Ready-to-use formulation for Vincristine Sulfate Liposome Injection
Disclosed herein are various compositions comprising neoplastic formulations and their methods of use.
1. A method of preventing vincristine degradation at room temperature for a period of 4 weeks comprising formulating the vincristine as the only active agent in a composition comprising;
sphingomyelin-cholesterol liposomes consisting within them vincristine and an ammonium sulfate buffer at a pH of from about 3 to about 5, said liposomes dispersed within
a continuous aqueous phase consisting of a phosphate buffer solution at a pH of from about 7 to about 8.8, and
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units.
2. The method of claim 1 , wherein the vincristine comprises vincristine sulfate.
3. The method of claim 1 , wherein the pH of the continuous aqueous phase is from about 7.1 to about 8.8.
4. The method of claim 1 , wherein the vincristine is in a sulfate salt form.
5. The method of claim 1 , wherein the liposome is hydrolysis resistant.
6. The method of claim 1 , wherein the vincristine is more stable inside the liposome than in the continuous aqueous phase.
7. The method of claim 1 , wherein the ratio of the continuous aqueous phase and the ammonium sulfate buffer is such that mixing of the two would result in a combined aqueous phase with a pH from about 6 to about 8.8.
8. The method of claim 1 , wherein the ammonium sulfate is present at a concentration of about 150 mM to about 350 mM.
9. A method of treating cancer in a mammal comprising administration of a therapeutic amount of the composition of the method of claim 1 to the mammal in need thereof, wherein said cancer is lymphoma, leukemia, or myeloma.
10. The method of claim 9 , wherein the cancer is lymphoma or myeloma.
11. The method of claim 9 , wherein the vincristine is administered at a dose of from about 1.5 mg/m 2 to about 2.5 mg/m 2 .
12. A method of treating a relapse of cancer in a mammal comprising administering to said mammal the composition of the method of claim 1 , wherein said cancer is lymphoma, leukemia, or myeloma.
13. The method of claim 12 , wherein the relapse of cancer is a lymphoma or myeloma.
14. The method of claim 12 , wherein the mammal has previously undergone at least one multi-agent combination regime.
15. The method of claim 12 , wherein said composition is co-administered with at least one additional chemotherapeutic agent.
16. The method of claim 12 , wherein the mammal is a human.
17. A method of preventing vincristine degradation in a liposome for 4 weeks at room temperature comprising:
dispersing sphingomyelin-cholesterol liposomes encapsulating vincristine and an ammonium sulfate buffer at a concentration of about 150 mM to about 350 mM within a continuous aqueous phase consisting of a phosphate buffer solution at a pH of about 6.5 to about 8.0;
wherein the continuous aqueous phase and the ammonium sulfate buffer solution have a pH difference of at least 2 pH units.
18. The method of claim 17 , wherein the vincristine comprises vincristine sulfate.
19. The method of claim 17 , wherein the pH of the ammonium sulfate buffer is from about 3 to about 5.
20. The method of claim 17 , wherein the vincristine is in a sulfate salt form.
21. The method of claim 17 , wherein the liposome is hydrolysis resistant.
22. The method of claim 17 , wherein the vincristine is more stable in the ammonium sulfate buffer than in the continuous aqueous phase.
23. The method of claim 17 , wherein the ratio of the continuous aqueous phase and the ammonium sulfate buffer is such that mixing of the two would result in a combined aqueous phase with a pH from about 6 to about 8.8.
24. A method of preventing vincristine degradation for 12-24 months at 2° to 8° C. comprising formulating the vincristine in a composition comprising;
sphingomyelin-cholesterol liposomes consisting within them vincristine and an ammonium sulfate buffer at a pH of from about 3 to about 5, said liposomes dispersed within
a continuous aqueous phase consisting of a phosphate buffer solution at a pH of from about 7 to about 8.8,
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units.
25. A method of limiting vincristine degradation in a liposome for 12-24 months at 2° to 8° C. comprising:
dispersing a liposome phase consisting of sphingomyelin-cholesterol liposomes encapsulating vincristine and an ammonium sulfate buffer at a concentration of about 150 mM to about 350 mM within a continuous aqueous phase consisting of a phosphate buffer solution at a pH of about 6.5 to about 8.0;
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units.
26. A vincristine composition formulated to limit vincristine degradation comprising;
sphingomyelin-cholesterol liposomes consisting within them vincristine and an ammonium sulfate buffer at a pH of from about 3 to about 5, said liposomes dispersed within
a continuous aqueous phase consisting of a phosphate buffer solution at a pH of from about 7 to about 8.8,
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units; and wherein the vincristine degradation rate is less than 1.5% N-desformylvincristine formation per month.
27. A method of reducing vincristine degradation in a liposome comprising:
dispersing a liposome phase consisting of sphingomyelin-cholesterol liposomes encapsulating vincristine and an ammonium sulfate buffer at a concentration of about 150 mM to about 350 mM within a continuous aqueous phase consisting of a phosphate buffer solution at a pH of about 6.5 to about 8.0;
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units; and wherein the vincristine degradation rate is between about 0.1% and about 1.5% N-desformylvincristine formation per month.
28. A vincristine composition wherein vincristine is the only active agent, said composition comprising;
sphingomyelin-cholesterol liposomes consisting within them vincristine and an ammonium sulfate buffer at a pH of from about 3 to about 5, said liposomes dispersed within
a continuous aqueous phase consisting of a phosphate buffer solution at a pH of from about 7 to about 8.8,
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units; and wherein the vincristine degradation rate is 1.5% N-desformylvincristine formation per month or less.
29. A method of reducing vincristine degradation in a liposome comprising:
dispersing a liposome phase consisting of sphingomyelin-cholesterol liposomes encapsulating vincristine and an ammonium sulfate buffer at a concentration of about 150 mM to about 350 mM within a continuous aqueous phase consisting of a phosphate buffer solution at a pH of about 6.5 to about 8.0;
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units; and wherein the vincristine degradation rate is 1.5% N-desformylvincristine formation per month or less.
30. The composition of claim 26 , wherein said NFV formation rate is 0.5% per month or less.
31. The method of claim 27 , wherein said NFV formation rate is 0.5% per month or less.
32. The composition of claim 28 , wherein said NFV formation rate is 0.5% per month or less.
33. The method of claim 29 , wherein said NFV formation rate is 0.5% per month or less.
34. The method of claim 9 , wherein said cancer comprises non-Hodgkin's Lymphoma.
35. A method of reducing vincristine degradation in a liposome wherein the vincristine is the sole active agent in the liposome, the method comprising:
dispersing sphingomyelin-cholesterol liposomes consisting within them vincristine and an ammonium sulfate buffer at a concentration of about 150 mM to about 350 mM within a continuous aqueous phase consisting of a phosphate buffer solution at a pH of about 8.1 to about 8.4;
wherein the continuous aqueous phase and the ammonium sulfate buffer have a pH difference of at least 2 pH units; and wherein the vincristine degradation rate is less than 1.5% N-desformylvincristine formation per month.
36. The composition of claim 28 , wherein said pH is between 7.8 and 8.3.
37. The composition of claim 30 , wherein said NFV formation rate is 0.2% per month or less.
38. The method of claim 31 , wherein said NFV formation rate is 0.2% per month or less.
39. The composition of claim 32 , wherein said NFV formation rate is 0.2% per month or less.
40. The method of claim 33 , wherein said NFV formation rate is 0.2% per month or less.