Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-11963951-B2
Publication Date
2024-04-23
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 a composition comprising particles in which a protein kinase inhibitor has a degree of amorphicity of 100% and is present in an amount of about 10% by weight to about 70% by weight of the particles. The particles include at least one polymeric stabilizing and matrix-forming component and at least one pharmaceutically acceptable solubilizer selected from a defined group. The protein kinase inhibitor is axitinib, axitinib hydrate, axitinib solvate, axitinib salt, or combinations thereof.
The disclosed compositions are stable amorphous hybrid nanoparticles or amorphicity-based particles in which the protein kinase inhibitor is incorporated together with polymeric stabilizing and matrix-forming components and selected pharmaceutically acceptable solubilizers. The particles consist of a protein kinase inhibitor with a degree of amorphicity of 100% and are described with stability criteria including particle characteristics in terms of amorphicity and particle size ranges.
The compositions are intended to improve dissolution and apparent solubility by using particles containing a 100% degree of amorphicity protein kinase inhibitor combined with polymeric stabilizing and matrix-forming components and optional selected solubilizers. The document describes comparative dissolution and solubility performance versus raw crystalline PKIs, and it relates the compositions to dissolution testing in intestinal and gastric simulated fluids under sink conditions and stability assessments including XRPD after months.
Claims Coverage
The consolidated content provides two independent claims. Each independent claim is centered on particles containing a 100% degree of amorphicity protein kinase inhibitor, specifically axitinib forms, together with polymeric components and pharmaceutically acceptable solubilizers; the claims differ in whether the polymeric component is specified generally or fixed to copolyvidone.
100% amorphous axitinib particles with polymeric stabilizing and matrix-forming component and selected solubilizer(s)
A composition comprising particles in which the protein kinase inhibitor has a degree of amorphicity of 100% and is present from about 10% by weight to about 70% by weight of the particles, the particles include at least one polymeric stabilizing and matrix-forming component, and the composition includes at least one pharmaceutically acceptable solubilizer selected from a specified group; wherein the protein kinase inhibitor is axitinib, axitinib hydrate, axitinib solvate, axitinib salt, or combinations thereof.
Copolyvidone-based 100% amorphous axitinib particles with selected solubilizer(s)
A composition consisting of particles comprising a protein kinase inhibitor having a degree of amorphicity of 100% in an amount of from about 10% by weight to about 70% by weight of the particles, copolyvidone, and at least one pharmaceutically acceptable solubilizer selected from a specified group; wherein the protein kinase inhibitor is axitinib, axitinib hydrate, axitinib solvate, axitinib salt, or combinations thereof.
Across the independent claims, the inventive focus is the use of axitinib and specified axitinib forms at 100% degree of amorphicity within particles that also include polymeric stabilizing and matrix-forming components and selected pharmaceutically acceptable solubilizers, with one claim requiring copolyvidone as the polymeric component.
Stated Advantages
Improves dissolution and apparent solubility versus raw crystalline protein kinase inhibitors.
Provides improved dissolution performance in intestinal and gastric simulated fluids under sink conditions, evidenced by comparisons including initial dissolution rate and AUC.
Improves solubilization performance relative to raw crystalline PKIs across multiple listed protein kinase inhibitors.
Demonstrates effects from adding solubilizers separately or within particles, and differences versus physical mixtures.
Improved solubilization and increased AUC for multiple protein kinase inhibitors versus raw drug forms.
Improved initial dissolution rates under sink-condition dissolution testing versus crystalline raw forms.
Improved in vivo plasma exposure in dog pharmacokinetics for nilotinib base formulations versus a marketed formulation.
Reduced pH-dependence and enhanced exposure when combined with Soluplus.
Stability evidence indicating particles stable for at least approximately 11 months at room temperature.
Documented Applications
Oral administration performance is described using beagle dog oral PK studies comparing nilotinib base formulations versus a marketed nilotinib HCl product under differing stomach pH conditions.
Dissolution testing in simulated intestinal and gastric fluids is documented, including FaSSIF, FeSSIF, and SGF under sink conditions with measured dissolution metrics.
Use in vivo plasma pharmacokinetics in beagle dogs (protein kinase inhibitor formulations, including nilotinib base formulations) with improved plasma exposure.
Use in dissolution testing in FaSSIF (pH 6.5) and under sink-condition dissolution conditions to assess solubilization and dissolution rate behavior of multiple protein kinase inhibitors.
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