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Publication Number
US-11571388-B2
Publication Date
2023-02-07
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 relates to stable lyophilized formulations comprising particles of the Form I polymorph of tegavivint or a pharmaceutically acceptable salt. The formulations are characterized by a small particle size distribution, where the median particle diameter D50 is less than or equal to 500 nm and 90% of particles have a diameter of less than or equal to 1.0 micron when measured using laser diffraction. The lyophilized product includes poloxamer and one or more stabilizers selected from sucrose, trehalose, and sorbitol.
A further aspect defines lyophilized formulations of Form I tegavivint particles as being stable for at least eighteen months during storage at 5-25°C. The lyophilized formulation is prepared by a lyophilization process comprising freezing a pre-lyophilized formulation, followed by a primary drying step and a secondary drying step. The pre-lyophilized formulation comprises tegavivint, a poloxamer, and one or more stabilizers selected from sucrose, trehalose, and sorbitol.
The disclosed approach also addresses producing nanosuspensions from tegavivint Form I or Form IV polymorph materials so that the final lyophilized formulation contains Form I polymorph particles with the defined particle-size limits. Temperature-controlled high-energy milling is described as a route to nanosuspensions, including conversion from Form IV to Form I. The resulting lyophilized vials show cake integrity with negligible shrinkage and are readily resuspended upon reconstitution, while maintaining stability measures such as assay/relative substance after lyophilization.
The formulations are stated to be suitable for treatment of cancer or tumor metastasis via administration of an effective amount, and they are discussed in the context of the Wnt/β-catenin pathway. The document also includes fibrotic diseases, including pulmonary fibrosis and Dupuytren’s contracture, as described use cases for tegavivint formulations.
Claims Coverage
Two independent claims are present, covering a lyophilized Form I tegavivint formulation with defined particle size and specific excipients and long-term stability, and a lyophilization process for producing that formulation from a pre-lyophilized mixture containing tegavivint, poloxamer, and selected stabilizers. In total, the independent claims emphasize four core inventive features: Form I polymorph particles with laser-diffraction size limits, a poloxamer plus sucrose/trehalose/sorbitol stabilization system, stability for at least eighteen months at 5-25°C, and a freezing/primary drying/secondary drying workflow.
Form I polymorph Tegavivint lyophilized particles with laser-diffraction size limits
A lyophilized formulation comprising particles of Form I polymorph of tegavivint or a pharmaceutically acceptable salt thereof, wherein the particles have a median particle diameter D50 of less than or equal to 500 nm and wherein 90% of particles have a diameter of less than or equal to 1.0 micron when measured using laser diffraction.
Poloxamer with sucrose/trehalose/sorbitol stabilizers
The lyophilized formulation comprises a poloxamer and one or more stabilizers selected from the group consisting of sucrose, trehalose, and sorbitol.
Long-term storage stability at 5-25°C for at least eighteen months
The formulation is stable for at least eighteen months during storage at a temperature of between 5-25°C.
Lyophilization process with 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 the group consisting of sucrose, trehalose and sorbitol, followed by a primary drying step and a secondary drying step.
Across the independent claims, the invention is directed to a lyophilized formulation of Form I tegavivint particles with defined laser-diffraction particle size, stabilized with poloxamer plus sucrose/trehalose/sorbitol, and stable for at least eighteen months at 5-25°C. The second independent claim further defines the preparation as a lyophilization process using freezing, primary drying, and secondary drying starting from a corresponding pre-lyophilized mixture.
Stated Advantages
Long-term stability of the lyophilized formulation for at least eighteen months at 5-25°C.
Defined small particle size distribution in the lyophilized formulation.
Lyophilized vials exhibit uniform cake integrity with negligible shrinkage and are readily resuspended upon reconstitution while maintaining assay/relative substance after lyophilization.
Documented Applications
Treatment of cancer or tumor metastasis in a mammal by administering an effective amount of the lyophilized formulation.
Treatment of cancer where the cancer is acute myeloid leukemia.
Use in fibrotic diseases, including pulmonary fibrosis and Dupuytren’s contracture, as described for tegavivint.
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