Pharmaceutical compositions comprising stable amorphous hybrid nanoparticles of at least one protein kinase inhibitor and at least one polymeric stabilized matrix-forming component - Patents.com

Abstract

To provide novel pharmaceutical compositions comprising poorly water-soluble drugs capable of improving bioavailability and stability of pharmacologically active ingredients.SOLUTION: The pharmaceutical compositions comprise stable, amorphous solid dispersion particles, comprising at least one protein kinase inhibitor (such as nilotinib) and at least one polymeric stabilizing, matrix-forming component. The pharmaceutical compositions optionally further comprise at least one pharmaceutically acceptable solubilizer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical compositions containing poorly water-soluble drugs. In particular, the present invention relates to pharmaceutical compositions comprising stable amorphous hybrid nanoparticles of a protein kinase inhibitor (PKI) and a polymeric stabilized matrix-forming component. Furthermore, the present invention relates to a method for treating a proliferative disorder in a patient in need of such treatment, comprising administering a therapeutically effective amount of said composition. [Background technology]

[0002] Components of cell signaling pathways that control normal cell growth and differentiation, when dysregulated, give rise to cell proliferative disorders and cancer. Mutations in cell signaling proteins can cause such proteins to be expressed or activated at inappropriate levels or at inappropriate times during the cell cycle, which can lead to uncontrolled cell growth or altered cell-cell adhesion properties.

[0003] Many proliferative diseases, such as tumors and cancers, have been shown to involve overexpression or upregulation of protein kinase activity. Protein kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation usually results in a change in the function of the target protein by altering its enzymatic activity, cellular location, or association with other proteins. Protein kinases can be subdivided or characterized by the amino acid of the target protein that they control phosphorylation. Most kinases act on both serine and threonine, and tyrosine kinases act on tyrosine, but some (dual specificity kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, such as histidine kinases, which phosphorylate histidine residues. The human genome contains about 500 protein kinase genes, and up to 30% of all human proteins can be modified by protein kinases. Kinases are known to control a large proportion of cellular pathways, including those involved in signal transduction. Dysregulation of protein kinases, both by receptor and ligand mutations, gene rearrangements, gene amplification, and overexpression, has been implicated in the development and progression of human cancers. Therefore, protein kinase inhibitor compounds or protein kinase inhibitors (PKIs) are useful for treating diseases caused or exacerbated by overexpression or upregulation of protein kinases. For example, tyrosine kinase inhibitors (also known as tyrphostins, TKIs) have been shown to be effective antitumor and anti-leukemia agents (Lowery A et.al., Front Biosci. 2011 Jun 1; 17: 1996-2007).

[0004] A major goal of formulation chemistry is to improve the efficacy and safety of drugs, for example, by improving bioavailability and stability, as well as patient convenience. Bioavailability refers to the rate and extent to which an active substance or therapeutic agent is absorbed from a pharmaceutical form and becomes available at the site of action. The most common and preferred delivery method due to its simplicity, ease of ingestion, and high patient compliance with treatment is the oral route of drug delivery. However, for certain drugs, drug absorption from the gastrointestinal tract is limited by the low aqueous solubility and / or low membrane permeability of the drug molecule.

[0005] PKIs are generally weak bases that are only slightly soluble at low pH (e.g., 100-1000 mg / L) and practically insoluble at neutral pH (e.g., 0.1-10 mg / L). Therefore, increasing the solubility and dissolution rate of PKI drugs is important to improve the bioavailability and efficacy of most of these drugs. Typical PKIs exhibit a non-polypeptide structure and have a relatively low molecular weight, such as less than 10,000 daltons or less than 5,000 daltons.

[0006] There are several reported methods to improve the dissolution properties of poorly water-soluble drugs, such as micronization, salt or solvate formation, complexation, and microsphere formation. In addition, efforts have been made to improve the bioavailability provided by solid dosage forms by forming particles containing the drug or by mixing poorly water-soluble drugs with hydrophilic excipients. However, these methods have traditionally had inherent limitations in terms of the physical stability of the particles during storage, problems with grinding, or the difficulty of removing the often toxic solvent. Furthermore, it is important that the drug released from the solid phase does not precipitate in the gastrointestinal tract, precipitates as little as possible, and remains water-soluble in the aqueous fluids of the gastrointestinal tract, since precipitation reduces bioavailability (see, for example, Herve J. et al. Pharm Dev Technol. 2011 Jun;16(3):278-86).

[0007] Since most of the drug absorption occurs in the small and large intestines where pH is close to neutral, pH-dependent solubility is a well-known problem for many oral formulations of poorly water-soluble substances such as PKIs.Therefore, there is a continuous need to develop oral solid dosage forms of PKI-based drugs and improve their dissolution properties (Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, Holden SN, Benet LZ, Ware JA.Clin Pharmacol Ther.2012 Aug;92(2):203-13).Therefore, a method to improve the solubility of PKI-based drugs as well as other poorly water-soluble drugs at neutral (intestinal) pH is highly desirable.

[0008] US Patent Publication No. 20090203709 discloses a pharmaceutical dosage form comprising a solid dispersion product of at least one tyrosine kinase inhibitor, at least one pharma- ceutically acceptable polymer, and at least one pharma- ceutically acceptable solubilizer. Furthermore, the reference discloses a method of preparing the above-mentioned pharmaceutical dosage form, comprising preparing a homogenous melt of at least one tyrosine kinase inhibitor, at least one pharma- ceutically acceptable polymer, and at least one pharma-ceutically acceptable solubilizer, and solidifying the melt to obtain the solid dispersion product.

[0009] EP2105130 discloses a pharmaceutical formulation comprising a solid dispersion or solution comprising a polymer and an active agent in amorphous form. Furthermore, the formulation comprises an external polymer that stabilizes the solution, such that the weight percentage of the external polymer is less than 20% of the total weight of the pharmaceutical formulation. Furthermore, the reference discloses a hot melt extrusion process for the manufacture of the above-mentioned formulation. Summary of the Invention

[0010] The present invention relates to a pharmaceutical composition comprising stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix forming component. Optionally, one or more solubilizing agents may be added to the particles, either separately or present within the particles. [Brief description of the drawings]

[0011] [Figure 1] Figure 1 provides a graph showing the apparent solubility of nilotinib in a representative composition of the present invention. Further experiments with both nilotinib base and nilotinib HCl are found in Example 1. Particle details are described in Example 1, Table 1 for experiments 3, 30, and 37, respectively. Briefly, experiment 30 represents stable amorphous hybrid nanoparticles containing nilotinib HCl and HPMCP HP55, with the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer present separately from the hybrid nanoparticles. Experiment 3 represents untreated crystalline nilotinib HCl, and experiment 37 represents hybrid nanoparticles of nilotinib HCl, HPMCP HP55, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer present within the hybrid nanoparticles. The experiments depicted in the graphs were carried out in FaSSIF at pH 6.5. [Diagram 2] Figure 2 provides a graph showing the apparent solubility of erlotinib in a representative composition of the present invention. Further experiments with erlotinib are found in Example 2. Details of the stable amorphous hybrid nanoparticles are described in Example 2, Table 7 for experiments 58, 65, and 67, respectively. Briefly, experiment 65 represents stable amorphous hybrid nanoparticles containing erlotinib HCl and HPMC-AS, where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. Experiment 58 represents unprocessed crystalline erlotinib HCl, and experiment 67 represents stable amorphous hybrid nanoparticles of erlotinib HCl, HPMC-AS, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer present within the hybrid nanoparticles. The experiments shown in the graphs were carried out in FaSSIF at pH 6.5. [Diagram 3]Figure 3 provides a graph showing the apparent solubility of pazopanib in a representative composition of the present invention. Further experiments with pazopanib are found in Example 3. Details of the stable amorphous hybrid nanoparticles are described in Example 3, Table 13, for Experiments 84, 91, and 93, respectively. Briefly, Experiment 91 represents stable amorphous hybrid nanoparticles containing pazopanib and PVP 90K, where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles, and Experiment 93 represents hybrid nanoparticles containing pazopanib, PVP 90K, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer present within the stable amorphous hybrid nanoparticles. Experiment 84 represents unprocessed crystalline pazopanib. The experiments shown in the graph were performed in FaSSIF at pH 6.5. [Figure 4] Figure 4 provides a graph showing the apparent solubility of lapatinib in a representative composition of the present invention. Further experiments with both lapatinib base and lapatinib tosylate are found in Example 4. Details of the stable amorphous hybrid nanoparticles are described in Example 4, Table 19 for experiments 110, 122, and 126, respectively. Briefly, experiment 122 represents stable amorphous hybrid nanoparticles containing lapatinib base and HPC EF, where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. Experiment 110 represents untreated lapatinib base, and experiment 126 represents stable amorphous hybrid nanoparticles of lapatinib base, HPC LF, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer present within the hybrid nanoparticles. The experiments shown in the graph were performed in FaSSIF at pH 6.5. [Diagram 5]Figure 5 provides a graph showing the apparent solubility of nilotinib in a representative composition of the present invention. Details of the stable amorphous hybrid nanoparticles are described in Example 5, Table 21 for experiments 127, 128, and 129, respectively. Briefly, experiment 129 represents a physical mixture of unprocessed crystalline nilotinib HCl, HPMCP HP55, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer. Experiment 128 represents stable amorphous hybrid nanoparticles containing nilotinib HCl and HPMCP HP55, where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. Experiment 127 represents stable amorphous hybrid nanoparticles of nilotinib HCl and HPMCP HP55. The experiments shown in the graph were performed in SGF at pH 1.4. [Figure 6] FIG. 6 provides a graph showing the apparent solubility of gefitinib in a representative composition of the present invention. Further experiments with gefitinib are found in Example 6. Composition details are described in Example 6, Table 22 for experiments 131, 133, 135, and 137, respectively. Briefly, experiment 131 represents unprocessed crystalline gefitinib. Experiment 133 represents a mixture of unprocessed crystalline gefitinib, HPMCP HP55, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer. Experiment 135 represents stable amorphous hybrid nanoparticles of gefitinib and HPMCP HP55. Experiment 137 represents stable amorphous hybrid nanoparticles of gefitinib and HPMCP HP55, where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. The experiments shown in the graph were carried out in FaSSIF at pH 6.5. [Figure 7]FIG. 7 provides a graph showing the apparent solubility of dasatinib in a representative composition of the present invention. Details of the stable amorphous hybrid nanoparticles are described in Example 7, Table 24 for experiments 138-141. Briefly, experiment 138 represents unprocessed crystalline dasatinib. Experiment 139 represents a mixture of unprocessed crystalline dasatinib, Kollidon VA64, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer. Experiment 140 represents hybrid nanoparticles of dasatinib and Kollidon VA64. Experiment 141 represents stable amorphous hybrid nanoparticles of dasatinib and Kollidon VA64 where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. The experiments shown in the graph were performed in FaSSIF at pH 6.5. [Figure 8] FIG. 8 provides a graph showing the apparent solubility of sorafenib in a representative composition of the present invention. Details of the stable amorphous hybrid nanoparticles are described in Example 8, Table 26 for runs 142-145. Briefly, run 142 represents unprocessed crystalline sorafenib tosylate. Run 143 represents a mixture of unprocessed crystalline sorafenib tosylate, HPMCP HP55, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer. Run 144 represents stable amorphous hybrid nanoparticles of sorafenib tosylate and HPMCP HP55. Run 145 represents hybrid nanoparticles of sorafenib tosylate and HPMCP HP55 where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. The runs shown in the graph were performed in FaSSIF at pH 6.5. [Figure 9]Figure 9 provides a graph showing the apparent solubility of crizotinib in representative compositions of the present invention. Further experiments with crizotinib are found in Example 10. Composition details are described in Example 10, Table 30 for experiments 150, 152, 153, and 156, respectively. Briefly, experiment 150 represents unprocessed crystalline crizotinib. Experiment 152 represents a mixture of unprocessed crystalline crizotinib, PVP 30K, and the solubilizer Cremophor RH40. Experiment 153 represents stable amorphous hybrid nanoparticles of crizotinib and PVP 30K. Experiment 156 represents stable amorphous hybrid nanoparticles of crizotinib and PVP 30K, where the solubilizer Cremophor RH40 is present separately from the stable amorphous hybrid nanoparticles. The experiments shown in the graph were performed in FaSSIF at pH 6.5. [Figure 10] FIG. 10 provides a graph showing the apparent solubility of axitinib in representative compositions of the present invention. Further experiments with axitinib are found in Example 11. Composition details are described in Example 11, Table 32 for experiments 157, 158, 160, and 162, respectively. Briefly, experiment 157 represents unprocessed crystalline axitinib. Experiment 158 ​​represents a mixture of unprocessed crystalline axitinib, Kollidon VA64, and solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer. Experiment 160 represents stable amorphous hybrid nanoparticles of axitinib and Kollidon VA64. Experiment 162 represents stable amorphous hybrid nanoparticles of axitinib and Kollidon VA64 where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. The experiments shown in the graph were carried out in FaSSIF at pH 6.5. [Figure 11]Figure 11 provides a graph showing the apparent solubility of vemurafenib in a representative composition of the present invention. Further experiments with vemurafenib are found in Example 12. Composition details are described in Example 12, Table 34 for experiments 164, 166, 168, and 170, respectively. Briefly, experiment 164 represents unprocessed crystalline vemurafenib. Experiment 166 represents a mixture of unprocessed crystalline vemurafenib, CAP, and the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer. Experiment 168 represents stable amorphous hybrid nanoparticles of vemurafenib and CAP. Experiment 170 represents stable amorphous hybrid nanoparticles of vemurafenib and CAP, where the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is present separately from the stable amorphous hybrid nanoparticles. The experiments shown in the graph were carried out in FaSSIF at pH 6.5. [Figure 12] Figure 12 provides a graph showing the dissolution rate measured under sink conditions of nilotinib base in a representative composition of the present invention. Details can be found in Examples 13 and 13.1 and Table 36 for experiments 500 and 501. Briefly, experiment 500 represents unprocessed nilotinib HCl. Experiment 501 represents stable amorphous hybrid nanoparticles of nilotinib base and HPMCP HP55. The experiments shown in the graph were carried out in FaSSIF at pH 6.5. [Figure 13] Figure 13 provides a graph showing the dissolution rate measured under sink conditions of erlotinib in a representative composition of the method of the present invention. Details can be found in Examples 13 and 13.2, Table 37 for Runs 510 and 511. Briefly, Run 510 represents unprocessed erlotinib HCl. Run 511 represents stable amorphous hybrid nanoparticles of erlotinib HCl and HPMC AS. [Figure 14]Figure 14 provides a graph showing the dissolution rate measured under sink conditions of pazopanib in a representative composition of the present invention. Details can be found in Examples 13 and 13.3, Table 38 for Experiments 520 and 521. Briefly, Experiment 520 represents unprocessed pazopanib HCl. Experiment 521 represents stable amorphous hybrid nanoparticles of pazopanib HCl and PVP90K. [Figure 15] Figure 15 provides a graph showing the dissolution rate measured under sink conditions of lapatinib in a representative composition of the present invention. Details can be found in Examples 13 and 13.4, Table 39 for Runs 530 and 531. Briefly, Run 530 represents unprocessed lapatinib tosylate. Run 531 represents stable amorphous hybrid nanoparticles of lapatinib base and HPC lf. [Figure 16] Figure 16 provides a graph showing the dissolution rate measured under sink conditions of gefitinib in a representative composition of the present invention. Details can be found in Examples 13 and 13.5., Table 40 for Runs 540 and 541. Briefly, Run 540 represents unprocessed gefitinib. Run 541 represents stable amorphous hybrid nanoparticles of gefitinib and HPMCP HP55. [Figure 17] Figure 17 provides a graph showing the dissolution rate measured under sink conditions of dasatinib in a representative composition of the present invention. Details can be found in Examples 13 and 13.6., Table 41 for Runs 550 and 551. Briefly, Run 550 represents unprocessed dasatinib. Run 551 represents stable amorphous hybrid nanoparticles of dasatinib and Kollidon VA64. [Figure 18] Figure 18 provides a graph showing the dissolution rate measured under sink conditions of sorafenib in a representative composition of the present invention. Details can be found in Examples 13 and 13.7., Table 42 for Runs 560 and 561. Briefly, Run 560 represents unprocessed sorafenib tosylate. Run 561 represents stable amorphous hybrid nanoparticles of sorafenib tosylate and HPMCP HP55. [Figure 19]Figure 19 provides a graph showing the dissolution rate measured under sink conditions of crizotinib in a representative composition of the present invention. Details can be found in Examples 13 and 13.8., Table 43 for Experiments 570 and 571. Briefly, Experiment 570 represents unprocessed crizotinib. Experiment 571 represents stable amorphous hybrid nanoparticles of crizotinib and PVP 30K. [Figure 20] Figure 20 provides a graph showing the dissolution rate measured under sink conditions of axitinib in a representative composition of the present invention. Details can be found in Examples 13 and 13.9., Table 44 for Runs 580, 581, and 582. Briefly, Run 580 represents untreated axitinib. Run 581 represents hybrid nanoparticles of axitinib and Kollidon VA64, and Run 582 represents stable amorphous hybrid nanoparticles of axitinib and HPMC AS. [Figure 21] Figure 21 provides a graph showing the dissolution rate measured under sink conditions of vemurafenib in a representative composition of the present invention. Details can be found in Examples 13 and 13.10., Table 45 for runs 590, 591, and 592. Briefly, run 590 represents unprocessed vemurafenib. Run 591 represents hybrid nanoparticles of vemurafenib and Kollidon VA64, and run 592 represents stable amorphous hybrid nanoparticles of vemurafenib and CAP. [Figure 22]Figure 22 provides a graph showing in vivo measurements of plasma levels after oral administration to beagle dogs of representative compositions containing stable amorphous hybrid nanoparticles (I / P) of nilotinib base and polymeric stabilized matrix forming components PVAP and HPMCP HP55, respectively, and stable amorphous hybrid nanoparticles (I / P+S) with added solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, respectively, referred to as HP55s and PVAPs. Experiments were performed in beagle dogs pretreated to have neutral stomach contents. Stable amorphous hybrid nanoparticles are further described in experiments 146 and 147 (Example 9), and details of the in vivo experiments are described in Example 14. The experiments used a commercially available formulation containing nilotinib HCl ("Tasigna") as a reference. [Diagram 23] Figure 23 provides a graph showing in vivo measurements of plasma levels after oral administration to beagle dogs of representative compositions containing stable amorphous hybrid nanoparticles (I / P) of nilotinib base and polymeric stabilized matrix forming components PVAP and HPMCP HP55, referred to as PVAP and HP55, respectively, and stable amorphous hybrid nanoparticles (I / P+S) with added solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, referred to as PVAPs and HP55s, respectively. Experiments were performed in beagle dogs pretreated with acidic stomach contents. The stable amorphous hybrid nanoparticles are further described in experiments 146 and 147 (Example 9), and details of the in vivo experiments are described in Example 14. The experiments used a commercially available formulation containing nilotinib HCl ("Tasigna") as a reference. [Figure 24]Figure 24 provides a graph showing in vivo measurements of plasma levels after oral administration to beagle dogs of representative compositions containing stable amorphous hybrid nanoparticles (I / P) of nilotinib base and polymeric stabilizing matrix forming components PVAP and HPMCP HP55, referred to as PVAP and HP55, respectively, and stable amorphous hybrid nanoparticles (I / P+S) in which the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer is added after the formation of the hybrid nanoparticles, referred to as PVAPs and HP55s, respectively. Experiments were performed in beagle dogs pretreated to have acidic or neutral stomach contents. Stable amorphous hybrid nanoparticles are further described in Experiments 146 and 147 (Example 9), and details of the in vivo experiments are set out in Example 14. [Diagram 25] Figure 25 provides a graph showing in vivo measurements of plasma levels of a representative composition comprising stable amorphous hybrid nanoparticles (I / P) of nilotinib base and polymeric stabilized matrix forming components PVAP and HPMCP HP55, designated PVAP and HP55, respectively, in beagle dogs after oral administration. Experiments were performed in beagle dogs pretreated with acidic or neutral stomach contents. The stable amorphous hybrid nanoparticles are further described in Experiments 146 and 147 (Example 9), and details of the in vivo experiments are set out in Example 14. [Figure 26] Figure 26 provides a graph showing the apparent solubility of representative compositions before and after 11 months of storage at room temperature. The experiments provide stable amorphous hybrid nanoparticles (I / P+S) containing nilotinib base, HPMCP HP55, with the addition of solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer as Experiment 171 and Experiment 172, further details of which are described in Example 15. [Figure 27]Figure 27 provides the overlaid X-ray powder diffraction patterns (XRPD) of stable hybrid nanoparticles, I / P nilotinib base / HPMCP HP55, at 40% drug load, initially (top) and after 12 months of storage at ambient temperature (bottom). The XRPD patterns are offset to improve visual comparison. Further details are provided in Example 15. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

[0013] As used herein, the phrase "hybrid nanoparticles" refers to a group of particles composed of at least two components, one of which is a PKI and the other of which is a polymeric stabilized matrix-forming component, typically with an average size ranging from 1 to 1000 nm. The particles may be crystalline, amorphous, or a mixture thereof. Typically, in the sense of the present disclosure, the particles are "amorphous" or "essentially amorphous". This means that almost all, if not all, of the particle's content comprises an amorphous protein kinase inhibitor and a polymeric stabilized matrix-forming component. The level or degree of amorphism is at least 60%, such as 70%, such as 80% or 85%, preferably at least 90%, more preferably more than 95%, with 100% representing that all material is amorphous in the particle.

[0014] Quantification of crystalline PKI or the absence of crystalline PKI can be measured by X-ray powder diffraction methodologies as described in Saleki-Gerhardt A et al. Int J Pharm. 1994;101:237-247) or water vapor sorption as described in Dash AK et al. J Pharm Sci. 2002 Apr;91(4):983-90.

[0015] The term "solid dispersion particles" relates to the "hybrid nanoparticles" defined above, however, the solid dispersion particles are typically larger or much larger in size (typically μm-mm, as described in Wu K.et al.J Pharm Sci.2009 Jul;98(7):2422-3). The smaller size of the hybrid nanoparticles contributes to further stabilizing the PKI to prevent crystallization. Typically, the hybrid nanoparticles have an average size range of 1 to 1000 nm, such as less than 500 nm, preferably less than 250 nm.

[0016] The phrase "stable" refers to the level of stability of the particles produced by the methods of the present invention, which can be measured as the ability of the hybrid nanoparticles to remain in their physical state during storage at ambient temperature (e.g., 18-25° C.) for 6-12 months. The level of stability can be measured by AUC measurement of the dissolution rate of the particles after such storage, e.g., over 80 minutes.

[0017] The phrase "protein kinase inhibitor" or "PKI" refers to an enzyme inhibitor that specifically inhibits the action of one or more protein kinases. PKIs include, but are not limited to, protein kinase inhibitors and tyrosine kinase inhibitors, such as axitinib, afatinib, bosutinib, crizotinib, cediranib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, lestaurtinib, motesanib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, semaxanib, sunitinib, tandunitib, tipifamib, vandetanib, and vemurafenib; or salts, hydrates, or solvates thereof, or combinations thereof.

[0018] The phrase "polymeric stabilizing matrix-forming components" refers to components present in the hybrid nanoparticles together with the PKI. Typically, the polymeric stabilizing matrix-forming components are, for example, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., HPC ef, HPC lf, and HPC jf), hydroxypropylmethylcellulose (e.g., Methocel E3 and E15 and Pharmacoat), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (e.g., HPMCP-HP55), polyvinylpyrrolidone (e.g., PVP 30K and PVP 90K), polyvinyl acetate phthalate (PVAP), copolyvidone (e.g., Kollidon VA 64), crospovidone (e.g., Kollidon CL), copolymers of methacrylic acid and ethyl acrylate (e.g., Kollicoat ME), copolymers of methacrylic acid and methyl methacrylate (e.g., Eudragit PTFE), and the like. Examples of polymer structures include, but are not limited to, poly(DL-lactide), poly(L100), polyethylene glycol (PEG), DL-lactide / glycolide copolymer, poly(DL-lactide), cellulose acetate phthalate (CAP), aminoalkyl methacrylate copolymers (e.g., Eudragit RL100, RL PO, or RS PO), carbomer homopolymer type A (e.g., Carbopol 971P), carbomer homopolymer type B (e.g., Carbopol 974P), and poloxamers (e.g., Pluronics, Kolliphor).

[0019] The terms "polymer" or "polymeric" are used herein to mean a compound made of monomers linked together to form a larger molecule. A polymer generally consists of 20 or more monomers linked together, although less than 20 monomers linked together are also referred to herein as polymers.

[0020] The term "solubilizer" is used herein to mean a compound that increases the solubility of a substance, such as, but not limited to, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer (Soluplus), d-α-tocopheryl acid polyethylene glycol 1000 succinate (TPGS), PEG-40 hydrogenated castor oil (Cremophor RH40), PEG-35 castor oil (Cremophor EL), PEG-40 stearate (MYRJ 540), hard fats (e.g., Gelucire 33 / 01), polyoxylglycerides (e.g., Gelucire 44 / 14), stearoyl polyoxylglycerides (e.g., Gelucire 50 / 13), PEG-8 caprylic / capric glycerides (e.g., Labrasol), and poloxamers (e.g., Pluronics, Kolliphor).

[0021] As used herein, the phrase "primary particles" refers to the smallest granular objects formed during the precipitation process. Particle boundaries are analyzed by SEM microscopy. Depending on the process parameters, primary particles may join together to form denser or less dense porous networks to form larger agglomerated or bridged particles. Parameters that affect agglomeration are, for example, temperature, which can change the softness of the primary particles; precipitation time, solvent / antisolvent ratio, which affects the concentration of the PKI solution; and the nature of the polymeric stabilizing and matrix-forming agent(s). The average size of the primary particles is typically 1 to 1000 nm, preferably less than 500 nm, more preferably less than 250 nm.

[0022] As used herein, the phrases "supercritical" and "supercritical fluid" refer to a chemical substance that is set at both a temperature above its critical temperature (Tc) and a pressure above its critical pressure (Pc).

[0023] As used herein, the phrases "subcritical" and "subcritical fluid" refer to one of the critical temperature (Tc) and critical pressure (Pc) being set at a temperature or pressure higher than the critical temperature (Tc) or critical pressure (Pc), respectively, and the other of the critical temperature (Tc) and critical pressure (Pc) being set at a temperature or pressure lower than the critical temperature (Tc) or critical pressure (Pc), respectively.

[0024] The phrase "area under the curve (AUC)" refers to the area under the concentration-time curve, where the x-axis represents time and the y-axis represents solubilized drug concentration.

[0025] The phrase "apparent solubility" refers to the concentration of a substance at apparent equilibrium. See further the Examples section.

[0026] The term "supersaturated" is used herein to mean a solvent that contains more dissolved material than can be dissolved by the solvent or medium under normal circumstances.

[0027] As used herein, the term "Soluplus" refers to polyvinylcaprolactam-polyvinylacetate-polyethylene glycol copolymer.

[0028] As used herein, the term "TPGS" means d-α-tocopherol acid polyethylene glycol 1000 succinate.

[0029] As used herein, the term "Chremophor RH40" means PEG-40 hydrogenated castor oil.

[0030] As used herein, the term "PVAP" means polyvinyl acetate phthalate.

[0031] As used herein, the term "PVP 90K" means polyvinylpyrrolidone K-90.

[0032] As used herein, the term "PVP 30K" means polyvinylpyrrolidone K-30.

[0033] As used herein, the term "HPMC-AS" means hydroxypropyl methylcellulose acetate succinate.

[0034] As used herein, the term "HPMCP HP55" means hydroxypropyl methylcellulose phthalate.

[0035] As used herein, the term "HPC" refers to hydroxypropyl cellulose, such as HPC EF and HPC LF.

[0036] As used herein, the term "Kollidon VA64" means copolyvidone.

[0037] As used herein, the term "CAP" means cellulose acetate phthalate.

[0038] Dissolution media used for testing the hybrid nanoparticles of the present invention include fasting simulated intestinal fluid, referred to as FaSSIF, fed simulated intestinal fluid, referred to as FeSSIF, and simulated gastric fluid, referred to as SGF. FaSSIF medium is adjusted to represent the fasting state, with a pH of about 6.5 and specific osmolality properties. FeSSIF medium is adjusted to represent the fed state, with a pH of about 5 and specific osmolality properties. SGF is adjusted to represent gastric fluid, with a pH of about 1.4 and specific osmolality properties. FaSSIF, FeSSIF, and SGF media are commonly used in in vitro models of dissolution of poorly water-soluble drugs. The choice of medium will depend on the location in the digestive tract and the conditions (fasting or fed) in which it is desired for the particles to dissolve and be absorbed. Further details regarding these fluids can be found, for example, in Herve J. et al. Pharm Dev Technol. 2011 Jun;16(3):278-86 and Jantratid, E., and Dressman, J. Dissolut. Technol. 2009 8,21-25.

[0039] The phrase "amorphous form" refers to a non-crystalline solid form. The ease of dissolution may be due, at least in part, to the amount of energy required to dissolve a component from a crystalline or amorphous solid phase. Amorphous particles require less energy to dissolve than crystalline particles of the same compound.

[0040] The compositions of the present invention comprise particles of a PKI or a combination of two or more PKIs. However, the particles may also comprise one or more PKIs and at least one further active ingredient, such as one or more drugs. Various types of PKIs can be effectively utilized.

[0041] The term PKI (protein kinase inhibitor) as used herein is also intended to include hydrates, solvates (alcoholates), pharma- ceutically acceptable acid salts, base salts, or co-crystals of such protein kinase inhibitor compounds.

[0042] As used herein, the term water-insoluble or poorly water-soluble (or hydrophobic) compound refers to a compound having a solubility in water of less than 1 g / 100 ml at 25° C., in particular less than 0.1 g / 100 ml in pure water at neutral pH.

[0043] The stable amorphous hybrid nanoparticles contained in the composition of the present invention are typically in the form of particles described elsewhere herein. There are several different methods of forming larger particles, such as granulation, melt extrusion, spray drying, precipitation, etc., all of which typically involve the formation of a mixture of the active pharmaceutical ingredient (API) and the polymeric stabilizing matrix-forming component. The particles contained in the composition of the present invention are manufactured by a continuous process of producing hybrid nanoparticles. Continuous process in this context means that the particle formation proceeds continuously while at the same time the hybrid nanoparticles are continuously withdrawn, collected and stored from the mixture after their formation. In a preferred method, i.e. the precipitation method, this means that a fluid, which is a solution of PKI, preferably in the form of a fluid stream, is mixed with a fluid of the anti-solvent, preferably in the form of a stream of anti-solvent fluid. The polymeric stabilizing matrix-forming component may be present in one or both of the two fluids depending on its solubility characteristics. The mixing of the two fluids is carried out in a mixing function, e.g. a mixing chamber. If the process is continuous, i.e., the two fluids are fluid streams, the mixing function is typically associated with a particle-forming separation function where the hybrid nanoparticles are stored while the mixed fluid streams pass through. Agents that do not become incorporated into the particles but change the properties of the particles can be added to one or both of the two fluids before the mixing step. The fluids are typically conventional liquids or supercritical fluids, which also include subcritical fluids (i.e., fluids where only one of the pressure and temperature is above its supercritical value). Typical combinations are a) conventional (i.e., non-supercritical) liquids for both the API solution and the antisolvent, b) conventional liquid for the antisolvent combined with a supercritical solution of the API, c) supercritical fluid for the antisolvent combined with a conventional liquid for the API solution, and d) supercritical fluid for both of the two fluids. In certain variants, the antisolvent can be omitted. The fluid stream, preferably supercritical, containing both the API and the polymeric stabilizing matrix-forming components is then spread within the particle-forming function. In the above precipitation method, it is preferred that at least one of the fluids is in a supercritical state.These types of precipitation methods are discussed in WO2005061090 (Censdelivery AB), WO2009072950 (XSpray Microparticles AB), WO2009072953 (XSpray Microparticles AB), WO2011159218 (XSpray Microparticles AB), and references cited therein.

[0044] The term "solution" encompasses solutes that are either true solutes or microscopic particles of colloidal dimensions (typically 1-1000 nm) smaller than the particles to be produced.

[0045] A preferred particle formation system is the "Right Size system" developed by XSpray Microparticles AB, Sweden. A detailed description of this technology can be found in the International Patent Publication in the previous paragraph. The key characteristic of the system is that the two fluid streams should merge in the nozzle and be sprayed during the particle formation / separation function at an angle in the interval of 45°-135°, preferentially about 90°. In principle, the system can produce particles of a given size / morphology. Herein, the Right Size system and device are described as a system for the preparation of a PKI as a drug and CO as a supercritical fluid antisolvent. 2 will be explained using the following non-limiting examples.

[0046] The system consists of one pumping configuration for the PKI dissolved in a liquid solvent, referred to as the API solution, and one pumping configuration for the anti-solvent, e.g., CO 2 The system comprises one pumping setup for the anti-solvent, although other anti-solvents may be used as appropriate. Each pumping setup contains devices such as flow and pressure meters that are used to control the process conditions. The two pumping setups are fluidly connected at the spray nozzle.

[0047] The liquid API solution stream is sprayed under flow conditions through the spray nozzle. 2The polymeric stabilized matrix forming components are mixed with the API solution and the CO 2 At the outlet of the nozzle, these streams are sprayed under controlled conditions (typically pressure and temperature) into the precipitation vessel. 2 The antisolvent acts as an antisolvent to precipitate the API together with the polymeric stabilizing matrix forming components into microparticles. The particles are collected in a vessel by a filtration arrangement. Typically, a back pressure control valve is used to regulate the pressure in the precipitation vessel.

[0048] To prepare hybrid nanoparticles of certain drugs, such as, but not limited to, pazopanib and erlotinib, additional solvents, referred to as modifiers, are added to the CO 2 It may be advantageous to have an extra pumping arrangement for injecting CO into the mixer, where a pumping arrangement control is provided for the modifier, which injects CO in the mixer before entering the nozzle. 2 and mixed.

[0049] When using the system, the system operator typically increases and decreases the CO2 flow rate until the flow, pressure, and temperature reach the desired steady state. 2 Start by equilibrating the system by pumping the "PKI-like solution" (a solution similar in composition to the PKI solution but containing neither PKI nor excipients), and modifiers (if used) through the system. The important parameters for setting up the system are the PKI solution composition, the PKI solution flow rate, and the CO 2 flow rate, CO 2 the pressure and temperature, the nature of the modifier, if used, and its flow rate.

[0050] The "PKI-like solution" is then replaced with the PKI solution to produce a solution that is pooled downstream of the mix, e.g., downstream of the nozzle exit. The system is then typically cleaned by pumping the "PKI-like solution" through the system. The particles are then sprayed with large amounts of CO2 to remove residual solvent. 2 The precipitation vessel is then depressurized and the particles can be recovered.

[0051] The solution / solvent and the anti-solvent are typically miscible with each other. The pressure and temperature in the particle formation function and / or upstream of this function, such as in the mixing function, create supercritical or subcritical conditions for the anti-solvent.

[0052] The concentration of PKI in the solution is typically below the saturation concentration, such as 50% or less, such as 60% or less, such as 75% or less, such as 85% or less, or 95% or less of the saturated concentration. Suitable concentrations are typically found in intervals of 20% or less, such as 10% or less, or 5% or less, or 3% or less (all w / v %), with a lower limit of 0.05% or less, or 0.1%. The term "volatile" with respect to the solvent means a boiling point of 200°C or less, such as 150°C or less, or 100°C or less, at atmospheric pressure. Examples are inorganic and organic solvents, with particular emphasis on dimethylsulfoxide and trifluoroethanol and mixtures thereof. The term solvent includes mixtures of liquids that are miscible with each other. The solution may contain agents that increase or decrease the solubility of PKI, such as acidic, alkaline, buffer components and / or other organic solvents.

[0053] Illustrative fluids that can be used as antisolvents are: a) is a gas at room temperature and atmospheric pressure, or b) It is a liquid at room temperature and atmospheric pressure.

[0054] Antisolvents are typically selected for their ability to disperse easily into small droplets and to act as antisolvents for the PKI in the propellant and in solution.

[0055] The compounds / elements according to group (a) may be selected from carbon dioxide (Pc=74 bar and Tc=31° C.) (preferred), nitrous oxide (Pc=72 bar and Tc=36° C.), sulphur hexafluoride (Pc=37 bar and Tc=45° C.), ethane (Pc=48 bar and Tc=32° C.), ethylene (Pc=51 bar and Tc=10° C.), xenon (Pc=58 bar and Tc=16° C.), trifluoromethane (Pc=47 bar and Tc=26° C.), chlorotrifluoromethane (Pc=39 bar and Tc=29° C.), and nitrogen (Pc=34 bar and Tc=−147° C.), and mixtures comprising these compounds / elements, where Pc means the critical pressure and Tc means the critical temperature. Compounds according to group (b) are typically selected from conventional liquids of the same general type as discussed above with respect to the solvent, except that the PKI present in the solution must be poorly soluble in the antisolvent. Particular solvents of group (b) include methanol, ethanol, acetone, water and mixtures comprising one or more of these fluids.

[0056] Antisolvents of group (a) above are typically used at pressures and temperatures which provide i) supercritical conditions (supercritical fluids) or ii) subcritical conditions (subcritical fluids) in the particle formation function and / or upstream of this function, such as the mixing function and upstream of this latter function.

[0057] Variant (i) typically refers to pressures and temperatures above the critical pressure Pc and critical temperature Tc of the antisolvent used. For pressure, this is typically within the interval (1.0-7.0) x Pc, or within an interval of 10 bar or more, preferably 20 bar or more, preferentially 30 bar or more above Pc, with illustrative upper limits of 100 bar, 200 bar, and 300 bar above Pc. For temperature, this is typically within (1.0-4.0) x Tc, or within an interval of 5°C or more of Tc, preferably 10°C or more, preferentially 15°C or more, with illustrative upper limits of 10°C, 40°C, and 50°C above Tc.

[0058] Variant (ii) means that at least one of the temperature and the pressure, but preferentially only the temperature, is below the critical value (Tc and Pc, respectively). The temperature can therefore be in the interval (0.1-1) x Tc, (0.5-1) x Tc or even lower. Furthermore, the temperature can be as low as -10°C or -30°C. These temperatures can be combined with pressures defined in the previous paragraph or with pressures lower than the Pc of the antisolvent employed. For carbon dioxide, this means that the temperature during the particle formation function is lower than +31°C, such as about +25°C or lower, combined with pressures higher or lower than 74 bar.

[0059] Antisolvents in group (b) above are typically used in the subcritical state, ie, as subcritical fluids.

[0060] In one aspect of the present invention, there is provided a pharmaceutical composition comprising stable amorphous hybrid nanoparticles of at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component, optionally further comprising at least one pharma- ceutically acceptable solubilizing agent.

[0061] In one embodiment of this aspect, a pharmaceutical composition is provided that comprises stable amorphous hybrid nanoparticles of at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component, further comprising at least one pharma- ceutically acceptable solubilizer. Typically, the solubilizer is present in the composition apart from the hybrid nanoparticles. Or, typically, the solubilizer is distributed on the surface of the hybrid nanoparticles. The solubilizer can be selected from polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, d-α-tocopherol acid polyethyleneglycol 1000 succinate, and hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. Additionally, the solubilizer can be a poloxamer.

[0062] Compositions comprising stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component exhibit increased dissolution rates.

[0063] As a result, in another embodiment of this aspect, there is provided a composition comprising stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix forming component, the hybrid nanoparticles exhibiting an increased dissolution rate of the protein kinase inhibitor compared to the dissolution rate of the protein kinase inhibitor in its unprocessed crystalline form.

[0064] Typically, the dissolution rate is measured by a flow-through cell system under sink conditions, for example according to the United States Pharmacopeia (USP4). Dissolution measurements of hybrid nanoparticles under sink conditions can be performed by a method that consists of adding the desired amount of powder to a flow-through cell system (SOTAX, Allschwill, Switzerland), attaching the cell to the device, and then pumping the appropriate medium (typically FaSSIF, FeSSIF, SGF) through the powder. The temperature of the device is typically set to 37°C. The amount of powder added to the cell depends on the drug loading of the powder. The exact amount of powder can be calculated from the results obtained from the drug loading analysis of the powder. PKI can be added to the flow-through cell and a flow rate of 5 to 25 ml of medium / min is pumped through the powder. 1 ml samples of the medium passing through the cell are collected at predetermined time points and then analyzed by HPLC (e.g. C18 column Eclipse, 4.6 mm x 15 cm, 1 ml / min, detection 254 to 400 nm). Samples are typically taken at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, and 40 minutes from the moment the medium leaves the flow-through cell. The cumulative % solubilized of the amount of active substance added to the flow-through cell can be calculated and plotted against time (in minutes). The initial slope of the graph ("initial dissolution rate", corresponding to 0-10 minutes) can be estimated and taken as the dissolution rate of the substance in a given dissolution medium at sink conditions at 37°C.

[0065] Preferably, the dissolution rate is measured within the first 0 to 10 minutes of dissolution.

[0066] The increased dissolution rate is preferably measured in solution as the ratio of the dissolution rates of the stable amorphous hybrid nanoparticles to the unprocessed crystalline form of the protein kinase inhibitor, preferably, said ratio being from about 1.5:1 to about 500:1, such as from about 10:1 to about 30:1.

[0067] Preferably, the dissolution rate is measured in a solution with intestinal pH, such as FaSSIF or FeSSIF, or in a solution with gastric pH, such as SGF.

[0068] Typically, the dissolution rate is measured, for example, by a flow-through cell system at sink conditions. Dissolution measurements of stable amorphous hybrid nanoparticles under sink conditions can be performed by a method that consists of adding the desired amount of powder to a flow-through cell system (SOTAX, Allschwill, Switzerland), attaching the cell to the device, and then pumping the appropriate medium (typically FaSSIF, FeSSIF, SGF) through the powder. The temperature of the device is typically set at 37°C. The amount of powder added to the cell depends on the drug loading of the powder. The exact amount of powder can be calculated from the results obtained from the drug loading analysis of the powder. PKI can be added to the flow-through cell and a flow rate of 5 to 25 ml of medium / min is pumped through the powder. 1 ml samples of the medium passing through the cell are collected at predetermined time points and then analyzed by HPLC (e.g., C18 column Eclipse, 4.6 mm x 15 cm, 1 ml / min, detection 254 to 400 nm). Samples are typically taken at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, and 40 minutes from the moment the medium leaves the flow-through cell. The cumulative % solubilized of the amount of active substance added to the flow-through cell can be calculated and plotted against time (in minutes). The initial slope of the graph ("initial dissolution rate", corresponding to 0-10 minutes) can be estimated and taken as the dissolution rate of the substance in a given dissolution medium at sink conditions at 37°C.

[0069] In another embodiment of this aspect, a composition is provided that comprises stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix forming component, which produces an increase in solubility of the inhibitor in solution, said increase being measured as the area under the curve (AUC) between about 40 minutes and about 90 minutes in said solution compared to the AUC of the unprocessed crystalline form of the inhibitor. Typically, said increase is about 2:1 to about 10000:1, where 1 represents the AUC of the unprocessed crystalline form of the inhibitor. The increase can be measured in a solution with intestinal pH, such as FaSSIF or FeSSIF, or in a solution with gastric pH, such as SGF.

[0070] The polymeric stabilized matrix forming components of the present invention include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., HPC ef, HPC lf, and HPC jf), hydroxypropyl methylcellulose (e.g., Methocel E3 and E15 and Pharmacoat), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (e.g., HPMCP HP55), polyvinylpyrrolidone (e.g., PVP 30K and PVP 90K), polyvinyl acetate phthalate (PVAP), copolyvidone (e.g., Kollidon VA 64), crospovidone (e.g., Kollidon CL), copolymers of methacrylic acid and ethyl acrylate (e.g., Kollicoat ME), copolymers of methacrylic acid and methyl methacrylate (e.g., Eudragit L100), polyethylene glycol (PEG), DL-lactide / glycolide copolymer, poly DL-lactide, cellulose acetate phthalate (CAP), carbomer homopolymer type A (e.g., Carbopol 971P), carbomer homopolymer type B (e.g., Carbopol 974P), aminoalkyl methacrylate copolymers (e.g., Eudragit RL100, RL PO, or RS PO), and poloxamers (e.g., Pluronics, Kolliphor).

[0071] Thus, in another embodiment of this aspect, the polymeric stabilizing matrix-forming component is selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinylpyrrolidone, polyvinylacetate phthalate, copolyvidone, crospovidone, copolymer of methacrylic acid and ethyl acrylate, copolymer of methacrylic acid and methyl methacrylate, polyethylene glycol, DL-lactide / glycolide copolymer, poly DL-lactide, cellulose acetate phthalate, carbomer homopolymer type A, carbomer homopolymer type B, aminoalkyl methacrylate copolymer, and poloxamer. Preferably, the polymeric stabilizing matrix-forming component is selected from hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate, cellulose acetate phthalate, and polyvinylpyrrolidone.

[0072] In another embodiment of this aspect, there is provided a composition comprising stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix forming component, characterized by providing an amorphous X-ray powder diffraction pattern.

[0073] In another embodiment of this aspect, there is provided a composition comprising stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix forming component, wherein the dissolution rate of said stable amorphous hybrid nanoparticles remains stable at at least about 90% after storage at room temperature for 6 months or more.

[0074] In another embodiment of this aspect, the protein kinase inhibitor is a tyrosine kinase inhibitor selected from the group consisting of lapatinib, pazopanib, nilotinib, erlotinib, dasatinib, gefitinib, sorafenib, crizotinib, vemurafenib, and axitinib; or a salt or hydrate or solvate thereof, or a combination thereof.In some embodiments, it may be advantageous to use other PKIs.Examples of PKIs include, but are not limited to, afatinib, bosutinib, cediranib, fostamatinib, imatinib, lenvatinib, lestaurtinib, motesanib, mubritinib, pegaptanib, ruxolitinib, semaxanib, sunitinib, tandunitib, tipifamib, and vandetanib; or a salt or hydrate or solvate thereof, or a combination thereof.

[0075] In another embodiment of this aspect, the stable amorphous hybrid nanoparticles have an average particle size of less than about 1000 nm, such as less than about 500 nm, preferably less than 250 nm.

[0076] In other embodiments of this aspect, the solvent is an organic solvent selected from DMSO and trifluoroethanol, or a mixture of these solvents, or a mixture of these solvents with other organic solvents, such as DMSO / acetone, DMSO / tetrahydrofuran, or trifluoroethanol / ethyl acetate.

[0077] The compositions of the present invention can dissolve and the protein kinase inhibitor can be systemically absorbed in an environment independent of pH, typically in approximately equal amounts at a gastric pH, such as about pH 1.2 to about pH 2.1, preferably about 1.7, and an intestinal pH, such as about pH 4.5 to about pH 8, preferably about 6. By systemically absorbed, it is meant that the protein kinase inhibitor is released from the stable amorphous hybrid nanoparticles and absorbed by the systemic bloodstream. Thus, in another embodiment of this aspect, a composition is provided in which the protein kinase inhibitor is systemically absorbed independent of pH. Typically, the protein kinase inhibitor is systemically absorbed in approximately equal amounts at both gastric and intestinal pH. Preferably, the acidic pH is about pH 1.4, and preferably, the neutral pH is about pH 6.5.

[0078] By approximately equal amounts is meant that the concentration of the protein kinase inhibitor in the bloodstream after exposure is approximately similar. This can be expressed as a ratio where the concentration of the protein kinase inhibitor in the bloodstream measured after administration at gastric pH conditions (A) is compared to the concentration of the protein kinase inhibitor in the bloodstream measured after administration at intestinal pH conditions (N). Typically, the ratio A:N is about 0.75:1 to about 1.5:1, preferably about 1:1 to about 1.25:1. The concentration of the protein kinase inhibitor in the bloodstream can be measured as the area under the curve (AUC), the maximum concentration (Cmax) or bioavailability between 0 and 24 hours.

[0079] Thus, in another embodiment of this aspect, there is provided a composition comprising stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix forming component, wherein the concentration of the protein kinase inhibitor systemically absorbed at gastric pH conditions compared to the concentration of the protein kinase inhibitor systemically absorbed at intestinal pH conditions is from about 0.75:1 to about 1.5:1, preferably from about 1:1 to about 1.25:1. Typically, said gastric pH conditions represent a pH of about 1.4 and said intestinal pH conditions represent a pH of about 6. Typically, the concentration is measured as the area under the curve (AUC) between 0 and 24 hours of exposure to the composition or as the maximum concentration (Cmax).

[0080] The amount of systemically absorbed protein kinase inhibitor can be measured in a variety of ways. In Example 14 of the present disclosure, a method is provided to measure the systemically absorbed protein kinase inhibitor at various pHs, i.e., both acidic and neutral conditions.

[0081] In another embodiment of this aspect, there is provided a composition comprising stable amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix forming component, which produces an increase in solubility of the inhibitor in solution to supersaturation, said increase being measured as area under the curve (AUC) during 90 minutes in said solution and compared to the AUC of the inhibitor in crystalline form, said increase can be from about 2:1 to about 1000:1, where 1 represents the AUC of the inhibitor in crystalline form.

[0082] In order to understand how the hybrid nanoparticles in the composition of the present invention dissolve in vivo in the different environments of the stomach, small intestine, large intestine, and colon, it is important to select an appropriate solution for in vitro dissolution testing. It is essential that the in vitro testing conditions mimic as closely as possible the in vivo environment, such as pH and osmolality. Typically, for intestinal uptake, the pH is between 6 and 7. Thus, the solution may be maintained at about pH 6 to about pH 7, such as about pH 6.5.

[0083] Thus, in an embodiment of the invention, the test solution has a pH of about pH 4.5 to about pH 8, such as about pH 6.5 or about pH 5. The solution may be fasting simulated intestinal fluid (FaSSIF) or fed simulated intestinal fluid (FeSSIF).

[0084] Typically, for uptake in the stomach, the pH is between 1 and 2. Thus, the solution may have a pH of about pH 1 to about pH 2, such as about pH 1.4. Thus, in an embodiment of the invention, the solution for testing may be simulated gastric fluid (SGF).

[0085] The choice of solution will depend on the location in the gastrointestinal tract and the conditions (fasted or fed) under which it is desired that the composition be dissolved and absorbed. Formulations and preparations of these solutions are available from the manufacturer (Biorelevant, Croydon, UK). Further details are also disclosed in Jantratid, E., and Dressman, J. (2009) Dissolut. Technol. 8, 21-25).

[0086] The amount of PKI in the hybrid nanoparticles in the compositions of the present invention may be low or high, such as when the amount of PKI in the hybrid nanoparticles is from about 0.01% to about 99.9% by weight.

[0087] In another embodiment of this aspect, there is provided a composition comprising the stable amorphous hybrid nanoparticles of the invention, wherein the amount of PKI in the hybrid nanoparticles is from about 10% to about 70% by weight.

[0088] In another embodiment of this aspect, there is provided a composition comprising the stable amorphous hybrid nanoparticles of the invention, wherein the amount of PKI in the hybrid nanoparticles is from about 10% to about 50% by weight.

[0089] In some embodiments, it may be advantageous for the amount of PKI in the stable amorphous hybrid nanoparticles to be from 5% to about 50% by weight, from 10% to about 40% by weight, from about 10% to about 30% by weight, or from about 10% to about 20% by weight.

[0090] Control of particle properties can be convenient for certain applications. Particle size, particle agglomeration, particle porosity, and the selection and ratio of polymeric stabilizing matrix-forming agents can be altered to increase or decrease the surface area to volume ratio of the particles or the behavior of the particles in gastrointestinal fluids, resulting in an increase or decrease in dissolution rate. Depending on the desired dissolution properties, such particle properties can be adapted. Furthermore, particles with different properties can be present in the same pharmaceutical composition to provide an initial dose and an extended or delayed dose of the active ingredient. Furthermore, it can be advantageous to provide different PKIs and / or other active ingredient(s) in different primary particles with different properties adapted to provide the desired dissolution rate for each active ingredient(s).

[0091] Another embodiment of the present invention provides a pharmaceutical composition comprising the stable amorphous hybrid nanoparticles. Such a composition may further comprise at least one pharma- ceutically acceptable solubilizer. The solubilizer may be present in the composition separately from the stable amorphous hybrid nanoparticles (i.e., physically mixed with the pre-prepared solid nanoparticles) or may be randomly mixed within the stable amorphous hybrid nanoparticles in the pharmaceutical composition. The pharmaceutical composition may be in the form of several layers, such as a laminated or multi-layered tablet, such that the hybrid nanoparticles are separate from the solubilizer. The solubilizer may be selected from polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, d-α-tocopherol acid polyethyleneglycol 1000 succinate, and hydrogenated castor oil, such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated castor oil. The solubilizer may be a poloxamer.

[0092] In other embodiments of this aspect, the inhibitor is a tyrosine kinase inhibitor selected from the group consisting of lapatinib, pazopanib, nilotinib, erlotinib, dasatinib, gefitinib, sorafenib, axitinib, crizotinib, and vemurafenib; or a salt, hydrate, or solvate thereof, or a combination thereof.

[0093] In another embodiment of this aspect, the inhibitor is nilotinib; and the polymeric stabilizing matrix forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate.

[0094] In other embodiments of this aspect, the inhibitor is nilotinib; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate; and the solubilizing agent is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer or d-α-tocopherol acid polyethylene glycol 1000 succinate.

[0095] In another embodiment of this aspect, the inhibitor is erlotinib and the polymeric stabilizing matrix forming component is hydroxypropyl methylcellulose acetate succinate.

[0096] In other embodiments of this aspect, the inhibitor is erlotinib; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose acetate succinate; and the solubilizing agent is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer or d-α-tocopherol acid polyethylene glycol 1000 succinate.

[0097] In another embodiment of this aspect, the inhibitor is pazopanib; and the polymeric stabilizing matrix-forming component is polyvinylpyrrolidone.

[0098] In other embodiments of this aspect, the inhibitor is pazopanib; the polymeric stabilizing matrix-forming component is polyvinylpyrrolidone; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer or d-α-tocopherol acid polyethylene glycol 1000 succinate.

[0099] In another embodiment of this aspect, the inhibitor is lapatinib; and the polymeric stabilizing matrix-forming component is hydroxypropylcellulose.

[0100] In other embodiments of this aspect, the inhibitor is lapatinib; the polymeric stabilizing matrix-forming component is hydroxypropylcellulose; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer or d-α-tocopherol acid polyethylene glycol 1000 succinate.

[0101] In another embodiment of this aspect, the inhibitor is gefitinib; and the polymeric stabilizing matrix forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate or polyvinylpyrrolidone.

[0102] In other embodiments of this aspect, the inhibitor is gefitinib; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate or polyvinylpyrrolidone; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0103] In another embodiment of this aspect, the inhibitor is dasatinib; and the polymeric stabilized matrix-forming component is copolyvidone.

[0104] In another embodiment of this aspect, the inhibitor is dasatinib; the polymeric stabilizing matrix-forming component is copolyvidone; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0105] In another embodiment of this aspect, the inhibitor is sorafenib; and the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate.

[0106] In another embodiment of this aspect, the inhibitor is sorafenib; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0107] In another embodiment of this aspect, the inhibitor is nilotinib base; and the polymeric stabilizing matrix forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate.

[0108] In another embodiment of this aspect, the inhibitor is nilotinib base; the polymeric stabilizing matrix-forming component is hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate; and the solubilizing agent is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0109] In another embodiment of this aspect, the inhibitor is axitinib; and the polymeric stabilizing matrix forming component is copolyvidone or hydroxypropyl methylcellulose acetate succinate.

[0110] In other embodiments of this aspect, the inhibitor is axitinib; the polymeric stabilizing matrix-forming component is copolyvidone or hydroxypropyl methylcellulose acetate succinate; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer.

[0111] In another embodiment of this aspect, the inhibitor is crizotinib; and the polymeric stabilizing matrix-forming component is copolyvidone or polyvinylpyrrolidone.

[0112] In other embodiments of this aspect, the inhibitor is crizotinib; the polymeric stabilizing matrix-forming component is copolyvidone or polyvinylpyrrolidone; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer or PEG-40 hydrogenated castor oil.

[0113] In another embodiment of this aspect, the inhibitor is vemurafenib; and the polymeric stabilizing matrix forming component is copolyvidone or cellulose acetate phthalate.

[0114] In another embodiment of this aspect, the inhibitor is vemurafenib; the polymeric stabilizing matrix forming component is copolyvidone or cellulose acetate phthalate; and the solubilizing agent is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol.

[0115] In another embodiment of this aspect, the protein kinase inhibitor is partially released from the composition at a pH of about 1 to about 2, preferably at about pH 1.4.

[0116] In another aspect of the present invention, there is provided a stable amorphous hybrid nanoparticle comprising at least one protein kinase inhibitor and at least one polymeric stabilizing matrix-forming component as defined in the present disclosure.

[0117] In another embodiment of this aspect, there is provided a composition of the invention for use in therapy.

[0118] In another embodiment of this aspect, there is provided a composition of the invention for use in treating a proliferative disorder. Typically, the proliferative disease is selected from tumors and cancers including, but not limited to, neurofibromatosis, tuberous sclerosis, hemangioma and lymphangiogenesis, cervical cancer, anal cancer, and oral cancer, eye or ocular cancer, stomach cancer, colon cancer, bladder cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, head and neck cancer, pharyngeal cancer, cutaneous melanoma, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, lymphoma, multiple myeloma; cardiac hypertrophy, age-related macular degeneration, and diabetic retinopathy.

[0119] In another embodiment of this aspect, there is provided a composition of the invention that is administered during ingestion of food.

[0120] In another aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of such treatment comprising administering a therapeutically effective amount of a composition of the present invention. Said proliferative disease is typically selected from tumors and cancers including, but not limited to, neurofibromatosis, tuberous sclerosis, hemangioma and lymphangiogenesis, cervical cancer, anal cancer, and oral cancer, eye or ocular cancer, stomach cancer, colon cancer, bladder cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, head and neck cancer, pharyngeal cancer, cutaneous melanoma, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, lymphoma, multiple myeloma; cardiac hypertrophy, age-related macular degeneration, and diabetic retinopathy.

[0121] It will be appreciated that the amount of protein kinase inhibitor in the stable amorphous hybrid nanoparticles of the present invention required for therapeutic use will vary not only with the particular inhibitor selected, but also with the route of administration, the nature of the condition requiring treatment, and the age, weight, and condition of the patient, and will ultimately be at the discretion of the attending physician. In general, however, suitable dosages may range from about 0.005 to about 30 mg per kg of body weight per day, preferably from 0.05 to 10 mg / kg / day.

[0122] The desired dosage may conveniently be presented as a single dose or as divided doses administered at appropriate intervals, for example, two, three, four or more doses per day. Depending on the therapeutic and / or prophylactic needs, the desired dosage may be, for example, once every two days, once every three days, or even once a week.

[0123] The compositions are conveniently administered in unit dosage form, for example containing 0.5 to 1500 mg, conveniently 1 to 1000 mg, most conveniently 5 to 700 mg of active ingredient per unit dosage form. The compositions of the invention are usually administered orally, parenterally, intravenously, intramuscularly, subcutaneously or by other injectable means, by buccal, rectal, intravaginal, transdermal and / or intranasal routes, and / or by inhalation, in a pharma-ceutically acceptable dosage form. Depending on the disease and patient to be treated and the route of administration, the compositions may be administered in various dosage amounts.

[0124] Pharmaceutical compositions include, but are not limited to, those suitable for oral, rectal, intranasal, topical (including buccal and sublingual), transdermal, intravaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or in a form suitable for administration by inhalation or insufflation. Compositions may, where appropriate, be conveniently presented in discrete dosage units and prepared by any of the methods well known in the art of pharmacy. Pharmaceutical compositions suitable for oral administration are conveniently presented as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active substance.

[0125] Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated by methods well known in the art.

[0126] The compositions can be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and can be presented in unit dosage form in ampoules, prefilled syringes, small volume injections, or multi-dose containers with added preservatives. The compositions can also take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0127] The above-described compositions can be modified to provide sustained release of the active inhibitor.

[0128] The following examples are given to illustrate various embodiments of the invention and are not to be construed as limiting the scope. EXAMPLES

[0129] Below are some non-limiting examples of compositions comprising stable amorphous hybrid nanoparticles. In the tables, the following abbreviations for "composition" apply:

[0130] "I" represents protein kinase inhibitor (PKI); "P" represents a polymeric stabilizing matrix forming component; "S" represents a solubilizer; "I+P" represents a physical mixture of inhibitor and polymeric stabilized matrix forming components, i.e., without further processing; "I+S" represents a physical mixture of inhibitor and solubilizer; "I+P+S" represents a physical mixture of inhibitor, polymeric stabilizing matrix forming components, and solubilizing agent; "I / P" stands for stable amorphous hybrid nanoparticles of inhibitor and polymeric stabilized matrix-forming components; "I / P+S" stands for stable amorphous hybrid nanoparticles of inhibitor and polymeric stabilizing matrix forming components with additional solubilizing agent; "I / P / S" stands for stable amorphous hybrid nanoparticles of an inhibitor, a polymeric stabilizing matrix-forming component, and a solubilizing agent. "Exp" represents the experiment number.

[0131] Stable amorphous hybrid nanoparticles were prepared with the exemplary PKI, polymeric stabilizing matrix-forming component ("polymer"), solubilizer, solution concentration, ratio, solvent, anti-solvent, temperature, and pressure shown in Table A below.

[0132] A 3-6% w / v PKI / polymer solution in solvent, with a PKI / polymer ratio of approximately 20-70% w / w, was purified using a high-performance liquid chromatography pump at a flow rate of 1 ml / min with 100 g / min CO. 2 The CO was pumped along with the precipitation (supercritical or subcritical) stream through the RightSize nozzle of the XSpray. The pressure in the precipitation chamber was set at about 100-175 bar and the temperature was set at about 10 to 50°C. Both streams met in the nozzle and hybrid nanoparticles were formed, which were then collected in the particles in the collection chamber. 2 The solvent was passed through a filtration system in the collection chamber and discharged by a back-pressure regulated outlet that maintained pressure in the precipitation and collection chambers. After pumping the PKI / polymer solution and rinsing the lines with the same solvent used to prepare the PKI / polymer solution, the solvent remaining in both the precipitation and collection chambers was pumped into these chambers with pure scCO. 2 After the process of flushing, CO 2 CO was slowly vented from the collection chamber. 2 Once complete removal of the particles was achieved, the particles remaining in the filtration system were collected for analysis.

[0133] For I / P / S type particles, a defined amount of solubilizer was added to the PKI / polymer solution to dissolve it before pumping the solution through a nozzle for precipitation by the method described above.

[0134] For I / P+S type particles, a defined amount of solubilizer is added to the stable amorphous hybrid nanoparticles in a glass vial. The glass vial is slowly rotated to mix the solubilizer with the hybrid nanoparticles. TIFF0007659297000001.tif166161

[0135] General Description of Dissolution Measurement Test The method consisted of adding the desired amount of stable amorphous hybrid nanoparticle powder to a glass vial and then pouring it with the appropriate vehicle (typically FaSSIF, FeSSIF, or SGF). The vehicle was prepared according to the manufacturer's instructions. The amount of powder added depended on the desired "total PKI concentration." In some experiments testing and comparing powders with high drug loading, the actual amount of PKI in the stable amorphous hybrid nanoparticles was not taken into account. In other experiments, the drug loading was first estimated by HPLC to calculate the amount of powder to obtain the drug concentration.

[0136] Typically, the powder was added to an 8 mL vial and 7 mL of solution was added (typically FaSSIF, FeSSIF, or SGF). The vial was placed on a shaker (approximately 1 revolution per minute) to allow dissolution. 500 μl samples were taken at different time points and then centrifuged at approximately 15000 g for 3 minutes. The resulting supernatant was then analyzed by HPLC (C 18 Column Eclipse, 4.6 mm x 15 cm, 1 mL / min, detection 254-400 nM. Generally, samples were taken after 5, 30, and 90 min, and finally after 150 min.

[0137] Example 1. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Nilotinib - Solubility at pH 6.5 and pH 5 Several experiments were performed in which nilotinib base or nilotinib HCl were examples of protein kinase inhibitors. The experiments were performed by measuring the concentration (mg / L) of solubilized PKI after 5, 30, and 90 minutes of dissolution in a solution of about pH 6.5, namely FaSSIF (fasting simulated intestinal fluid). In addition, experiments were performed in another solution of about pH 5, namely FeSSIF (fed simulated intestinal fluid). Samples of the solution were taken at various time intervals and the amount of protein kinase inhibitor was measured by the dissolution measurement test described above.

[0138] Representative results in FaSSIF solution are given in Tables 1 and 2 below, where Table 1 gives data on the concentration (mg / L) of nilotinib HCl after 5, 30, and 90 minutes of dissolution, and Table 2 gives data on the % of nilotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC-mg / min / L) at 90 minutes of dissolution, and the AUC increase of stable amorphous hybrid nanoparticles compared to the unprocessed crystalline form of nilotinib HCl added to the solution (runs 1-40). In Tables 3 and 4, dissolution data in FeSSIF solution, shown similarly to Tables 1 and 2, are given (runs 41-55). Table 5 gives data on comparative experiments with similar stable amorphous hybrid nanoparticles carried out in FaSSIF and FeSSIF, respectively (runs 56-57). Table 6 presents further comparative data of experiments carried out in FaSSIF and FeSSIF, respectively. TIFF0007659297000002.tif37128TIFF0007659297000003.tif250128TIFF000 7659297000004.tif69128TIFF0007659297000005.tif172151TIFF00076592970 00006.tif250151TIFF0007659297000007.tif182161TIFF0007659297000008. tif195161TIFF0007659297000009.tif51161TIFF0007659297000010.tif86170

[0139] Conclusion of Example 1 Experiments 17-23 show that solubility enhancement is obtained for compositions containing stable amorphous hybrid nanoparticles of nilotinib HCl and polymeric stabilized matrix-forming components. Particular enhancement is achieved for the polymeric stabilized matrix-forming components, hydroxypropyl methylcellulose phthalate (HPMCP HP55) and polyvinyl acetate phthalate (PVAP). These enhancements are not obtained when nilotinib HCl is physically mixed with the polymeric stabilized matrix-forming components. Experiments 24-36 clearly show that further solubility enhancement is obtained for stable amorphous hybrid nanoparticles of nilotinib HCl and polymeric stabilized matrix-forming components when an independent solubilizer is added. Particular enhancement is achieved by the addition of an independent solubilizer, such as polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) or d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS). These improvements were not obtained when nilotinib HCl, solubilizer, and / or polymeric stabilized matrix-forming components were physically mixed (I+S or I+P+S).No particular improvements were obtained with stable amorphous hybrid nanoparticles of nilotinib HCl, polymeric stabilized matrix-forming, and solubilizer (I / P / S).

[0140] The results carried out in FaSSIF and FeSSIF, respectively, show that the stable amorphous hybrid nanoparticles of the present invention provide similar increases in solubility. One problem with PKI formulations is food effect. Despite the fact that food increases the bioavailability of PKI in most cases, some PKIs are indicated to be administered in fasting state. The low bioavailability may partially explain the digestive problems associated with PKI. The similar dissolution rates in FaSSIF and FeSSIF indicate that the stable amorphous hybrid nanoparticles of the present invention (e.g., Experiment 56 / 57) can reduce the food effect and digestive problems of patients due to their improved solubility, thereby allowing for a reduction in dosage. Thus, the stable amorphous hybrid nanoparticles of the present invention can be given with food intake.

[0141] Example 2. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Erlotinib HCl - Solubility at pH 6.5 and pH 5 Several experiments were performed in which erlotinib HCl was an example of a PKI. The experiments were performed by measuring the concentration of PKI (mg / L) after 5, 30, and 90 minutes of dissolution in a solution of about pH 6.5, namely FaSSIF (fasting simulated intestinal fluid). Additionally, experiments were performed in another solution of about pH 5, namely FeSSIF (fed simulated intestinal fluid). Samples of the solution were taken at various time intervals and the amount of PKI was measured by the dissolution measurement test described above.

[0142] Representative results for FaSSIF solutions are given in Tables 7 and 8 below, where Table 7 gives data on the concentration (mg / L) of erlotinib HCl after 5, 30, and 90 minutes of dissolution, and Table 8 gives data on the % of erlotinib HCl solubilized after 30 minutes of dissolution, the area under the curve (AUC-mg / min / L) at 90 minutes of dissolution, and the increase in AUC for stable amorphous hybrid nanoparticles compared to the unprocessed crystalline form of erlotinib HCl added to the solution (Experiments 58-68). In Tables 9 and 10, dissolution data for FeSSIF solutions are given (Experiments 69-73), as shown in Tables 7 and 8. In Table 11, data for comparative experiments with similar stable amorphous hybrid nanoparticles performed in FaSSIF and FeSSIF, respectively (Experiments 74-83). Table 12 presents further comparative data for experiments performed in FaSSIF and FeSSIF, respectively. TIFF0007659297000011.tif144161TIFF0007659297000012.tif152161TIFF0007659297000013.tif88161 TIFF0007659297000014.tif100161TIFF0007659297000015.tif182161TIFF0007659297000016.tif106161

[0143] Conclusion of Example 2 The experiments show that an increase in solubility is obtained for compositions containing stable amorphous hybrid nanoparticles with erlotinib HCl and a polymeric stabilizing matrix-forming component. A particular improvement is achieved with the polymeric stabilizing matrix-forming component, hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Experiments 65-66 and 72 show that a further increase in solubility is obtained for stable amorphous hybrid nanoparticles with erlotinib HCl and a polymeric stabilizing matrix-forming component when an independent solubilizer is added. A particular improvement is achieved with the addition of an independent solubilizer, where the solubilizer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS). This improvement was not observed when the solubilizer was incorporated into the stable amorphous hybrid nanoparticles.

[0144] Physical mixing of erlotinib HCl with solubilizers and / or HPMC AS also improves solubility in FaSSIF (Experiments 59, 60-61, 62-63) but not in FeSSIF (Experiments 69-72). One issue with PKI formulations is food effect. Despite the fact that food increases the bioavailability of PKI in most cases, some PKIs are indicated to be administered in fasted state. The low bioavailability may partially explain the digestive problems associated with PKI. The data indicate that the stable amorphous hybrid nanoparticles, due to their equal solubility improvement in both FaSSIF and FeSSIF, may reduce the food effect and digestive problems of patients (Experiments 76 / 77, and 82 / 83), and potentially even allow for a reduction in dose. Thus, compositions containing these stable amorphous hybrid nanoparticles can be given with food intake.

[0145] Example 3. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Pazopanib - Solubility at pH 6.5 and pH 5 Several experiments were performed in which pazopanib is an example of a PKI. The experiments were performed by measuring the concentration of PKI (mg / L) after 5, 30, and 90 minutes of dissolution in a solution of about pH 6.5, namely FaSSIF (fasting simulated intestinal fluid). Additionally, experiments were performed in another solution of about pH 5, namely FeSSIF (fed simulated intestinal fluid). Samples of the solution were taken at various time intervals and the amount of PKI was measured by the dissolution measurement test described above.

[0146] Representative results for FaSSIF solutions are given in Tables 13 and 14 below, where Table 13 gives data on the concentration of pazopanib (mg / L) after 5, 30, and 90 minutes of dissolution, and Table 14 gives data on the % of solubilized pazopanib after 30 minutes of dissolution, the area under the curve (AUC-mg / min / L) at 90 minutes of dissolution, and the increase in AUC with stable amorphous hybrid nanoparticles compared to the unprocessed crystalline form of pazopanib added to the solution (Experiments 84-93). In Tables 15 and 16, dissolution data for FeSSIF solutions are given (Experiments 94-101), shown similarly to Tables 13 and 14. In Table 17, data for comparative experiments with similar stable amorphous hybrid nanoparticles performed in FaSSIF and FeSSIF, respectively (Experiments 102-109). Table 18 presents further comparative data for experiments with stable amorphous hybrid nanoparticles performed in FaSSIF and FeSSIF, respectively. TIFF0007659297000017.tif146161TIFF0007659297000018.tif155161TIFF0007659297000019.tif125161 TIFF0007659297000020.tif133161TIFF0007659297000021.tif163161TIFF0007659297000022.tif169161

[0147] Conclusion of Example 3 The experiments show that an increase in solubility is obtained for compositions containing pazopanib and stable amorphous hybrid nanoparticles with a polymeric stabilizing matrix-forming component. A particular improvement is achieved with the polymeric stabilizing matrix-forming component, polyvinylpyrrolidone K-90 (PVP 90K). Experiments 91-92 show that a further increase in solubility is obtained for stable amorphous hybrid nanoparticles with pazopanib and a polymeric stabilizing matrix-forming component when an independent solubilizer is added. A particular improvement is achieved with the addition of an independent solubilizer, where the solubilizer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS). This improvement was not observed when the solubilizer was incorporated into the stable amorphous hybrid nanoparticles of the present invention.

[0148] The results carried out in FaSSIF and FeSSIF respectively show that the stable amorphous hybrid nanoparticles of the present invention provide similar increase in solubility. One problem with PKI formulations is food effect. Despite the fact that food increases the bioavailability of PKI in most cases, some PKIs are indicated to be administered in fasting state. The low bioavailability may partially explain the digestive problems associated with PKI. The similar dissolution rates in FaSSIF and FeSSIF indicate that the stable amorphous hybrid nanoparticles can reduce the food effect and digestive problems of patients due to their equal solubility improvement in both FaSSIF and FeSSIF (e.g., Experiments 89 / 100 and 104 / 105), and further allow for a reduction in dosage. Thus, the stable amorphous hybrid nanoparticles of the present invention can be given with food intake.

[0149] Example 4. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Lapatinib - Solubility at pH 6.5 Several experiments were performed in which lapatinib base or lapatinib tosylate is an example of PKI. The experiments were performed by measuring the concentration of PKI (mg / L) after 5, 30, and 90 minutes of dissolution in a solution of about pH 6.5, i.e., FaSSIF (fasting simulated intestinal fluid). Samples of the solution were taken at various time intervals and the amount of PKI was measured by the dissolution measurement test described above.

[0150] Representative results for FaSSIF solutions are provided in Tables 19 and 20 below, where Table 19 provides data for the concentration of lapatinib (mg / L) after 5, 30, and 90 minutes of dissolution, and Table 20 provides data for the % of lapatinib solubilized after 30 minutes of dissolution, the area under the curve (AUC-mg / min / L) over 90 minutes of dissolution, and the increase in AUC with stable amorphous hybrid nanoparticles of the invention compared to unformulated lapatinib tosylate added to the solution (Experiments 110-126). TIFF0007659297000023.tif207161TIFF0007659297000024.tif214161

[0151] Conclusion of Example 4 Experiments 122-125 clearly show that increased solubility is obtained with the stable amorphous hybrid nanoparticles of the present invention with lapatinib, particularly lapatinib base, and a polymeric stabilizing matrix-forming component when an independent solubilizer is added to the composition. Particular improvements are achieved with the polymeric stabilizing matrix-forming components, hydroxypropylcellulose EF and hydroxypropylcellulose LF. Furthermore, improvements are achieved with the addition of an independent solubilizer, where the solubilizer is selected from polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer (Soluplus) and d-α-tocopherol acid polyethyleneglycol 1000 succinate (TPGS).

[0152] Example 5. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Nilotinib HCl - Solubility at pH 1.4 Several experiments were performed in which Nilotinib HCl was an example of a PKI. The experiments were performed by measuring the concentration of PKI (mg / L) after 5, 30, and 90 minutes of dissolution in a solution of about pH 1.4, i.e., SGF (artificial gastric fluid). Samples of the solution were taken at various time intervals and the amount of PKI was measured using the dissolution measurement test described above.

[0153] Representative results in SGF solutions are given in Table 21 below, which gives the percentage of solubilized nilotinib HCl from both the physical mixture of unprocessed crystalline form nilotinib HCl and the stable amorphous hybrid nanoparticles of the invention after 5, 30, and 90 minutes after dissolution. Nilotinib present in a physical mixture of unprocessed nilotinib HCl, the polymeric stabilizing matrix forming component PVAP, and the solubilizer Soluplus (Experiment 129) was completely dissolved in SGF within 5 minutes, whereas in the stable amorphous hybrid nanoparticles of the invention, nilotinib was only partially dissolved in SGF after 90 minutes, where the components are composed of stable amorphous hybrid nanoparticles with (Experiment 128) or without (Experiment 127) the solubilizer. TIFF0007659297000025.tif79161

[0154] Conclusion of Example 5 Experiments 127-129 show that nilotinib HCl in the stable amorphous hybrid nanoparticles of the present invention (Experiments 127 and 128) is partially solubilized at pH 1.4. The stable amorphous hybrid nanoparticles by polymeric stabilizing matrix forming components such as PVAP are partially protected from the acidic environment.

[0155] Example 6. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Gefitinib - Solubility at pH 6.5 Several experiments were carried out in which gefitinib is an example of a PKI. The experiments were carried out by measuring the concentration (mg / L) of PKI after 3, 40 and 80 minutes of dissolution in a solution of about pH 6.5, i.e., FaSSIF (fasting state simulated intestinal fluid). Samples of the solution were taken at various time intervals and the amount of PKI was measured by the dissolution measurement test described above.

[0156] Representative results for FaSSIF solutions are given in Tables 22 and 23 below, where Table 22 provides data on the concentration of gefitinib (mg / L) after 3, 40, and 80 minutes of dissolution, and Table 23 provides data on the % of gefitinib solubilized after 40 minutes of dissolution, the area under the curve during 80 minutes of dissolution (AUC-mg / min / L), and the increase in AUC with stable amorphous hybrid nanoparticles of the present invention compared to unformulated gefitinib added to the solution (Experiments 131-137). TIFF0007659297000026.tif109161TIFF0007659297000027.tif115161

[0157] Experiments 131-137 show that solubility enhancement is obtained with compositions containing stable amorphous hybrid nanoparticles of gefitinib, particularly gefitinib, and polymeric stabilizing matrix-forming components of the present invention when an independent solubilizer is added to the composition. Particular enhancement is achieved with the polymeric stabilizing matrix-forming components polyvinylpyrrolidone K-30 (PVP 30K) and hydroxypropyl methylcellulose phthalate (HPMCP HP55). Furthermore, enhancement is achieved with the addition of an independent solubilizer, in this case polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

[0158] Example 7. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Dasatinib - Solubility at pH 6.5 Several experiments were performed in which Dasatinib is an example of a PKI. The experiments were performed in a solution of about pH 6.5, i.e., FaSSIF (fasting state simulated intestinal fluid), measuring the concentration of PKI (mg / L) after dissolution 3, 40, and 80 minutes. Samples of the solution were taken at various time intervals and the amount of PKI was measured using the dissolution measurement test described above.

[0159] Representative results for FaSSIF solutions are given in Tables 24 and 25, where Table 24 provides data for the concentration of dasatinib (mg / L) after 3, 40, and 80 minutes of dissolution, and Table 25 provides data for the % of dasatinib solubilized after 40 minutes of dissolution, the area under the curve during 80 minutes of dissolution (AUC-mg / min / L), and the increase in AUC with stable amorphous hybrid nanoparticles of the invention compared to unformulated dasatinib added to the solution (Experiments 138-141). TIFF0007659297000028.tif88161TIFF0007659297000029.tif88161

[0160] Experiments 138-141 show that increased solubility is obtained with compositions comprising stable amorphous hybrid nanoparticles of dasatinib, particularly dasatinib and a polymeric stabilizing matrix-forming component of the present invention, when an independent solubilizer is added to the composition. Particular improvement is achieved with the polymeric stabilizing matrix-forming component, copolyvidone (Kollidon VA64). Further improvement is achieved with the addition of an independent solubilizer, in this case polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer (Soluplus).

[0161] Example 8. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Sorafenib Tosylate - Solubility at pH 6.5 Several experiments were performed in which sorafenib tosylate was an example of a PKI. The experiments were performed in a solution of about pH 6.5, i.e., FaSSIF (fasting state simulated intestinal fluid), measuring the concentration of PKI (mg / L) after dissolution at 3, 40, and 80 minutes. Samples of the solution were taken at various time intervals and the amount of PKI was measured using the dissolution measurement test described above.

[0162] Representative results for FaSSIF solutions are provided in Tables 26 and 27 below, where Table 26 provides data for sorafenib concentration (mg / L) after 3, 40, and 80 minutes of dissolution, and Table 27 provides data for % sorafenib solubilized after 40 minutes of dissolution, area under the curve during 80 minutes of dissolution (AUC-mg / min / L), and the AUC increase of the composition compared to unformulated sorafenib tosylate added to the solution (Experiments 142-145). TIFF0007659297000030.tif97161TIFF0007659297000031.tif106161

[0163] Experiments 138-141 show that increased solubility is obtained with compositions comprising stable amorphous hybrid nanoparticles of dasatinib, particularly dasatinib and a polymeric stabilizing matrix-forming component of the present invention, when an independent solubilizer is added to the composition. Particular improvement is achieved with the polymeric stabilizing matrix-forming component, hydroxypropyl methylcellulose phthalate (HPMCP HP55). Further improvement is achieved with the addition of an independent solubilizer, in this case polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer (Soluplus).

[0164] Example 9. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Nilotinib Base - Solubility at pH 6.5 Several experiments were carried out in which Nilotinib base was an example of a PKI. The experiments were carried out in a solution of about pH 6.5, i.e. FaSSIF (fasting simulated intestinal fluid), measuring the concentration of PKI (mg / L) after dissolution 3, 40 and 80 minutes. Samples of the solution were taken at various time intervals and the amount of PKI was measured using the dissolution measurement test described above.

[0165] Representative results for FaSSIF solutions are presented in Tables 28 and 29 below, where Table 28 provides data for the concentration (mg / L) of nilotinib base after 3, 40, and 80 minutes of dissolution, and Table 29 provides data for the % of nilotinib base solubilized after 40 minutes of dissolution, the area under the curve (AUC-mg / min / L) during 80 minutes of dissolution, and the AUC increase of the composition compared to unformulated nilotinib base added to the solution (Experiments 146-149). TIFF0007659297000032.tif80161TIFF0007659297000033.tif88161

[0166] Example 10. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Crizotinib - Solubility at pH 6.5 Several experiments were performed in which crizotinib is an example of a PKI. The experiments were performed in a solution of about pH 6.5, i.e., FaSSIF (fasting simulated intestinal fluid), measuring the concentration of PKI (mg / L) after 3, 40, and 80 minutes of dissolution. Samples of the solution were taken at various time intervals, and the amount of PKI was measured by the dissolution measurement test described above. Representative results in FaSSIF solution are presented in Tables 30 and 31 below, where Table 30 gives data on the concentration of crizotinib (mg / L) after 3, 40, and 80 minutes of dissolution, and Table 31 gives data on the % of crizotinib solubilized after 40 minutes of dissolution, the area under the curve during dissolution at 80 minutes (AUC-mg / min / L), and the AUC increase with the stable amorphous hybrid nanoparticles of the present invention compared to unformulated crizotinib added to the solution (Experiments 150-156). TIFF0007659297000034.tif121161TIFF0007659297000035.tif125161

[0167] Experiments 150-156 show that solubility enhancement is obtained with compositions comprising stable amorphous hybrid nanoparticles of crizotinib, particularly crizotinib, and polymeric stabilizing matrix-forming components of the present invention when an independent solubilizer is added to the composition. Particular enhancement is achieved with the polymeric stabilizing matrix-forming components polyvinylpyrrolidone K-30 (PVP 30K) and copolyvidone (Kollidon VA64). Additionally, enhancement is achieved with the addition of an independent solubilizer, where the solubilizer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and PEG-40 hydrogenated castor oil (Cremophor RH40).

[0168] Example 11. Compositions Comprising Stable Amorphous Hybrid Nanoparticles Containing Axitinib - Solubility at pH 6.5 Several experiments were performed in which axitinib is an example of a PKI. The experiments were performed in a solution of about pH 6.5, i.e., FaSSIF (fasting simulated intestinal fluid), measuring the concentration of PKI (mg / L) after 3, 40, and 80 minutes of dissolution. Samples of the solution were taken at various time intervals, and the amount of PKI was measured by the dissolution measurement test described above. Representative results in FaSSIF solution are presented in Tables 32 and 33 below, where Table 32 gives data on the concentration of axitinib (mg / L) after 3, 40, and 80 minutes of dissolution, and Table 33 gives data on the % of axitinib solubilized after 40 minutes of dissolution, the area under the curve during dissolution at 80 minutes (AUC-mg / min / L), and the AUC increase with the stable amorphous hybrid nanoparticles of the present invention compared to unformulated axitinib added to the solution (Experiments 157-163). TIFF0007659297000036.tif110161TIFF0007659297000037.tif121161

[0169] Experiments 157-163 show that solubility enhancement is obtained with compositions containing axitinib, particularly the stable amorphous hybrid nanoparticles of the present invention with axitinib and a polymeric stabilizing matrix-forming component, when an independent solubilizer is added to the composition. Particular enhancement is achieved with the polymeric stabilizing matrix-forming components, copolyvidone (Kollidon VA64) and hydroxypropyl methylcellulose acetate succinate (HPMC AS). Further enhancement is achieved with the addition of an independent solubilizer, in this case polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

[0170] Example 12. Composition of stable amorphous hybrid nanoparticles containing Vemurafenib - solubility at pH 6.5 Several experiments were performed in which Vemurafenib is an example of a PKI. The experiments were performed in a solution of about pH 6.5, i.e., FaSSIF (fasting state simulated intestinal fluid), measuring the concentration of PKI (mg / L) after dissolution 3, 40, and 80 minutes. Samples of the solution were taken at various time intervals and the amount of PKI was measured using the dissolution measurement test described above.

[0171] Representative results for FaSSIF solutions are presented in Tables 34 and 35 below, where Table 34 provides data for the concentration of vemurafenib (mg / L) after 3, 40, and 80 minutes of dissolution, and Table 35 provides data for the % of vemurafenib solubilized after 40 minutes of dissolution, the area under the curve during 80 minutes of dissolution (AUC-mg / min / L), and the increase in AUC with stable amorphous hybrid nanoparticles of the present invention compared to unformulated vemurafenib added to the solution (Experiments 164-170). TIFF0007659297000038.tif113161TIFF0007659297000039.tif117161

[0172] Experiments 164-170 show that solubility enhancement is obtained with compositions containing vemurafenib, particularly vemurafenib and the stable amorphous hybrid nanoparticles of the present invention with a polymeric stabilizing matrix-forming component, when an independent solubilizer is added to the composition. Particular enhancement is achieved with the polymeric stabilizing matrix-forming components copolyvidone (Kollidon VA64) and cellulose acetate phthalate (CAP). Further enhancement is achieved with the addition of an independent solubilizer, in this case polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus).

[0173] Example 13. Dissolution rate measurements of compositions of the present invention under sink conditions Dissolution measurements of the compositions of the present invention under sink conditions were performed by a method that consisted of adding the desired amount of powder to a flow-through cell system (SOTAX, Allschwill, Switzerland), attaching the cell to the device, and then pumping the appropriate medium (typically FaSSIF, FeSSIF, SGF) through the powder. The temperature of the device was set at 37°C. The amount of powder added to the cell depends on the drug loading of the powder. The exact amount of powder was calculated from the results obtained from the drug loading analysis of the powder.

[0174] Typically, 3.5 to 7 mg of PKI was added to the flow-through cell, and a flow rate of 8 to 16 ml of medium / min (preferably about 8 ml of medium / min) was pumped through the powder. 1 ml samples of the medium passing through the cell were collected at the designated times. These samples were analyzed by HPLC (e.g., C18 column Eclipse, 4.6 mm x 15 cm, 1 ml / min, detection 254-400 nm). Samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, and 40 minutes from the moment the medium left the flow-through cell. The cumulative % solubilized of the amount of active substance added to the flow-through cell was calculated and plotted against time (min). The initial slope of the graph measured from 0 to 10 minutes ("initial dissolution rate") was estimated and taken as the dissolution rate of the substance in a given dissolution medium at sink conditions of 37°C.

[0175] Each experiment involves a comparison of the native form of PKI with a composition comprising an inhibitor and stable amorphous hybrid particles of the present invention with representative polymeric stabilizing matrix forming components.

[0176] Example 13.1. Dissolution Rate Measurements of Compositions of the Invention Containing Nilotinib HCl Under Sink Conditions In the experiment with nilotinib HCl, 4 mg was weighed into the flow-through cell (experiment 500) and compared with the stable amorphous hybrid nanoparticles of the present invention with nilotinib base and polymeric stabilizing matrix forming component HPMCP HP55 (experiment 501). The results are shown in Table 36 below. TIFF0007659297000040.tif196161

[0177] Experiments 500-501 demonstrate that the initial dissolution rate of the stable amorphous hybrid nanoparticles of the present invention with nilotinib base is superior to the initial dissolution rate of the unprocessed crystalline form of nilotinib HCl.

[0178] Example 13.2. Dissolution Rate Measurements of Compositions of the Invention Containing Erlotinib HCl Under Sink Conditions In the experiment with erlotinib HCl, 3.5 mg was weighed into the flow-through cell (experiment 510) and compared with stable amorphous hybrid nanoparticles of the present invention with erlotinib HCl and polymeric stabilizing matrix forming component HPMC AS (experiment 511). The results are presented in Table 37 below. TIFF0007659297000041.tif184161

[0179] Experiments 510-511 show that the initial dissolution rate of a composition comprising stable amorphous hybrid nanoparticles of the present invention with erlotinib HCl and a polymeric stabilizing matrix forming component HPMC AS is superior to the initial dissolution rate of the unprocessed crystalline form of erlotinib HCl.

[0180] Example 13.3. Dissolution Rate Measurements of Compositions of the Invention Containing Pazopanib HCl Under Sink Conditions In the experiment with pazopanib HCl, 3.5 mg was weighed into the flow-through cell (experiment 520) and compared with the stable amorphous hybrid nanoparticles of the present invention with pazopanib HCl and the polymeric stabilizing matrix-forming component PVP90K (experiment 521). The results are presented in Table 38 below. TIFF0007659297000042.tif179161

[0181] Experiments 520-521 show that the initial dissolution rate of a composition comprising stable amorphous hybrid nanoparticles of the present invention with pazopanib HCl and the polymeric stabilizing matrix-forming component PVP90K is superior to the initial dissolution rate of the unprocessed crystalline form of pazopanib HCl.

[0182] Example 13.4. Dissolution Rate Measurements of Compositions of the Invention Containing Lapatinib Tosylate Under Sink Conditions In the experiment with lapatinib tosylate, 4 mg was weighed into the flow-through cell (experiment 530) and compared with the stable amorphous hybrid nanoparticles of the invention with lapatinib base and polymeric stabilizing matrix forming component HPC lf (experiment 531). The results are presented in Table 39 below. TIFF0007659297000043.tif181161

[0183] Experiments 530-531 show that the initial dissolution rate of a composition comprising lapatinib base and the stable amorphous hybrid nanoparticles of the present invention with the polymeric stabilizing matrix forming component HPC lf is superior to the initial dissolution rate of the unprocessed crystalline form of lapatinib tosylate.

[0184] Example 13.5. Dissolution rate measurements of compositions of the invention containing gefitinib under sink conditions In the experiment with gefitinib, 3.5 mg was weighed into the flow-through cell (experiment 540) and compared with the stable amorphous hybrid nanoparticles of the present invention with gefitinib and the polymeric stabilizing matrix forming component HPMCP HP55 (experiment 541). The results are shown in Table 40 below. TIFF0007659297000044.tif181161

[0185] Experiments 540-541 show that the initial dissolution rate of a composition comprising gefitinib and the stable amorphous hybrid nanoparticles of the present invention with the polymeric stabilizing matrix forming component HPMCP HP55 is superior to the initial dissolution rate of the unprocessed crystalline form of gefitinib.

[0186] Example 13.6. Dissolution Rate Measurements of Compositions of the Invention Containing Dasatinib Under Sink Conditions In the experiment with dasatinib, 3.5 mg was weighed into the flow-through cell (experiment 550) and compared with the stable amorphous hybrid nanoparticles of the present invention with dasatinib and the polymeric stabilizing matrix-forming component copolyvidone-Kollidon VA64 (experiment 551). The results are shown in Table 41 below. TIFF0007659297000045.tif183161

[0187] Experiments 550-551 show that the initial dissolution rate of a composition comprising a stable amorphous hybrid of dasatinib and the polymeric stabilizing matrix-forming component copolyvidone (Kollidon VA64) of the present invention is superior to the initial dissolution rate of the unprocessed crystalline form of dasatinib.

[0188] Example 13.7. Dissolution Rate Measurements of Compositions of the Invention Containing Sorafenib Tosylate Under Sink Conditions In an experiment with sorafenib tosylate, 3.5 mg was weighed into the flow-through cell (experiment 560) and compared with stable amorphous hybrid nanoparticles of the present invention with sorafenib tosylate and polymeric stabilizing matrix forming component HPMCP HP55 (experiment 561). The results are presented in Table 42 below. TIFF0007659297000046.tif182161

[0189] Experiments 560-561 show that the initial dissolution rate of a composition comprising sorafenib tosylate and stable amorphous hybrid nanoparticles of the present invention with the polymeric stabilizing matrix forming component HPMCP HP55 is superior to the initial dissolution rate of the unprocessed crystalline form of sorafenib tosylate.

[0190] Example 13.8. Dissolution Rate Measurements of Compositions of the Invention Containing Crizotinib Under Sink Conditions In the experiment with crizotinib, 3.5 mg was weighed into the flow-through cell (experiment 570) and compared with stable amorphous hybrid nanoparticles of the invention with crizotinib and the polymeric stabilizing matrix-forming component PVP 30K (experiment 571). The results are presented in Table 43 below. TIFF0007659297000047.tif146161

[0191] Experiments 570-571 show that the initial dissolution rate of a composition comprising crizotinib and the stable amorphous hybrid nanoparticles of the present invention with the polymeric stabilizing matrix forming component PVP 30K is superior to the initial dissolution rate of the unprocessed crystalline form of crizotinib.

[0192] Example 13.9. Dissolution rate measurements of compositions of the invention containing axitinib under sink conditions In the experiment with axitinib, 3.5 mg was weighed into the flow-through cell (experiment 580) and compared with the stable amorphous hybrid nanoparticles of the present invention with axitinib and the polymeric stabilizing matrix forming components Kollidon VA64 (experiment 581) or HPMC AS (experiment 582). The results are presented in Table 44 below. TIFF0007659297000048.tif151161

[0193] Experiments 580-582 show that the initial dissolution rate of a composition comprising stable amorphous hybrid nanoparticles of the present invention with axitinib and polymeric stabilizing matrix forming components Kollidon VA64 or HPMC AS is superior to the initial dissolution rate of the unprocessed crystalline form of axitinib.

[0194] Example 13.10. Dissolution Rate Measurements of Compositions of the Invention Containing Vemurafenib Under Sink Conditions In experiments with vemurafenib, 3.5 mg was weighed into the flow-through cell (experiment 590) and compared with stable amorphous hybrid nanoparticles of the present invention with vemurafenib and the polymeric stabilizing matrix forming components Kollidon VA64 (experiment 591) or CAP (experiment 592). The results are presented in Table 45 below. TIFF0007659297000049.tif148161

[0195] Experiments 590-592 clearly show that the initial dissolution rate of a composition comprising vemurafenib and the stable amorphous hybrid nanoparticles of the present invention with the polymeric stabilizing matrix forming components Kollidon VA64 or CAP is superior to the initial dissolution rate of the unprocessed crystalline form of vemurafenib.

[0196] Example 14. In vivo measurement of plasma levels after oral administration of compositions of the present invention Groups of four beagle dogs were given a single oral dose (5 mg / kg) of a capsule composition containing stable amorphous hybrid nanoparticles of the present invention with nilotinib base and either of the polymeric stabilizing matrix forming components PVAP and HPMCP HP55, optionally with the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethylene glycol copolymer, and compared to a commercial formulation containing nilotinib HCl. The stable amorphous hybrid nanoparticles tested are described in experiments 146-149 of Example 9. The stomach contents of the dogs were neutralized with sodium bicarbonate solution 5 minutes prior to capsule dosing or acidified with HCl-KCl buffer 10 minutes prior to dosing. One group of dogs was also given a single intravenous dose of nilotinib (1 mg / kg). Plasma levels of nilotinib were determined by a selective LC-MS / MS method. No side effects were observed in any of the animals tested.

[0197] Results and Conclusions The mean ± SEM plasma concentration-time profiles of nilotinib base are shown in Figures 22-25 and the pharmacokinetic parameters and results are shown in Tables 46A and 46B.

[0198] Outliers were calculated and excluded based on whether a value was a significant outlier from the others at the 95% confidence interval (α = 5%) according to the Grubbs test. The critical value Z of the Grubbs test at the 95% confidence interval for n = 4 is 1.48. Z = (mean - suspected value) / SD TIFF0007659297000050.tif71161

[0199] T of commercial nilotinib formulations given to the acidic stomach 1 / 2 Values ​​are expressed as mean ± SD, with the exception of , for which only two values ​​were obtained.

[0200] Intravenous (IV) data were obtained by constant-rate IV infusion of 1 mg / kg of 0.2 mg / mL nilotinib solution in 10% HPβCD adjusted to pH 3.3 to 3.5. Co: 511 ± 46 ng / mL; T 1 / 2: 3.3±1.8 hours; AUC0-24 hours: 1000±300ng*hour / mL. TIFF0007659297000051.tif75161

[0201] Values ​​are given as mean ± SD. Intravenous (IV) data were obtained by constant rate IV infusion of 1 mg / kg of 0.2 mg / mL nilotinib solution in 10% HPβCD adjusted to pH 3.3 to 3.5. Co: 511 ± 46 ng / mL; T 1 / 2 : 3.3±1.8 hours; AUC0-24 hours: 1000±300ng*hour / mL.

[0202] The commercial nilotinib formulation administered to acidified stomach showed approximately double the plasma levels after the same formulation was administered to neutralized stomach. Both formulations containing nilotinib base and the stable amorphous hybrid nanoparticles of the present invention with PVAP and HPMCP HP55 as polymeric stabilizing matrix forming components showed a significant improvement in plasma exposure, with approximately double the plasma levels of the commercial formulation administered to acidified stomach. Furthermore, the combination of the stable amorphous hybrid nanoparticles produced by the method of the present invention may provide plasma exposure that is more or less independent of gastric pH.

[0203] Further improvement in oral availability was observed when the formulation of the stable amorphous hybrid nanoparticles of the present invention was combined with the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer. Thus, the composition of the present invention with nilotinib base and PVAP and HPMCP HP55 as polymeric stabilizing matrix forming components, added with the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, administered to acidified stomach, showed 2.3- to 3.1-fold higher plasma levels than the commercial formulation. In this study, high oral bioavailability was achieved when the stable amorphous hybrid nanoparticles of the present invention with nilotinib base and HPMCP HP55 as polymeric stabilizing matrix forming components, added with the solubilizer polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer (I / P+S), administered to neutralized stomach contents. In this study, the exposure was increased by about 7 times compared to the commercial oral formulation administered under the same neutralized conditions. The highest bioavailability in this study, 36±24%, was achieved when the stable amorphous hybrid nanoparticles of nilotinib base and PVAP as the polymeric stabilizing matrix-forming component of the present invention were administered to the neutralized stomach. However, this study run was also accompanied by the highest standard deviation in this study.

[0204] The in vivo performance of the composition of the present invention with nilotinib stable amorphous hybrid nanoparticles was improved based on the improved absorption and bioavailability due to the optimization of the physical properties of the dosage form. Since the gastrointestinal drug absorption process of dogs and humans is likely to be closely related (Persson, EM et al. Pharm. Res. 2005, 22, 2141-2151), the results of the in vivo study in dogs can predict similar absorption of the stable amorphous hybrid nanoparticles of the present invention in patients. The stable amorphous hybrid nanoparticles of the present invention with favorable absorption also predict that the oral dosage used in current clinical practice can be reduced. Furthermore, the stable amorphous hybrid nanoparticles of the present invention can reduce the pH dependency of the absorption and bioavailability of PKI.

[0205] Example 15. Determination of the degree / level of stability of compositions with hybrid nanoparticles of the present invention Stability testing of compositions containing the hybrid nanoparticles of the invention, as measured by X-ray powder diffraction and dissolution rate by AUC measurements, showed that the particles were stable at room temperature (18-25°C) for at least 11 months.

[0206] In a series of experiments with stable amorphous hybrid nanoparticles produced by the method of the present invention containing nilotinib and HPMCP HP55, the resulting particles gave stable amorphous hybrid nanoparticles at 40% drug loading as measured by XRPD as well as dissolution rate by AUC measurement (I / P nilotinib base / HPMCP HP55: experiment 146). The material showed one glass transition temperature at approximately 127°C, indicating a single amorphous phase with intrinsic stability. Partially crystalline batches also processed with similar intrinsic stability. Storage of partially crystalline hybrid nanoparticles, I / P nilotinib base / HPMCP HP55, at 40% drug loading at room temperature (18-25°C) for 6 months did not show any signs of physical instability.

[0207] Thermogravimetry showed a mass loss of 1.7% from ambient to 120°C.

[0208] Dynamic water vapor sorption analysis at 25°C showed a relative mass gain of approximately 7% from 0 to 90% RH (three cycles from 0 to 90% RH did not result in a phase change).

[0209] The high glass transition temperature, 1.7% mass gain from room temperature to 120°C, and moderate hygrospopicity suggest inherent stability. This is supported by stability studies of several batches at various conditions. The longest stability point is 12 months at room temperature (18-25°C). None of the batches or conditions showed signs of physical instability (Figure 27).

[0210] Modulated Differential Scanning Calorimetry (mDSC) Modulated differential scanning calorimetry (mDSC) analysis was performed on a TA Instruments model Q200 (New Castle, USA) equipped with an RC90 refrigerated cooling system (Home Automation, New Orleans, USA). Samples were weighed to 7±2 mg in Tzero low mass aluminum pans and sealed with Tzero lids. They were then heated from 0 to 170°C at a heating rate of 3°C / min with a conventional modulation temperature amplitude of 1°C and a modulation period of 40 s. Ultra-high purity nitrogen was used as purge gas at a flow rate of 50 mL / min. All data analysis was performed using TA Universal Analysis software, version 4.7A. Cell constant and temperature calibration was performed using an indium standard prior to instrument operation. DSC results were evaluated in terms of both forward and reverse components of heat flow.

[0211] Thermogravimetric analysis (TG) was performed on a Seiko TG / DTA 6200 in open 90 μl Pt pans containing approximately 10 to 20 mg of sample with a nitrogen flow of 200 mL / min. The temperature program was from ambient (20° C.) to 400° C. with a heating rate of 10° C. / min. Blanks were subtracted and TG data were normalized to sample size and analyzed using Muse Standard Analysis software, version 6.1 U.

[0212] Dynamic Vapor Sorption (DVS) Hygroscopicity of the samples was tested by dynamic water vapour sorption gravimetry (DVS) using a DVS-1 (Surface Measurement Ltd., UK). Approximately 10 mg of material was weighed into a glass cup. Relative weights were recorded at 20 second intervals as the target relative humidity (RH) on the sample was increased stepwise from 0% to 90% at 10% RH per step and then similarly decreased to 0% RH. Each sample was tested in three complete successive cycles. The condition for proceeding to the next level of RH was a weight change of 0.002% or less within 15 minutes, with a maximum total time per step of 24 hours. Due to the slow equilibration in this type of experiment, the numbers obtained should be considered as a low estimate of water absorption. Temperature was kept at 25°C.

[0213] X-ray powder diffraction (XRPD) XRD experiments were performed on an X'Pert Pro diffractometer (PANanalytical, Almelo, Netherlands) set up in the Bragg-Brentano configuration. The diffractometer was equipped with a 20 μm nickel filter and an X'Celerator RTMS detector with an active length of 2.122° 2θ. Representative samples were placed on a zero-background quartz single crystal specimen support (Siltronix, Archamps, France). Experiments were performed at ambient temperature and humidity using Cu Kα radiation (45 kV and 40 mA). Scans were performed in continuous mode, in the range of 4.5–40° 2θ, with automatic divergence and anti-scatter slits, an observed length of 10 mm, a common counting time of 299.72 s, and a step size of 0.0167° 2θ. Data collection was performed using application software, X'Pert Data Collector V.2.2j and instrument control software V.2.1E, and pattern analysis was performed using X'Pert Data Viewer V.1.2c (all software was obtained from PANanalytical, Almelo, Netherlands).

[0214] Dissolution rate by measuring AUC Stable hybrid nanoparticles (I / P) described below in Experiment 171 and Experiment 172 were prepared with nilotinib base, HPMCP HP55 according to Experiment 148 and stored at room temperature for 11 months. Non-sink dissolution rates were tested at different time points and the results are presented in Table 47 and Figure 26. Polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer was added to enhance solubility. Comparison of AUC over 80 minutes clearly showed that the dissolution rate profile of the particles was practically unchanged after 11 months of storage, e.g. the ratio of AUC of the prepared and tested particles compared to the prepared and tested particles stored for 11 months was more than 97%. TIFF0007659297000052.tif61161

Claims

1. 1. A pharmaceutical composition comprising stable amorphous solid dispersion particles, comprising: the solid dispersion particles comprise a protein kinase inhibitor selected from the group consisting of nilotinib, nilotinib hydrate, nilotinib solvate, nilotinib salt, and combinations thereof, and at least one polymeric stabilizing matrix-forming component selected from the group consisting of hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, and copolymers of methacrylic acid and ethyl acrylate; the degree of amorphousness of the solid dispersion particles is 100%; The amount of the protein kinase inhibitor in the solid dispersion particles is 10% to 70% by weight. A pharmaceutical composition comprising:

2. 10. The pharmaceutical composition of claim 1, further comprising at least one pharma- ceutically acceptable solubilizer selected from the group consisting of d-α-tocopherol acid polyethylene glycol 1000 succinate, PEG-40 hydrogenated castor oil, and PEG-35 castor oil.

3. 3. The pharmaceutical composition according to claim 2, wherein the solubilizing agent is d-α-tocopherol acid polyethylene glycol 1000 succinate.

4. 4. The pharmaceutical composition according to claim 2 or 3, wherein the solubilizer is distributed on the surface of the solid dispersion particles.

5. 5. The pharmaceutical composition according to claim 1, wherein the stable amorphous solid dispersion particles have an average particle size of less than 1000 nm.

6. 6. The pharmaceutical composition according to claim 5, wherein the average particle size is less than 500 nm.

7. The pharmaceutical composition according to claim 5, wherein the average particle size is less than 250 nm.

8. A pharmaceutical composition according to any one of claims 1 to 7 for use in therapy.

9. 8. A pharmaceutical composition according to any one of claims 1 to 7 for use in the treatment of a proliferative disorder.

10. 10. The pharmaceutical composition of claim 9, wherein the proliferative disease is selected from neurofibromatosis, tuberous sclerosis, hemangioma and lymphangiogenesis, cervical, anal and oral cancer, eye or ocular cancer, stomach cancer, colon cancer, bladder cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, head and neck cancer, pharyngeal cancer, cutaneous melanoma, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, lymphoma, multiple myeloma, cardiac hypertrophy, age-related macular degeneration, and diabetic retinopathy.

11. 11. The pharmaceutical composition according to claim 9 or 10, characterized in that said pharmaceutical composition is administered during ingestion of food.

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