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Publication Number
US-11793759-B2
Publication Date
2023-10-24
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 tegavivint formulations comprising particles of tegavivint or a pharmaceutically acceptable salt thereof. The particles are defined by particle size distribution parameters measured using laser diffraction, with a median particle diameter D50 of less than or equal to 500 nm and with 90% of particles having a diameter D90 of less than or equal to 1.0 micron. The lyophilized formulation further comprises a poloxamer and one or more stabilizers selected from sucrose, trehalose, and sorbitol.
The formulations are produced starting from a defined tegavivint polymorph material, specifically Form I polymorph of tegavivint or Form IV polymorph of tegavivint. The lyophilized product comprises the tegavivint particles after a process that includes freezing, primary drying, and secondary drying, and the starting material constraint is maintained for producing the lyophilized formulation.
The document characterizes the resulting nanosuspensions and lyophilized vials as showing uniform well-dispersed particles and an absence of un-milled material or crystal growth during storage. It further reports that a solvent-mediated conversion from Form IV to Form I can occur during elevated-temperature milling to obtain nanosuspensions predominantly of Form I, and that the reconstituted composition is described as readily reconstituting with stable particle size distribution and minimal chemical impact over the early stability period, including good cake integrity.
Claims Coverage
The independent claims are directed to lyophilized formulations of tegavivint particles with defined particle size distribution, formulation excipients, and polymorph-constrained starting material, and to a lyophilized formulation prepared by a lyophilization process including freezing, primary drying, and secondary drying. Across the independent claims, three main inventive groupings recur: particle size distribution by laser diffraction, poloxamer plus stabilizers, and Form I or Form IV polymorph starting material.
Lyophilized tegavivint particles with D50 and D90 by laser diffraction
A lyophilized formulation comprising particles 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 D90 of less than or equal to 1.0 micron when measured using laser diffraction.
Poloxamer plus sucrose, trehalose, or sorbitol stabilizers
The lyophilized formulation comprises a poloxamer and one or more stabilizers selected from the group consisting of sucrose, trehalose, and sorbitol.
Form I or Form IV polymorph starting material
A starting material to produce the lyophilized formulation is Form I polymorph of tegavivint or Form IV polymorph of tegavivint.
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 primary drying and secondary drying.
Overall, the claim set covers lyophilized formulations of tegavivint or a salt thereof characterized by laser-diffraction particle size distribution, containing a poloxamer and stabilizers selected from sucrose, trehalose, and sorbitol, and produced from Form I polymorph or Form IV polymorph starting material. The second independent claim further requires preparation by a lyophilization process including freezing, primary drying, and secondary drying.
Stated Advantages
Provides stability for the lyophilized formulation for three months at storage between 5°C and 25°C.
Reconstituted compositions are described as readily reconstituting with stable particle size distribution and minimal chemical impact over the early stability observations.
Lyophilized vials are described as having uniform cake structure with good cake integrity over storage.
Form conversion and milling-produced nanosuspensions are described as yielding predominantly Form I and as showing narrow unimodal particle size distribution with uniform particle dispersion.
Documented Applications
Treating cancer or tumor metastasis in a mammal by administering an effective amount of the lyophilized formulation.
The cancer treatment method is for acute myeloid leukemia.
Reconstituted tegavivint formulations where the reconstituted product contains tegavivint as the Form I polymorph.
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