Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-12076314-B2
Publication Date
2024-09-03
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 tablet comprising particles that comprise amorphous dasatinib and at least one polymeric stabilizing and matrix-forming component selected from polyvinylpyrrolidone, copolyvidone, and methacrylic acid and ethylacrylate copolymer. The particles exclude at least one pharmaceutically acceptable solubilizer, and the tablet further comprises one or more excipients.
The disclosed subject matter relates to pharmaceutical compositions for poorly water-soluble protein kinase inhibitors, including tyrosine kinase inhibitors, that employ stable amorphous hybrid nanoparticles. The hybrid nanoparticles include amorphous protein kinase inhibitor material and polymeric stabilizing and matrix-forming components, and are characterized by high amorphicity with small particle size.
The compositions further address the role of pharmaceutically acceptable solubilizers, which are described as optional and as being either separate from the hybrid nanoparticles or associated with the nanoparticles. The disclosure includes pH-dependent dissolution using FaSSIF, FeSSIF, and SGF conditions, and extensive experimental results are described for multiple protein kinase inhibitors, including nilotinib, erlotinib, pazopanib, lapatinib, gefitinib, dasatinib, sorafenib, crizotinib, and axitinib.
Claims Coverage
The document includes one independent claim directed to a tablet formulation. The inventive features focus on amorphous dasatinib particles combined with specified polymeric stabilizing and matrix-forming components while excluding at least one pharmaceutically acceptable solubilizer, together with one or more excipients.
Tablet comprising amorphous dasatinib particles with stabilizing and matrix-forming polymers
A tablet comprising particles comprising amorphous dasatinib and at least one polymeric stabilizing and matrix-forming component selected from polyvinylpyrrolidone, copolyvidone, and methacrylic acid and ethylacrylate copolymer.
Particles exclude at least one pharmaceutically acceptable solubilizer
The particles exclude at least one pharmaceutically acceptable solubilizer.
Tablet includes one or more excipients
The tablet comprises one or more excipients.
Across the independent claim, the main inventive structure is a tablet formulation where amorphous dasatinib particles are stabilized and structured by specified polymeric stabilizing and matrix-forming components, while the particles exclude at least one pharmaceutically acceptable solubilizer, in combination with excipients.
Stated Advantages
Increased % solubilization and AUC for amorphous nanoparticles including polymeric stabilizing and matrix-forming components.
Higher initial dissolution rates versus raw crystalline API under sink conditions.
Increased dissolution rate and apparent solubility in intestinal and gastric pH conditions compared with raw crystalline drug.
Higher Cmax and AUC and improved bioavailability for nilotinib compositions.
Reduced pH-dependence of performance for nilotinib compositions.
Improved stability of the amorphous formulation, with maintained dissolution and AUC and single glass transition behavior over about 11–12 months.
Documented Applications
Tablet compositions for treatment involving specific leukemia types, including lymphocytic leukemia and/or myelogenous leukemia.
In vivo pharmacokinetics in beagle dogs for nilotinib compositions, including reported Cmax, Tmax, AUC, and bioavailability.
Oral dosing and evaluation in beagle dogs for nilotinib base formulations, including plasma levels and pharmacokinetics (AUC metrics) compared to a marketed nilotinib HCl reference.
Dissolution and solubilization performance in FaSSIF at pH about 6.5 for multiple poorly soluble protein kinase inhibitors, including crizotinib, axitinib, and vemurafenib.
Sink-condition dissolution rate measurements for multiple inhibitors, including nilotinib, erlotinib, pazopanib, lapatinib ditosylate, gefitinib, dasatinib, sorafenib tosylate, crizotinib, axitinib, and vemurafenib.
Treatment context for leukemia in the dependent-claim indication language, including lymphocytic leukemia and/or myelogenous leukemia.
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