Crystalline form of tegavivint, method of preparation, and use thereof
Inventors
Ostovic, Drazen • Sukumar, Gowri
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11136307-B1
Publication Date
2021-10-05
Expiration Date
Abstract
The present invention relates to crystalline forms of (9E,10E)-2,7-bis((3,5-dimethylpiperidin-1-yl)sulfonyl)anthracene-9,10-dione dioxime, pharmaceutical compositions comprising the crystalline form, processes for preparing the crystalline form and methods of use therefore.
Core Innovation
The document describes crystalline tegavivint Form IV as a specific hydrate characterized by an XRPD-defined set of diffraction peaks at defined 2θ angle values with tolerances of ±0.2°. The Form IV material is further characterized by DSC thermal behavior, including a DSC endotherm peak maximum at about 115.9°C and a DSC exotherm onset at about 147.1°C. The Form IV is described with a needle-like morphology and thermal dehydration behavior, including a dehydration half-point of about 60°C.
The document explains that Form IV is sufficiently unstable to convert to Form I during milling at elevated temperature within a range of about 40°C to about 60°C, and that milling is preferably around 60°C. Using this behavior, the document links processing starting from Form IV to generation of a stable nanosuspension with predominantly single polymorph Form I. The document further links this approach to improved long-term physical stability versus nanoparticle formulations that are described as prone to Oswald ripening and polymorphic change.
The document provides supporting experimental narrative across polymorph investigations involving Forms I–III and Forms IV–VI, using XRPD, TGA, DSC, DVS, and PLM along with slurry competition and ball-milling results. The compositions and nanosuspensions described are further linked to preventing, treating, or ameliorating cancer and/or tumor metastasis in mammals through administration of therapeutically effective amounts, with acute myeloid leukemia (AML) referenced as an example context.
Claims Coverage
The provided claims include four independent claims covering four inventive features: XRPD-defined Form IV crystalline tegavivint, nanosuspensions prepared by milling Form IV at 40–60°C, pharmaceutical compositions using the Form IV-to-crystalline-form process, and a nanosuspension where the stable form consists of Form I. Across these independent claims, the inventive features focus on the XRPD-defined characterization of Form IV, the use of Form IV as a starting material, milling temperature selection, and the resulting polymorph identity as Form I.
Xrpd-defined form IV crystalline tegavivint
A crystalline form of a compound having the formula of tegavivint, wherein the crystalline form is designated as Form IV and has an XRPD comprising diffraction peaks with 2θ angle values independently selected from 5.0±0.2°; 7.5±0.2°; 14.8±0.2°; 15.2±0.2°; 15.4±0.2°; 20.0±0.2°; and 22.2±0.2°.
Form IV-to-nanosuspension milling at 40°C to 60°C
A nanosuspension of tegavivint prepared by a process comprising using Form IV as the starting material and milling Form IV at a temperature of between about 40°C and about 60°C, wherein Form IV has an XRPD comprising diffraction peaks with 2θ angle values independently selected from 5.0±0.2°; 7.5±0.2°; 14.8±0.2°; 15.2±0.2°; 15.4±0.2°; 20.0±0.2°; and 22.2±0.2°.
Pharmaceutical composition with Form IV-derived crystalline tegavivint
A pharmaceutical composition, comprising a therapeutically effective amount of a crystalline form of tegavivint prepared by a process utilizing Form IV as the starting material, and a pharmaceutically acceptable excipient and/or diluent, wherein Form IV has an XRPD comprising diffraction peaks with 2θ angle values independently selected from 5.0±0.2°; 7.5±0.2°; 14.8±0.2°; 15.2±0.2°; 15.4±0.2°; 20.0±0.2°; and 22.2±0.2°.
Stable nanosuspension consisting of form I
A nanosuspension of tegavivint prepared by a process comprising using Form IV as the starting material and milling Form IV at a temperature of between about 40°C and about 60°C, wherein Form IV has an XRPD comprising diffraction peaks with 2θ angle values independently selected from 5.0±0.2°; 7.5±0.2°; 14.8±0.2°; 15.2±0.2°; 15.4±0.2°; 20.0±0.2°; and 22.2±0.2°, wherein the stable nanosuspension consists of Form I of tegavivint.
Overall, the claim set defines Form IV using an XRPD peak set, uses Form IV as the starting material for milling at 40–60°C to produce nanosuspensions, and covers pharmaceutical compositions containing crystalline tegavivint prepared using Form IV. In one independent claim, the nanosuspension is further limited such that the stable nanosuspension consists of Form I.
Stated Advantages
Improved long-term physical stability versus nanoparticle formulations prone to Oswald ripening and polymorphic change.
Documented Applications
Preventing, treating, or ameliorating cancer and/or tumor metastasis in mammals by administration of a therapeutically effective amount of the described nanosuspension or pharmaceutical composition; acute myeloid leukemia (AML) is referenced as an example cancer context.
Interested in licensing this patent?