Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
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Publication Number
US-10772877-B2
Publication Date
2020-09-15
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 provides pharmaceutical compositions for poorly water-soluble protein kinase inhibitors that use amorphous solid dispersion particles. The particles consist of a protein kinase inhibitor having a degree of amorphicity of 100% together with at least one polymeric stabilizing and matrix-forming component, with the protein kinase inhibitor loading ranging from about 10% by weight to about 70% by weight of the particles. The protein kinase inhibitor is nilotinib, nilotinib hydrate, nilotinib solvate, nilotinib salt, or combinations thereof.
In certain embodiments, the composition optionally includes at least one pharmaceutically acceptable solubilizer selected from d-α-tocopherol acid polyethylene glycol 1000 succinate, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-40 stearate, a hard fat, a polyoxylglyceride, a PEG-8 caprylic/capric glyceride, and a poloxamer. Where present, the solubilizer is a physical mixture with the amorphous solid dispersion particles.
The composition consists of the amorphous solid dispersion particles plus an excipient in another formulation. Additional refinements specify selected polymeric stabilizing and matrix-forming components, particle diameter size thresholds, and stability over storage with amorphous form characterized by XRPD.
Claims Coverage
The independent claims cover three inventive features. They define pharmaceutical compositions built around amorphous solid dispersion particles with a protein kinase inhibitor at 100% amorphicity and specified loading, along with optional or additional formulation components and nilotinib solid-form limitations.
Amorphous solid dispersion particles with 100% amorphicity PKI plus polymeric stabilizing and matrix-forming component
A pharmaceutical composition comprising amorphous solid dispersion particles in which the particles consist of a protein kinase inhibitor having a degree of amorphicity of 100% in an amount from about 10% by weight to about 70% by weight of the particles, and at least one polymeric stabilizing and matrix-forming component, wherein the protein kinase inhibitor is nilotinib, nilotinib hydrate, nilotinib solvate, nilotinib salt, or combinations thereof.
Optional pharmaceutically acceptable solubilizer physically mixed with amorphous solid dispersion particles
The pharmaceutical composition further optionally includes at least one pharmaceutically acceptable solubilizer selected from d-α-tocopherol acid polyethylene glycol 1000 succinate, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-40 stearate, a hard fat, a polyoxylglyceride, a PEG-8 caprylic/capric glyceride, and a poloxamer, wherein when present the solubilizer is a physical mixture with the amorphous solid dispersion particles.
Amorphous solid dispersion particles plus excipient with selected polymeric stabilizing and matrix-forming components
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 from about 10% by weight to about 70% by weight of the particles, and at least one polymeric stabilizing and matrix-forming component selected from named cellulose derivatives, vinyl polymers, carbomer types, methacrylic acid copolymers, polyethylene glycol, DL lactide/glycolide copolymers, cellulose acetate phthalate, carbomer homopolymers, aminoalkyl methacrylate copolymer, and poloxamer, and further comprising an excipient, wherein the protein kinase inhibitor is nilotinib, nilotinib hydrate, nilotinib solvate, nilotinib salt, or a combination thereof.
Collectively, the independent claims define pharmaceutical compositions in which the PKI is present as a 100% amorphous solid dispersion with polymeric stabilizing and matrix-forming components, using specified PKI loading from about 10% to about 70% by weight. The independent coverage also includes either an optional physically mixed solubilizer from a defined list or a formulation consisting of the particles plus an excipient, while limiting the PKI solid form to nilotinib and specified nilotinib forms.
Stated Advantages
Markedly increased % solubilized and AUC compared with non-formulated drug in FaSSIF (pH 6.5).
Higher initial dissolution rates versus raw crystalline drug for multiple protein kinase inhibitors under sink conditions.
Improved plasma exposure in a dog study for nilotinib base formulations versus marketed nilotinib HCl.
Reduced dependence on stomach pH in the in vivo dog study.
Further gains in exposure when a solubilizer is included.
Particles remain amorphous and maintain dissolution behavior for about 11–12 months at room temperature based on XRPD, DVS, mDSC, TG, and dissolution/AUC evidence.
Increased apparent solubility.
Increased dissolution rate compared with raw crystalline drug and physical mixes.
Improved dissolution performance under sink conditions as reported using AUC and dissolution-time metrics.
Stability over storage is characterized/reported.
Documented Applications
In vivo dog study: plasma exposure (Cmax/Tmax/t1/2/AUC) comparison of nilotinib base formulations versus marketed nilotinib HCl, including reduced dependence on stomach pH and additional gains with an included solubilizer.
Treatment of a proliferative disorder in a patient by administering a therapeutically effective amount of the pharmaceutical composition.
In vivo plasma performance is reported for nilotinib formulations in beagle dogs.
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