Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-11376243-B2
Publication Date
2022-07-05
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 and pharmaceutical compositions comprising particles with amorphous nilotinib or a salt thereof. The particles include at least one polymeric stabilizing and matrix-forming component selected from a defined list of polymeric materials, and the particles exclude at least one pharmaceutically acceptable solubilizer.
The compositions address poorly water-soluble drugs by improving dissolution and solubility behavior. The disclosed placement of pharmaceutically acceptable solubilizers includes exclusion from the particles and, where included, physical mixture with the particles or distribution at particle surfaces.
Comparative dissolution and solubilization data are presented in FaSSIF, FeSSIF, and SGF at intestinal and gastric pH, together with sink-condition flow-through cell testing and XRPD analysis. The document also reports stability and amorphicity-related behavior, including dissolution/AUC retention after storage and limited in vivo assessment in beagle dogs compared with a marketed nilotinib HCl product.
Claims Coverage
The independent claims identified are directed to amorphous nilotinib particles stabilized by at least one specified polymeric matrix-forming component, with an explicit exclusion of at least one pharmaceutically acceptable solubilizer. A second independent claim further requires formulation as a tablet or capsule with an excipient.
Amorphous nilotinib particle system with excluded solubilizer
A composition comprising particles including amorphous nilotinib or a salt thereof and at least one polymeric stabilizing and matrix-forming component selected from a specified list, wherein the particles exclude at least one pharmaceutically acceptable solubilizer.
Tablet or capsule with amorphous nilotinib particles excluding solubilizer and excipient
A tablet or capsule comprising particles including amorphous nilotinib or a salt thereof and at least one polymeric stabilizing and matrix-forming component selected from a specified list, wherein the particles exclude at least one pharmaceutically acceptable solubilizer, and an excipient.
Overall, the claim coverage centers on amorphous nilotinib or nilotinib salt in particles containing specified polymeric stabilizing and matrix-forming components, with explicit exclusion of at least one pharmaceutically acceptable solubilizer. The tablet or capsule claim further recites an excipient.
Stated Advantages
Improved solubility and dissolution versus raw crystalline PKIs.
Reported dissolution-rate enhancements at intestinal and gastric pH conditions using FaSSIF, FeSSIF, and SGF.
Higher nilotinib plasma exposure and oral bioavailability versus a marketed nilotinib HCl formulation.
Reduced stomach pH dependence.
Substantially higher initial dissolution rates under sink-condition flow-through testing versus raw crystalline forms.
Particle stability with dissolution/AUC retention after storage, with reported ratio >97% for at least about 11–12 months at room temperature.
Documented Applications
Pharmaceutical compositions for delivering protein kinase inhibitors (PKIs), including poorly water-soluble drugs.
Oral dosage forms including tablets and capsules comprising the disclosed particles and excipients.
Dissolution and solubilization assessment in FaSSIF, FeSSIF, and SGF at intestinal and gastric pH conditions.
Sink-condition flow-through cell testing for multiple PKIs including nilotinib, crizotinib, axitinib, and vemurafenib.
Limited in vivo plasma level assessment in beagle dogs comparing formulations to a marketed nilotinib HCl product.
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