Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-10314829-B2
Publication Date
2019-06-11
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 pharmaceutical compositions that include amorphous solid dispersion particles having a degree of amorphicity of 100%. The particles consist of a protein kinase inhibitor in an amount of about 10% by weight to about 70% by weight and at least one polymeric stabilizing and matrix-forming component.
The compositions further optionally include at least one pharmaceutically acceptable solubilizer selected from d-b1-tocopherol acid polyethylene glycol 1000 succinate, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-40 stearate, a hard fat, a polyoxylglyceride, PEG-8 caprylic/capric glyceride, and a poloxamer. When a solubilizer is present, it is a physical mixture with the amorphous solid dispersion particles.
The disclosed approach focuses on specific protein kinase inhibitors, including sorafenib, sorafenib hydrate, sorafenib solvate, sorafenib salt, or combinations thereof, and characterizes the solid dispersion particles by 100% amorphicity and composition-defined components. The document describes improved dissolution and reduced precipitation in intestinal pH-relevant media (FaSSIF/FeSSIF/SGF) and supports this with quantitative dissolution metrics and comparative evaluations versus crystalline drug.
Claims Coverage
The document includes two independent claims that define amorphous solid dispersion pharmaceutical compositions with 100% degree of amorphicity and specific composition constraints. Together, the independent claims cover compositions using at least one polymeric stabilizing and matrix-forming component with optional listed solubilizers, and a narrower composition defined by copolyvidone plus an excipient.
100% amorphous solid dispersion particles with protein kinase inhibitor and polymeric stabilizing and matrix-forming component
A pharmaceutical composition comprising amorphous solid dispersion particles having a degree of amorphicity of 100%, wherein the particles consist of a protein kinase inhibitor in an amount of about 10% by weight to about 70% by weight of the particles and at least one polymeric stabilizing and matrix-forming component.
Optional physical-mixture solubilizer selected from specified group
Optionally at least one pharmaceutically acceptable solubilizer selected from the group consisting of d-b1-tocopherol acid polyethylene glycol 1000 succinate, a PEG-40 hydrogenated castor oil, a PEG-35 castor oil, a PEG-40 stearate, a hard fat, a polyoxylglyceride, a PEG-8 caprylic/capric glyceride, and a poloxamer, wherein the at least one pharmaceutically acceptable solubilizer, when present, is a physical mixture with the amorphous solid dispersion particles.
Sorafenib (and sorafenib forms) as the protein kinase inhibitor
Wherein the protein kinase inhibitor is sorafenib, sorafenib hydrate, sorafenib solvate, sorafenib salt, or combinations thereof.
Copolyvidone as the polymeric component in 100% amorphous particles with excipient
A pharmaceutical composition consisting of amorphous solid dispersion particles having a degree of amorphicity of 100%, where the particles consist of a protein kinase inhibitor in an amount of about 10% by weight to about 70% by weight of the particles, copolyvidone, and an excipient.
The claim set is centered on 100% amorphous solid dispersion particles comprising a protein kinase inhibitor at 10-70 wt% and a polymeric component. One independent claim allows at least one polymeric stabilizing and matrix-forming component with optional physical-mixture solubilizers from a specified list, while the other specifies copolyvidone plus an excipient, with sorafenib and specified forms as the protein kinase inhibitor.
Stated Advantages
Improved dissolution and apparent solubility in intestinal pH-relevant media (FaSSIF/FeSSIF/SGF) compared with raw crystalline drug.
Reduced precipitation in intestinal pH-relevant media.
Increased dissolution rate for nanoparticle or amorphous solid dispersion formulations compared with crystalline counterparts.
Dissolution enhancements are evaluated with metrics including initial dissolution rate, solubilized fraction, AUC, and ratios versus raw crystalline drug.
Documented food-effect relevance via comparisons in FaSSIF versus FeSSIF.
Higher exposure/bioavailability for nanoparticle formulations versus marketed nilotinib HCl.
Reduced dependence on stomach pH.
Solubilizer-containing formulations yield further increases in exposure/bioavailability.
Improved dissolution performance, including initial dissolution rate improvements versus crystalline/raw salts or bases.
Particles remain amorphous and retain dissolution/AUC performance over about 11-12 months at room temperature.
Documented Applications
Treating a proliferative disorder in a patient by administering a therapeutically effective amount of the pharmaceutical composition.
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