wherein the daptomycin concentration is from about 1 mg/mL to about 25 mg/mL.
16. The long term storage stable daptomycin-containing composition of claim 15 , wherein the daptomycin concentration is from about 7.5 mg/mL to about 15 mg/mL.
17. The long term storage stable daptomycin-containing composition of claim 16 , wherein the daptomycin concentration is about 10 mg/mL.
18. The long term storage stable daptomycin-containing composition of claim 1 , wherein said long term storage is at least about 2 years.
19. A long term storage stable daptomycin-containing composition, comprising:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg/mL;
b) ADA (N-(2-acetamido)-2-iminodiacetic acid); and
c) calcium hydroxide;
said composition having a pH of about 6.5; and having less than about 10% total impurities, area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 18 months storage at a temperature of from about 5° C. to about 25° C.
20. The long term storage stable daptomycin-containing composition of claim 19 , wherein the less than about 10% total impurities include less than about 5% of the hydrolysis product of daptomycin and less than about 5% of the β-isomer of daptomycin, based on the amount daptomycin included in said composition.
21. A long term storage stable daptomycin-containing composition, comprising:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg/mL;
b) PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid)); and
c) calcium hydroxide;
said composition having a pH of about 6.75; and having less than about 10% total impurities, area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 18 months storage at a temperature of from about 5° C. to about 25° C.
22. The long term storage stable daptomycin-containing composition of claim 21 , wherein the less than about 10% total impurities include less than about 5% of the hydrolysis product of daptomycin and less than about 5% of the β-isomer of daptomycin, based on the amount daptomycin included in said composition.
23. A method of treating a daptomycin sensitive disease in mammals, comprising administering an effective amount of a long term storage stable daptomycin-containing composition of claim 1 to a mammal in need thereof.