Pharmaceutical formulations
Inventors
Xu, Jingrong • Jones, William • Flicker, Felicia • Berner, Bret
Assignees
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Publication Number
US-11266649-B2
Publication Date
2022-03-08
Expiration Date
Abstract
The disclosure provides, inter alia, pharmaceutical compositions comprising micronized drug particles of adenosine A2A receptor antagonists, and methods of treating cancer using the pharmaceutical compositions.
Core Innovation
The invention relates to a pharmaceutical composition comprising a compound of Formula (III) or a pharmaceutically acceptable salt thereof and excipients mannitol, microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, and hydroxypropyl cellulose. The composition includes about 20 wt % to about 30 wt % of the compound of Formula (III), with the Formula (III) component having a particle size distribution having a D90 of about 20 microns or less as measured by laser diffraction spectroscopy.
A key aspect is controlling the micronized particle size distribution, including a D90 of about 10 microns or less in certain aspects. The disclosed compositions include mannitol as a mixture of spray-dried mannitol and crystalline mannitol in a defined weight ratio range, and the formulation scope includes optional surfactants and lubricants/glidants as part of the formulation approach.
The patent addresses rapid dissolution/disintegration and performance consistency for a pharmaceutical composition containing an adenosine A2A receptor antagonist. The disclosed compositions and characterization metrics include impurity and assay stability under storage and performance attributes evaluated with USP <711> dissolution and USP <701> disintegration test methods, and the formulation scope extends to oral dosage forms such as tablets, capsules, granules, powders, and beads, including a bead dosage form with an inert core and a drug layer.
Claims Coverage
The claims cover a specific quantitative formulation architecture with particle-size control for the Formula (III) component, together with dependent refinements for performance and dosage-form structure.
Particle-size constrained formula (III) component for dissolution/disintegration
The composition comprises about 20 wt % to about 30 wt % of a compound of Formula (III) or a pharmaceutically acceptable salt thereof having a particle size distribution with a D90 of about 20 microns or less, as measured by laser diffraction spectroscopy.
Defined excipient weight-percentage ranges
The composition further comprises about 35 wt % to about 40 wt % of mannitol; about 15 wt % to about 30 wt % of microcrystalline cellulose; about 4 wt % to about 12 wt % of crosslinked sodium carboxymethyl cellulose; and about 1 wt % to about 8 wt % of hydroxypropyl cellulose.
Tightened D90 particle-size threshold for the Formula (III) component
The composition is characterized by the compound of Formula (III) or a pharmaceutically acceptable salt thereof having a particle size distribution with a D90 of about 10 microns or less as measured by laser diffraction spectroscopy.
Dissolution performance threshold using USP <711> Type II paddle
The composition is characterized by having at least 70% dissolution in 10 minutes when measured by the USP <711> Type II (Paddle) dissolution apparatus method.
Disintegration performance threshold using USP <701>
The composition is characterized by having a disintegration time of about 15 minutes or less when measured by the USP Chapter <701> Disintegration Test method.
Bead dosage form with inert core and drug layer
A bead is provided that has an inert core and a drug layer made from the composition, wherein the core has a particle size between about 100 microns and about 2.5 mm.
The claimed subject matter centers on a composition containing a compound of Formula (III) with laser diffraction-defined D90 micronization, specific excipient weight-percentage ranges, and dependent claims to dissolution and disintegration criteria and bead dosage forms with an inert core size range.
Stated Advantages
Rapid dissolution/disintegration and performance consistency.
Impurity and assay stability under storage.
Documented Applications
Treating cancer, including oral dosing regimens described as once daily (QD) or twice daily (BID).
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