Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-10561645-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 relates to pharmaceutical compositions comprising particles that include a protein kinase inhibitor having a degree of amorphicity of about 100% and a polymeric stabilizing and matrix-forming component. The protein kinase inhibitor is present in an amount of about 10% by weight to about 40% by weight of the particles, and the polymeric stabilizing and matrix-forming component is present in an amount of about 60% by weight to about 90% by weight of the particles.
The protein kinase inhibitor is dasatinib, dasatinib hydrate, dasatinib solvate, dasatinib salt, or combinations thereof. The disclosure further defines stable amorphous hybrid nanoparticles formed with the amorphous drug and a polymeric stabilizing and matrix-forming component, with the polymeric stabilizing and matrix-forming component selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone, polyvinyl acetate phthalate, copolyvidone, crospovidone, methacrylic acid and ethylacrylate copolymer, methacrylate acid and methyl methacrylate copolymer, polyethylene glycol, DL lactide/glycolide copolymer, poly DL-lactide, cellulose acetate phthalate, carbomer homopolymer Type A, carbomer homopolymer Type B, aminoalkyl methacrylate copolymers, and poloxamers.
The compositions are optionally formulated with solubilizers such as Soluplus, TPGS, and Cremophor. The disclosure describes evaluation in simulated gastric and intestinal fluids, including FaSSIF (pH ~6.5) under sink conditions and flow-through cell measurements, and reports dissolution/solubility performance compared with raw crystalline drug.
Claims Coverage
The independent claim set centers on three core inventive features: particles containing a protein kinase inhibitor at about 10–40 wt% with about 100% amorphicity, a polymeric stabilizing and matrix-forming component at about 60–90 wt% of the particles, and the protein kinase inhibitor being dasatinib or a specified dasatinib form. Dependent claims add polymer selection, particle size, inhibitor loading, solubilizer, and excipient refinements.
About 100% amorphous protein kinase inhibitor particles at 10–40 wt%
Particles include a protein kinase inhibitor having a degree of amorphicity of about 100% in an amount of from about 10% by weight to about 40% by weight of the particles.
Polymeric stabilizing and matrix-forming component at 60–90 wt%
Particles include at least one polymeric stabilizing and matrix-forming component in an amount of about 60% by weight to about 90% by weight of the particles.
Dasatinib as the specified protein kinase inhibitor
The protein kinase inhibitor is dasatinib, dasatinib hydrate, dasatinib solvate, dasatinib salt, or combinations thereof.
Selected polymeric stabilizing and matrix-forming components
The polymeric stabilizing and matrix-forming component is selected from enumerated cellulose, synthetic polymer, copolymer, and poloxamer materials.
Protein kinase inhibitor loading narrowed to 10–30 wt%
The protein kinase inhibitor is present in the particles in an amount of about 10% by weight to about 30% by weight.
Optional solubilizer at a defined level
A solubilizer is present at about 0.5% by weight relative to the combined weight of the particles and the solubilizer.
Excipient selection categories
An excipient includes one or more selected formulation components including at least one of a binding agent, disintegrant, filler, lubricant, solubilizer, and wetting agent.
Sub-1000/500/250 nm average particle diameter thresholds
The particles have an average particle diameter size less than about 1000 nm, about 500 nm, or about 250 nm.
Overall claim coverage is directed to amorphous solid dispersion particles comprising dasatinib or specified dasatinib forms as a protein kinase inhibitor phase in combination with a polymeric stabilizing and matrix-forming component at a complementary wt% range. Dependent claims refine polymer choices, particle size, inhibitor loading, and optional solubilizer and excipient component categories.
Stated Advantages
Increases dissolution and solubility relative to raw crystalline drug.
Substantially increases drug concentration, % solubilized, AUC, and initial dissolution rate compared with raw crystalline drug.
Improved plasma exposure versus marketed nilotinib.
Reduced stomach pH dependency.
Further gains when Soluplus is included.
Stability performance of about 11–12 months at room temperature supported by XRPD/mDSC/TGA/DVS, with dissolution profile retention where AUC is essentially unchanged after 11 months.
Documented Applications
In vivo dog pharmacokinetics for nilotinib nanoparticle formulations, including comparisons versus marketed nilotinib.
Dissolution/solubility evaluation under FaSSIF (pH ~6.5) sink conditions, including flow-through cell measurements.
Method of treating proliferative disorder therapy, including cancers and tumors/leukemia.
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