Spray-dried dispersions, formulations, and polymorphs of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide
Inventors
Brandhuber, Barbara J. • Brent, Lauren T. • Eary, Charles Todd • Kenna, Andrew • Khan, Firas • Renshaw, Vivian F. H. • Spencer, Stacey Renee
Assignees
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Publication Number
US-12109193-B2
Publication Date
2024-10-08
Expiration Date
Abstract
A spray-dried dispersions and pharmaceutical composition of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide, pharmaceutically acceptable salts thereof, or a combination thereof and the use of the spray-dried dispersion and pharmaceutical composition in the treatment of cancer and autoimmune and inflammatory diseases are disclosed. Also provided are crystalline forms of (S)-5-amino-3-(4-((5-fluoro-2-methoxy-benzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide also useful in the treatment of cancer and autoimmune and inflammatory diseases.
Core Innovation
The invention relates to a pharmaceutical composition comprising a spray-dried dispersion comprising a compound of Formula I or a pharmaceutically acceptable salt thereof. The composition further includes one or more polymers selected from an HPMCAS polymer, an HPMC polymer, a vinylpyrrolidone-vinyl acetate copolymer, and a polyvinylpyrrolidone (PVP) polymer, together with a pharmaceutically acceptable excipient.
Dependent formulations refine the polymer selection by specifying HPMCAS polymers and, in further dependent forms, specifying HPMCAS grade or variants selected from HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HPMCAS-HF, and HPMCAS-HG. Additional dependent forms characterize further structural and compositional constraints, including a tablet composition with microcrystalline cellulose, mannitol or lactose monohydrate, disintegrants including sodium starch glycolate and/or croscarmellose sodium, magnesium stearate, optional silicon dioxide, and a coating.
The document also characterizes crystalline Form A of the compound of Formula I using solid-state characterization data, including XRPD peak information and a DSC endotherm onset. The disclosure also mentions polymorphs and a Form C hemi-1,4-dioxane solvate context.
The disclosed therapeutic purpose is to treat or prevent BTK-associated cancer and autoimmune/inflammatory diseases, using methods described in terms of BTK/BCR signaling pathway dysregulation and BTK inhibitor resistance mutations.
Claims Coverage
One independent claim is identified. The claim coverage centers on a spray-dried dispersion pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof with selected polymers and a pharmaceutically acceptable excipient; dependent claims narrow the polymer selection to HPMCAS, specify particular HPMCAS grades, and add tablet formulation constraints and a coating.
Spray-dried dispersion composition with Formula I and selected polymers
A pharmaceutical composition comprising a spray-dried dispersion comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more polymers selected from HPMCAS polymer, an HPMC polymer, a vinylpyrrolidone-vinyl acetate copolymer, and a polyvinylpyrrolidone (PVP) polymer, and a pharmaceutically acceptable excipient.
Tablet formulation with HPMCAS at defined ratios and excipient composition
A pharmaceutical tablet composition including the compound of Formula I or a pharmaceutically acceptable salt with HPMCAS in about a 1:1 ratio, together with specified weight-percentage amounts of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, silicon dioxide when present, and a spray-dried dispersion at about 40–50% w/w.
HPMCAS polymer selection
A pharmaceutical composition wherein the one or more polymers are HPMCAS polymers.
Specific HPMCAS grade or variant selection
The pharmaceutical composition where the HPMCAS polymer is selected from HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HPMCAS-HF, or HPMCAS-HG.
Optional coating for the composition
A pharmaceutical composition characterized by additionally including a coating.
Overall, the claim set centers on a spray-dried dispersion-based pharmaceutical composition for a compound of Formula I using selected polymers, with dependent claims primarily narrowing the polymer to HPMCAS variants, defining tablet composition constraints, and optionally adding a coating.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating or preventing BTK-associated cancer.
Treating or preventing autoimmune/inflammatory diseases.
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