Lyophilized formulation
Inventors
Connolly, Joan • Erickson, Frederick • Kamat, Madhav • Wasserman, Jennifer • Zabrecky, James
Assignees
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Publication Number
US-12171800-B2
Publication Date
2024-12-24
Expiration Date
Abstract
Provided herein are improved formulations of tagraxofusp for lyophilization used to manufacture stable formulations of tagraxofusp for intravenous injection.
Core Innovation
The invention relates to a stable solution in a pharmaceutically acceptable aqueous carrier comprising tagraxofusp, sucrose, polysorbate 80, and Tris HCl at a defined pH. The solution is characterized by polysorbate 80 having no more than 3% peroxide, and the formulation is described in the context of an improved lyophilized tagraxofusp formulation and an associated development rationale.
The problem addressed is the formation of oxidation-related impurities and related stability and charge-variant behavior during handling and over shelf-life. Oxidation impurities are described using oxidized species at +16 Da, alongside acidic species and charge-variant behavior concerns that are linked to polysorbate-derived peroxide and oxidative degradation. The formulation approach selects the surfactant purity/peroxide level and excipient composition to reduce oxidation-related impurities.
The invention further addresses physical quality and downstream performance by including disaccharide sugars as stabilizers and optionally selecting bulking agents to support lyophilized cake quality. Documented evaluations within the disclosure address effects of stabilizer excipients on thermal behavior and buffer selection on stability, and they report outcomes such as particulate-free clarity after agitation and impurity/oxidation targets over shelf-life.
Claims Coverage
The independent claim provides a stable solution formulation for tagraxofusp with a defined set of inventive concentration constraints and a peroxide-limited polysorbate 80, together with a specified pH range. The dependent claims refine these requirements by narrowing solution conditions, specifying additional excipients and handling/performance conditions for downstream infusion use.
Peroxide-limited polysorbate 80 in a sucrose/tris solution
A stable solution comprising 0.5 to 1.5 mg/mL of tagraxofusp, 2 to 10% w/v of sucrose, 0.05 to 1.5% w/v of polysorbate 80, 5 to 25 mM Tris HCl, and having a pH from 6.5-9.0, wherein the polysorbate 80 has no more than 3% peroxide.
Bulking-agent reinforced stable tagraxofusp solution
The stable solution includes a bulking agent selected from glycine, maltose, glucose, mannitol, or sorbitol, while retaining the formulation framework of tagraxofusp with sucrose, polysorbate 80, and Tris HCl at the defined pH and polysorbate-peroxide limitation.
Stability under sub-zero storage temperature
The stable solution is maintained at a temperature of less than 0°C.
Dilution to substantially particle-free infusion fluid
When the stable solution is diluted into an infusion fluid bag, the fluid is substantially free of particulate matter.
Intravenous injection formulation using an infusion fluid bag ratio
An intravenous injection formulation is made by combining a stable solution with water for injection in an infusion fluid bag at a ratio of 1 part stable solution to 50 parts water.
Overall, claim coverage centers on a tagraxofusp stable aqueous solution defined by specific tagraxofusp/sucrose/polysorbate/Tris concentration ranges and a pH window, with polysorbate 80 peroxide limited to no more than 3%. Dependent claims further refine excipient selection, sub-zero stability, and downstream infusion performance including substantially particle-free fluid and an intravenous formulation context.
Stated Advantages
Reduces oxidation-related impurities and oxidation degradation associated with peroxide in polysorbate 80.
Improves stability and charge-variant behavior compared with non-lyophilized liquid formulations.
Supports particulate-free clarity performance after agitation when diluted for infusion.
Enables achievement of impurity/oxidation targets over shelf-life.
Improves lyophilized cake quality through selection of bulking agents.
Documented Applications
Therapeutic use of the reconstituted formulation for diseases and cancers, including BPDCN, MPN/PV/ET/MF/CMML, AML, MDS, multiple myeloma, autoimmune diseases, and solid tumors.
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