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Publication Number
US-11964054-B2
Publication Date
2024-04-23
Expiration Date
Abstract
Formulations of tegavivint, methods of making such formulations, and methods of treatment of cancer by administering the formulations.
Core Innovation
The invention relates to a formulation comprising particles of Form I or Form IV polymorph of tegavivint or a pharmaceutically acceptable salt thereof, with defined nanosuspension properties. The formulation includes a poloxamer and one or more stabilizers selected from sucrose, trehalose and sorbitol, and 90% of particles have a diameter (D90) of less than or equal to 0.2 micron when measured using laser diffraction.
The formulation is prepared by high energy agitator milling at a temperature between about 40°C and about 60°C. Temperature-controlled milling is used to convert Form IV to Form I polymorph and to obtain uniform, well-dispersed nanosuspensions with narrow particle size distributions characterized by D10, D50 and D90.
The disclosed formulation technology supports stable lyophilized and reconstitutable nanosuspensions. The description includes poloxamer 188 with stabilizers and considerations for optional anhydrous or dry storage, lyophilization, and post-processing handling, with DSC confirming polymorphic conversion and microscopy showing no crystal growth over storage periods reported in examples.
Claims Coverage
The independent claim is directed to a tegavivint polymorph formulation with defined nanosuspension particle-size criteria, specific excipient composition, and temperature-controlled high energy agitator milling. The claim set also includes dependent claim refinements that add additional particle-size thresholds, quantify poloxamer concentration, specify a particular polymorph selection, and constrain use to treating cancer or tumor metastasis in a mammal.
Defined Form I/Form IV tegavivint particle nanosizing by D90
A formulation comprising particles of Form I or Form IV polymorph of tegavivint or a pharmaceutically acceptable salt thereof, wherein 90% of particles have a diameter (D90) of less than or equal to 0.2 micron when measured using laser diffraction.
Poloxamer and sucrose/trehalose/sorbitol stabilization
The formulation comprises a poloxamer and one or more stabilizers selected from the group consisting of sucrose, trehalose and sorbitol.
High energy agitator milling at 40°C to 60°C
The formulation was prepared by high energy agitator milling at a temperature of between about 40°C and about 60°C.
Additional particle-size threshold by D50
The formulation is characterized such that 50% of its particles have a diameter (D50) of no more than 0.12 microns when measured by laser diffraction.
Additional particle-size threshold by D10
The formulation is defined such that 10% of its particles have a D10 diameter of 0.1 micron or less, as measured by laser diffraction.
Quantified poloxamer concentration
The formulation specifies that the poloxamer concentration is 6 mg/mL.
Selection of tegavivint Form I polymorph
The formulation includes tegavivint as Form I polymorph.
Overall claim coverage centers on a tegavivint Form I/Form IV polymorph formulation that achieves defined nanosuspension particle-size metrics, contains poloxamer plus stabilizers selected from sucrose, trehalose and sorbitol, and is prepared via high energy agitator milling at 40°C to 60°C; dependent claims further specify poloxamer concentration, select Form I, and provide a use limitation for treating cancer or tumor metastasis.
Stated Advantages
Stable lyophilized and reconstitutable nanosuspensions.
Uniform, well-dispersed nanosuspensions with narrow particle size distributions.
Polymorphic conversion to Form I confirmed by DSC.
No crystal growth over storage periods reported in examples.
Higher Cmax and AUClast with lyophilized versus non-lyophilized formulations after IV infusion, as described in the examples.
Enhanced tissue distribution benefits described in the examples.
Documented Applications
Treating cancer or tumor metastasis in a mammal by administering an effective amount of the formulation.
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