Polymorphic and amorphous salt forms of squalamine dilactate
Inventors
Chellquist, Eric • Doubleday, Mary • Gilbert, Charles W. • Zhang, Xuehai • McLane, Michael • Armbruster, Kyle • Levitt, Roy C.
Assignees
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Publication Number
US-8716270-B2
Publication Date
2014-05-06
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 document discloses squalamine dilactate salt forms, including an amorphous form and various crystalline or polymorphic forms, as well as solvates and hydrates. The amorphous form is characterized by an X-ray powder diffraction pattern having major diffraction angles and relative peak intensities, and the crystalline and other solid forms are further characterized using techniques including X-ray powder diffraction, DSC, and TGA.
The document addresses the need for antiangiogenic agents by providing squalamine dilactate salt forms with utility in inhibiting neovascularization and endothelial cell proliferation. The disclosed salt forms are described in connection with antiangiogenic activity and local irritancy assessment, together with characterization of multiple squalamine salt forms.
The document further describes manufacturability and product stability aspects of the dilactate salt forms, including accelerated stability study data. It also describes a manufacturing route that reduces or eliminates an HPLC purification step, and provides characterization and associated purity and yield outcomes for the resulting amorphous and recrystallized crystalline forms.
Claims Coverage
The partial content provides one independent claim. The independent claim is supported by dependent claims that specify crystallinity characteristics and a pharmaceutical composition including a pharmaceutically acceptable carrier.
Isolated amorphous squalamine dilactate defined by X-ray powder diffraction peaks
An isolated amorphous 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 15.5 to 15.6 degrees, 17.3 to 17.5 degrees, and 21.3 to 21.5 degrees with relative peak intensities of 286, 391, and 107, respectively.
Low crystallinity amorphous squalamine dilactate
The dilactate salt according to the amorphous form has low crystallinity.
Partially crystalline amorphous squalamine dilactate
The dilactate salt according to the amorphous form is partially crystalline.
Pharmaceutical composition containing amorphous squalamine dilactate with a pharmaceutically acceptable carrier
A pharmaceutical composition includes the amorphous form of the dilactate salt, as defined for the amorphous form, together with a pharmaceutically acceptable carrier.
Across the claim set shown, the core coverage centers on an isolated amorphous squalamine dilactate salt defined by specific X-ray powder diffraction major diffraction angles and relative peak intensities, with dependent coverage for low crystallinity and partially crystalline variants, and for pharmaceutical compositions comprising the amorphous form with a pharmaceutically acceptable carrier.
Stated Advantages
Manufacturability is improved by reducing or eliminating an HPLC purification step in the manufacturing process.
Product stability is supported by accelerated stability study data.
Reduced toxicity is stated for the dilactate salt, including local irritancy results across multiple squalamine salt forms.
Documented Applications
Antiangiogenic use by inhibiting neovascularization and endothelial cell proliferation, including for conditions associated with neovascularization such as cancer and age-related macular degeneration, diabetic retinopathy, and atherosclerosis.
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