Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-10561644-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 stable amorphous hybrid nanoparticles and pharmaceutical compositions for poorly water-soluble protein kinase inhibitors. The particles contain a protein kinase inhibitor having a degree of amorphicity of 100% or amorphous PKI forms associated with polymer matrix formers, so that the PKI is present within an amorphous solid dispersion particle system or hybrid nanoparticle composition.
The compositions optionally further include at least one pharmaceutically acceptable solubilizer, where the solubilizer is a physical mixture with the amorphous solid dispersion particles, or an optional Soluplus-type solubilizer in hybrid nanoparticle capsules. The disclosed PKIs include dasatinib and its hydrate, solvate, salt, or combinations thereof, and other named PKIs such as nilotinib base, crizotinib, axitinib, and vemurafenib.
The disclosure addresses poor aqueous solubility and related dissolution/solubilized exposure, with solid-state and pharmacokinetic results reported for gastric and intestinal conditions, sink-condition performance, in vivo dog pharmacokinetics, and storage stability. The described compositions maintain physical stability over storage and provide enhanced dissolution and exposure compared with raw crystalline drug or marketed nilotinib HCl formulations.
Claims Coverage
The independent claims cover composition constructs defined around amorphous solid dispersion particles containing a PKI with 100% degree of amorphicity, paired with specific polymeric components and, in one construct, an optional solubilizer/excipient system. Overall, the claims emphasize amorphous solid dispersion particle structure, 100% amorphicity with defined PKI forms and loading ranges, polymeric stabilizing and matrix-forming components, copolyvidone, and optional pharmaceutically acceptable solubilizer selection.
Amorphous solid dispersion particles with 100% amorphicity PKI and polymeric stabilizing and matrix-forming component
A pharmaceutical composition comprising amorphous solid dispersion particles wherein the particles consist of 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, and at least one polymeric stabilizing and matrix-forming component.
Optional solubilizer as physical mixture with amorphous solid dispersion particles
The pharmaceutical composition further optionally includes at least one pharmaceutically acceptable solubilizer selected from a defined group, wherein the solubilizer, when present, is a physical mixture with the amorphous solid dispersion particles.
Dasatinib and defined forms as the PKI in amorphous solid dispersion particles
The protein kinase inhibitor is dasatinib, dasatinib hydrate, dasatinib solvate, dasatinib salt, or combinations thereof.
Amorphous solid dispersion particles with copolyvidone and a PKI with 100% amorphicity
A pharmaceutical composition consisting of amorphous solid dispersion particles where the particles consist of 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 and copolyvidone.
Excipient in the dasatinib/copolyvidone amorphous dispersion composition
The pharmaceutical composition additionally includes an excipient, with the protein kinase inhibitor in the particles being dasatinib, dasatinib hydrate, dasatinib solvate, dasatinib salt, or combinations thereof.
Across the independent claims, the inventive coverage centers on amorphous solid dispersion particles containing a PKI with 100% degree of amorphicity, combined with a polymeric stabilizing and matrix-forming component, including copolyvidone in one independent claim. One construct further permits an optional pharmaceutically acceptable solubilizer defined as a physical mixture, and both constructs specify dasatinib and its listed forms as the PKI.
Stated Advantages
Enhanced dissolution/solubilized exposure compared with raw crystalline drug.
Maintains physical stability over storage.
Provides solubility/dissolution benefits in intestinal (FaSSIF/FeSSIF) and gastric (SGF) conditions.
Improved dissolution performance under sink conditions compared with raw crystalline forms.
Increased in vivo exposure, reflected by AUC over 80 minutes and AUC increases versus raw drug for multiple PKIs.
Improved plasma exposure in dogs for nilotinib base hybrid nanoparticle capsules compared with a marketed nilotinib HCl formulation.
Reduced dependence on stomach pH, as described for the nilotinib base hybrid nanoparticle capsules.
Solid-state stability of stable amorphous hybrid nanoparticles for at least about 11 months at room temperature, with largely unchanged dissolution profile after storage.
Documented Applications
Evaluation of solubility/dissolution under gastric (SGF) and intestinal (FaSSIF/FeSSIF) conditions for the disclosed compositions.
Assessment of in vivo plasma exposure following oral administration in beagle dogs.
Storage stability assessment over time with physical characterization to support maintained amorphous state.
Formulation and evaluation of stable amorphous hybrid nanoparticles for protein kinase inhibitors, including dissolution (FaSSIF pH 6.5 and sink conditions) and in vivo dog pharmacokinetics (including comparisons to raw crystalline drug and marketed nilotinib HCl).
Assessment of solid-state stability of amorphous hybrid nanoparticles over storage at room temperature using XRPD and related measurements, including dissolution/AUC behavior after storage.
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