Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-10561643-B2
Publication Date
2020-02-18
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 concerns pharmaceutical compositions comprising amorphous solid dispersion particles having a degree of amorphicity of 100%. The particles comprise a protein kinase inhibitor in an amount of from about 10% by weight to about 70% by weight of the particles, at least one polymeric stabilizing and matrix-forming component, and at least one pharmaceutically acceptable solubilizer selected from a specified group including d-α-tocopherol acid polyethylene glycol 1000 succinate, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-40 stearate, hard fat, polyoxylglyceride, PEG-8 caprylic/capric glyceride, and poloxamer.
In one described embodiment, the protein kinase inhibitor is dasatinib, dasatinib hydrate, dasatinib solvate, dasatinib salt, or combinations thereof, and the solubilizer is present in an amount of about 0.5% by weight based on the weight of the particles and solubilizer. The composition further includes copolyvidone and an excipient in one claim context, and the particle system is described as 100%-amorphous hybrid nanoparticles.
The document describes improved dissolution and apparent solubility, dissolution rate, and AUC under sink conditions compared to raw crystalline drug. It further reports performance across multiple protein kinase inhibitors including nilotinib, erlotinib, pazopanib, lapatinib, gefitinib, dasatinib, sorafenib tosylate, crizotinib, axitinib, and vemurafenib, with dissolution improvements observed in FaSSIF and FeSSIF and stability over storage.
Claims Coverage
The partial content includes two independent claims. Both independent claims share 100%-amorphous solid dispersion particles containing a specified protein kinase inhibitor, a polymeric stabilizing and matrix-forming component, and a selected pharmaceutically acceptable solubilizer present at about 0.5% by weight based on the weight of the particles and solubilizer, with one claim additionally specifying copolyvidone and an excipient.
100%-amorphous solid dispersion particles for dasatinib species
Amorphous solid dispersion particles having a degree of amorphicity of 100% comprising a protein kinase inhibitor in an amount from about 10% by weight to about 70% by weight, at least one polymeric stabilizing and matrix-forming component, and at least one pharmaceutically acceptable solubilizer selected from the listed group; the protein kinase inhibitor is dasatinib, dasatinib hydrate, dasatinib solvate, dasatinib salt, or combinations thereof; and the solubilizer is present in an amount of about 0.5% by weight based on the weight of the particles and solubilizer.
Copolyvidone-based 100%-amorphous dasatinib solid dispersion with excipient
A pharmaceutical composition consisting of amorphous solid dispersion particles having a degree of amorphicity of 100% where the particles comprise a protein kinase inhibitor in an amount from about 10% by weight to about 70% by weight, copolyvidone, and at least one pharmaceutically acceptable solubilizer selected from the listed group; an excipient is present; the protein kinase inhibitor is dasatinib, dasatinib hydrate, dasatinib solvate, dasatinib salt, or combinations thereof; and the at least one pharmaceutically acceptable solubilizer is present in an amount of about 0.5% by weight based on the weight of the particles and solubilizer.
Across the independent claims, the inventive coverage centers on 100%-amorphous amorphous solid dispersion particle pharmaceutical compositions using dasatinib species, polymeric stabilizing and matrix-forming components including copolyvidone in one claim, and a specified class of pharmaceutically acceptable solubilizers present at about 0.5% by weight based on the particles and solubilizer.
Stated Advantages
Improved dissolution, including apparent solubility and dissolution rate, compared to raw crystalline drug.
Improved AUC under sink conditions compared to raw crystalline drug.
Performance improvement across multiple protein kinase inhibitors including nilotinib, erlotinib, pazopanib, lapatinib, gefitinib, dasatinib, sorafenib tosylate, crizotinib, axitinib, and vemurafenib.
Dissolution improvements observed in FaSSIF and FeSSIF.
Improves exposure and reduces pH-dependence versus marketed nilotinib HCl.
Provides further increases in exposure when Soluplus is included.
Demonstrates physical stability over at least about 11 months at room temperature, with minimal change in AUC after storage.
Documented Applications
Use of the pharmaceutical compositions as treatment for proliferative disorder in a patient.
Oral dosing in beagle dogs for pharmacokinetic assessment via dog plasma, including evaluation of pH-dependence versus marketed nilotinib HCl.
Assessment of dissolution and solubilization in FaSSIF (pH 6.5) under sink conditions and comparison of initial dissolution rates versus raw crystalline forms.
Use of amorphous hybrid nanoparticles in evaluating physical stability over storage and comparative AUC profiles after storage.
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