Oral formulations of belinostat
Inventors
PIVETTE, Perrine • Lemarchand, Caroline • Yates, Ian • Bloom, Corey
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11266614-B2
Publication Date
2022-03-08
Expiration Date
Abstract
The present application concerns new formulations of belinostat suitable for oral administration, their process of preparation, the pharmaceutical compositions comprising said formulations and their uses thereof.
Core Innovation
The invention concerns an oral amorphous solid dispersion of belinostat designed to address poor aqueous solubility and chemical instability when in amorphous or solution forms. The core formulation is characterized as an amorphous solid dispersion of belinostat in substantially amorphous form, comprising belinostat or a pharmaceutically acceptable salt, solvate, or ester and at least one polyvinyl lactam polymer, optionally together with at least one additive.
The polyvinyl lactam polymer focus is on non-ionizable, non-cellulosic polymer materials including polyvinylpyrrolidone, copovidone, and Soluplus. The document further attributes improved performance to prevention of recrystallization and to enhanced dissolution and supersaturation behavior, together with chemical stability improvements by limiting belinostat degradation impurities, specifically belinostat acid and belinostat dimer, to defined maximum levels upon release and after extended storage.
Example comparisons in the document describe improved in vitro dissolution and increased in vivo plasma exposure/bioavailability relative to crystalline belinostat. The preparation is described as using a solvent-containing solution followed by spray-drying.
Claims Coverage
The independent claim covers an amorphous solid dispersion of belinostat, a polyvinyl lactam polymer, and optionally an additive. Dependent claims refine the polymer definition, specify example polymer types, add drug/polymer weight ranges, constrain impurity levels, and define a preparation using a solvent-containing solution and spray-drying.
Amorphous solid dispersion of belinostat with polyvinyl lactam polymer and optional additive
An amorphous solid dispersion of belinostat comprising belinostat or a pharmaceutically acceptable salt, solvate or ester thereof; at least one polyvinyl lactam polymer; and optionally, at least one additive.
Polyvinyl lactam polymer defined by lactam sub-unit parameters
The amorphous solid dispersion of belinostat where the polyvinyl lactam polymer comprises a lactam sub-unit with m in 1–(β-, γ-, δ-, or ε-lactam) and n being the number of lactam repeating units.
Specified polyvinyl lactam polymer types
The amorphous solid dispersion of belinostat wherein the polyvinyl lactam polymer is selected from polyvinylpyrrolidone, copovidone, or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
Composition weight ranges of belinostat and polyvinyl lactam polymer
The amorphous solid dispersion of belinostat contains about 5–80 wt% belinostat and about 20–95 wt% of a polyvinyl lactam polymer.
Low belinostat acid and/or belinostat dimer levels during release and after storage
The amorphous solid dispersion of belinostat includes specified low levels of belinostat acid and/or belinostat dimer measured during release testing and/or after storage for at least 18 months.
The claims are directed to an amorphous solid dispersion of belinostat comprising belinostat plus at least one polyvinyl lactam polymer, optionally with additives, with additional limitations including polymer definition, specified polymer types, defined weight ranges, and impurity limits for belinostat acid and belinostat dimer during release and after at least 18 months storage.
Stated Advantages
Prevents recrystallization.
Improves dissolution and supersaturation behavior.
Achieves chemical stability by limiting belinostat degradation impurities (belinostat acid and belinostat dimer) to defined levels upon release and after extended storage.
Increases in vivo plasma exposure/bioavailability relative to crystalline belinostat.
Enhances in vitro dissolution relative to crystalline belinostat.
Documented Applications
Oral delivery of belinostat using amorphous solid dispersions prepared by spray-drying from a solution and characterized as substantially amorphous form.
Pharmacokinetic assessment in animals described as dog pharmacokinetics, reporting plasma exposure/bioavailability for oral formulations.
Interested in licensing this patent?