Polymorphic and amorphous salt forms of squalamine dilactate
Inventors
Chellquist, Eric • Doubleday, Mary • Gilbert, Charles • Zhang, Xuehai • McLane, Michael • Armbruster, Kyle • Levitt, Roy C.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-7981876-B2
Publication Date
2011-07-19
Expiration Date
Abstract
The invention relates to select squalamine salts, methods of their synthesis, their therapeutic use and their advantages relating to manufacturing, product stability and toxicity. More specifically, this application is directed to various forms of the dilactate salt of squalamine and their utility in inhibiting neovascularization and endothelial cell proliferation.
Core Innovation
The invention relates to squalamine dilactate polymorphs, including an amorphous form and crystalline forms that are optionally present as solvates and/or hydrates. The crystalline forms are identified and characterized by X-ray powder diffraction patterns with defined major diffraction angles and relative peak intensities, together with thermal analyses including DSC and TGA trends.
The document also describes a process for converting non-crystalline squalamine dilactate to crystalline material by dissolution and supersaturation using at least two solvents, followed by crystallization. The described solvent systems include combinations involving 2-propanol, ethanol, water, and/or 2-butanol, and the process is supported by reported polymorphic form shifts after recrystallization.
In addition, the document provides comparative data supporting therapeutic relevance of the squalamine dilactate polymorphs. The crystalline and amorphous forms are described as antiangiogenic agents for neovascularization-related diseases, including cancer and eye diseases, through inhibition of endothelial cell proliferation and angiogenesis.
Claims Coverage
The provided independent claims cover four crystalline forms of squalamine dilactate, each defined by a specific X-ray powder diffraction pattern with major diffraction angles and relative peak intensities. One claim-family also covers obtaining crystalline dilactate from non-crystalline material via dissolution and supersaturation.
Crystalline form defined by major XRPD diffraction angles and relative peak intensities
A crystalline form of the dilactate salt of 3β-(N-[3-aminopropyl]-1,4-butanediamine)-7α,24R-dihydroxy-5α-cholestane-24-sulfate, wherein an X-ray powder diffraction pattern has major diffraction angles of 12.5° , 16.6° and 18.8° with relative peak intensities of 890, 829 and 756, respectively.
Crystalline form defined by major XRPD diffraction angles and relative peak intensities
A crystalline form of the dilactate salt of 3β-(N-[3-aminopropyl]-1,4-butanediamine)-7α,24R-dihydroxy-5α-cholestane-24-sulfate, wherein an X-ray powder diffraction pattern has major diffraction angles of 10.2° , 13.0° and 16.6° with relative peak intensities of 1826, 2305 and 1817, respectively.
Crystalline form defined by major XRPD diffraction angles and relative peak intensities
A crystalline form of the dilactate salt of 3β-(N-[3-aminopropyl]-1,4-butanediamine)-7α,24R-dihydroxy-5α-cholestane-24-sulfate, wherein an X-ray powder diffraction pattern has major diffraction angles of 13.1° , 17.7° and 18.3° with relative peak intensities of 939, 937 and 967, respectively.
Crystalline form defined by major XRPD diffraction angles and relative peak intensities
A crystalline form of the dilactate salt of 3β-(N-[3-aminopropyl]-1,4-butanediamine)-7α,24R-dihydroxy-5α-cholestane-24-sulfate, wherein an X-ray powder diffraction pattern has major diffraction angles of 12.6° , 15.7° and 18.8° with relative peak intensities of 977, 891 and 1333, respectively.
Across the provided independent claims, the coverage is centered on crystalline forms of the dilactate salt defined by specific XRPD signatures. The inventive features are quantitative constraints on major diffraction angles and relative peak intensities, with claim-family summaries also indicating crystallization from non-crystalline material via dissolution and supersaturation.
Stated Advantages
Reduced local venous irritancy/toxicity versus other squalamine salt forms.
Dilactate stability.
Improved manufacturing yield/purity and polymorphic shift after recrystallization.
Documented Applications
Antiangiogenic use as agents for neovascularization-related diseases, including cancer and eye diseases.
Use in contexts involving inhibition of endothelial cell proliferation and angiogenesis.
Interested in licensing this patent?