Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-10555937-B2
Publication Date
2020-02-11
Expiration Date
Abstract
The present invention relates to the field of methods for providing pharmaceutical compositions comprising poorly water-soluble drugs. In particular the present invention relates to compositions comprising stable, amorphous hybrid nanoparticles, comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix-forming component, useful in pharmaceutical compositions and in therapy.
Core Innovation
The invention relates to stable amorphous hybrid nanoparticles for poorly water-soluble protein kinase inhibitors. The hybrid nanoparticles are defined as solid dispersion particles having a protein kinase inhibitor with a degree of amorphicity of 100% together with at least one polymeric stabilizing and matrix-forming component, with the amorphous protein kinase inhibitor present in an amount of from about 10% by weight to about 70% by weight of the particles.
The disclosure further defines the optional presence of at least one pharmaceutically acceptable solubilizer, where the solubilizer can be present as a physical mixture with the amorphous solid dispersion particles. Specific solubilizers include d-alpha-tocopherol acid polyethylene glycol 1000 succinate, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-40 stearate, a hard fat, a polyoxylglyceride, a PEG-8 caprylic/capric glyceride, and a poloxamer.
The disclosed compositions include protein kinase inhibitor particles with improved dissolution and solubilization behavior. The results support stable amorphous hybrid nanoparticles comprising the amorphous protein kinase inhibitor with polymeric components, and characterization includes XRPD/DSC and storage-related performance data over an extended period at room temperature.
Claims Coverage
The independent claims cover pharmaceutical compositions comprising particles with a protein kinase inhibitor having 100% degree of amorphicity in defined weight proportions, stabilized by polymeric matrix-forming components, with optional solubilizers. Across the independent claims, there are 2 main inventive feature groups.
Amorphous protein kinase inhibitor stabilized by polymeric matrix-forming component with optional solubilizer physical mixture
A pharmaceutical composition comprising particles that include a protein kinase inhibitor with a degree of amorphicity of 100% in an amount of from about 10% by weight to about 70% by weight of the particles, and at least one polymeric stabilizing and matrix-forming component; optionally at least one pharmaceutically acceptable solubilizer selected from a specified group; and when present, the solubilizer is a physical mixture with the amorphous solid dispersion particles.
Dasatinib amorphous solid dispersion with copolyvidone particles plus an excipient
A pharmaceutical composition consisting of particles comprising a protein kinase inhibitor with a degree of amorphicity of 100% in an amount of from about 10% by weight to about 70% by weight of the particles, wherein the particles further comprise copolyvidone, and further comprising an excipient.
The independent claims primarily cover dasatinib, dasatinib hydrate, dasatinib solvate, or dasatinib salt as a 100% amorphous protein kinase inhibitor incorporated into particles stabilized by polymeric matrix-forming components, with an optional pharmaceutically acceptable solubilizer present as a physical mixture. A second independent claim narrows the polymer selection to copolyvidone and requires the presence of an excipient.
Stated Advantages
Improved dissolution and solubilization behavior, including higher initial dissolution rates relative to raw crystalline drug and increased dissolution rate and apparent solubility at intestinal/gastric pH.
Sustained performance during storage at room temperature for approximately 11–12 months, supported by XRPD/DSC/AUC-related stability characterization.
Increased plasma exposure in an in vivo dog study for oral dosing of nilotinib base using the hybrid-nanoparticle formulations relative to marketed nilotinib HCl.
Reduced pH-dependence of exposure relative to the marketed nilotinib HCl.
Documented Applications
Treating a proliferative disorder in a patient by administering a therapeutically effective amount of the pharmaceutical composition.
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