Ready-to-use formulation for Vincristine Sulfate Liposome Injection
Inventors
Monte, William T. • Abra, Robert Malcolm • Luo, Bing • Zhang, Yuanpeng
Assignees
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Publication Number
US-11559486-B2
Publication Date
2023-01-24
Expiration Date
Abstract
Disclosed herein are various compositions comprising neoplastic formulations and their methods of use.
Core Innovation
Vincristine sulfate is chemically unstable, with vincristine degradation including formation of N-desformylvincristine (NFV), and this instability limits shelf life for vincristine sulfate liposome injection. The disclosure explains that previously observed rapid NFV formation is associated with degradation occurring inside the sphingomyelin-cholesterol liposome, and a central problem is preventing vincristine degradation at room temperature and for extended storage.
The disclosure provides a ready-to-use vincristine sulfate liposome formulation concept that is stable without pharmacy constitution by using sphingomyelin-cholesterol liposomes encapsulating vincristine and an ammonium sulfate buffer. Instead of using an external citric acid buffer, the formulation includes an internal ammonium sulfate buffer at a pH of from about 3 to about 5 within the liposomes and a continuous aqueous phase consisting of a phosphate buffer at a higher pH, with the internal and external phases defined to have a pH difference of at least 2 pH units.
The disclosure further describes the formulation architecture as a two-buffer system in which the ammonium sulfate buffer within the liposomes and the external phosphate buffer establish a multiplex of liposome membrane pH equilibria. The internal ammonium sulfate buffer is described in terms of ammonia/ammonium equilibrium and transmembrane potential loading, including leaving positively charged solute or hydronium ion species internally.
As a result, NFV formation is mitigated and the vincristine degradation rate is limited, including formulations where the vincristine degradation rate is less than 1.5% N-desformylvincristine formation per month.
Claims Coverage
The partial set includes multiple independent claims directed to preventing vincristine degradation at room temperature for 4 weeks, preventing degradation for 12–24 months at 2° to 8° C., limiting degradation metrics including quantitative NFV formation rates, and reducing degradation in liposomes and vincristine compositions where vincristine is the only active agent. Across the independent claims, a consistent set of inventive features is the sphingomyelin-cholesterol liposome containing an ammonium sulfate buffer at a lower pH, dispersed in a phosphate-buffer continuous aqueous phase at a higher pH with a pH difference of at least 2 pH units, with degradation limited by requiring low NFV formation per month.
Two-phase pH-managed liposome formulation with ammonium sulfate and phosphate buffers
Formulating vincristine as the only active agent in sphingomyelin-cholesterol liposomes encapsulating vincristine and an ammonium sulfate buffer at a pH of from about 3 to about 5, 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.
Room-temperature 4-week degradation prevention using internal ammonium sulfate and external phosphate continuous phase
Preventing vincristine degradation at room temperature for a period of 4 weeks by formulating vincristine as the only active agent in 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.
Extended storage stabilization at 2° to 8° C. for 12–24 months using the same pH-difference liposome system
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.
Limiting NFV formation per month by requiring a maximum degradation rate
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.
Reduced vincristine degradation in liposomes with quantitative degradation-rate range
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.
Vincristine-only composition with pH-difference liposome system and NFV formation ceiling
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.
Across the independent claims in the provided partial content, the claim coverage repeatedly centers on a pH-difference two-phase system using sphingomyelin-cholesterol liposomes with an encapsulated ammonium sulfate buffer and a continuous phosphate-buffer aqueous phase at a higher pH, with the defining requirement that the pH difference between phases is at least 2 pH units. The independent claims further distinguish use cases by specifying room-temperature duration and refrigerated storage duration and by imposing quantitative limits or ranges on vincristine degradation via N-desformylvincristine formation per month.
Stated Advantages
Stability of vincristine sulfate without pharmacy constitution by preventing vincristine degradation.
Improved NFV formation behavior relative to the disclosed prior behavior.
Extended shelf life by preventing vincristine degradation at room temperature for 4 weeks.
Extended storage by preventing vincristine degradation for 12–24 months at 2° to 8° C.
Limited vincristine degradation as quantified by N-desformylvincristine formation per month (e.g., less than 1.5% per month).
Documented Applications
Treating cancer, including relapsed non-Hodgkin’s lymphoma.
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