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Publication Number
US-11602501-B2
Publication Date
2023-03-14
Expiration Date
Abstract
Lyophilized formulations of tegavivint, methods of making such formulations, and methods of treatment of cancer by administering the formulations.
Core Innovation
The invention concerns tegavivint (BC2059) lyophilized formulations that comprise particles of tegavivint or a pharmaceutically acceptable salt thereof having nanoscale particle size parameters. The particles exhibit a median particle diameter D50 of less than or equal to 500 nm and 90% of particles have a diameter D90 of less than or equal to 1.0 micron when measured using laser diffraction. The lyophilized formulation further comprises a poloxamer and one or more stabilizers selected from sucrose, trehalose, and sorbitol.
A further aspect of the invention is the preparation of the lyophilized formulation using a lyophilization process that includes freezing a pre-lyophilized formulation comprising tegavivint, poloxamer, and the selected stabilizers, followed by a primary drying step and a secondary drying step. The description supports use of polymorph forms as starting materials and conversion between Form IV and Form I under milling conditions, with the reconstituted formulation being defined in terms of tegavivint polymorph.
The invention also addresses long-term stability of the lyophilized nanosuspension by requiring that the formulation is stable for at least eighteen months during storage at a temperature between 5-25°C. The documented stability criteria include maintenance of cake integrity, rapid resuspension, and absence of significant crystal growth, together with stability of particle size distribution and microscopy observations after reconstitution, while chemical stability is supported by assay/relative substance results.
Claims Coverage
The independent claims are directed to a tegavivint lyophilized nanosuspension formulation defined by nanoscale particle-size limits, specific excipient classes, and defined storage stability. Across the independent claims, the inventive features include the particle size criteria, the excipient selection, the long-term stability requirement, and preparation by lyophilization with freezing plus primary and secondary drying steps.
Nanoscale particle-size limits for tegavivint in a lyophilized formulation
Particles have a median particle diameter D50 of less than or equal to 500 nm and 90% of particles have a diameter D90 of less than or equal to 1.0 micron when measured using laser diffraction.
Poloxamer plus selected stabilizers in the lyophilized formulation
The lyophilized formulation comprises a poloxamer and one or more stabilizers selected from sucrose, trehalose, and sorbitol.
Long-term stability during storage
The formulation is stable for at least eighteen months during storage at a temperature of between 5-25°C.
Lyophilization process comprising freezing, primary drying, and secondary drying
The formulation is prepared by a lyophilization process comprising freezing a pre-lyophilized formulation comprising tegavivint, a poloxamer, and one or more stabilizers selected from sucrose, trehalose, and sorbitol, followed by a primary drying step and a secondary drying step.
Independent claim coverage centers on a tegavivint or salt lyophilized formulation with nanoscale particle size, a poloxamer plus sucrose, trehalose, or sorbitol stabilizers, and stability for at least eighteen months at 5-25°C. One independent claim further requires preparation by lyophilization including freezing of a pre-lyophilized formulation and separate primary and secondary drying steps.
Stated Advantages
Maintenance of cake integrity, rapid resuspension, and absence of significant crystal growth.
Stability of particle size distribution and microscopy observations after reconstitution.
Chemical stability supported by assay/relative substance results.
Documented Applications
Not explicitly described in patent.
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